Since their discovery in the 1980s and 1990s, the human protein lysine acetyltransferase encoded by the paralogous p300 and CBP genes has received much interest. p300/CBP functions in regulating the expression of genes controlling several basic cellular processes, such as proliferation and homeostasis, and plays a role in a variety of human diseases, particularly solid tumors.

Numerous natural product and synthetic inhibitors of the acetyltransferase activity have been identified and used to generate a crystal structure of the active site, probe the p300/CBP enzyme kinetics, and interrogate p300/CBP cellular functions. These studies revealed that acetyl-CoA binds in a tunnel enclosed by a unique loop, while the substrate protein transiently associates with an acidic patch, following a hit-and-run kinetic mechanism. p300/CBP acetylates histones as well as other proteins including other epigenetic enzymes and transcription factors. Studies with inhibitor compounds in cells and animals have confirmed that the p300/CBP acetylation activity has roles in diverse functions including cell migration and invasion, maintenance of the differentiated state, tau-mediated neurodegeneration, and learning and memory.

Also, important components of p300/CBP are the domains flanking the acetyltransferase domain, including three cysteine/histidine-rich domains and a bromodomain. Protein ligands of these have been identified. Their roles in regulating the acetyltransferase activity and substrate specificity, as well as identification of compounds that can block or mimic ligand binding, are topics of ongoing study.

Biochemical investigation of protein acetylation has posed unique challenges, due in part to its dynamic reversibility, the weak affinity of binding modules that recognize it, and the complexity of the multiprotein interaction networks. Therefore, diverse techniques in biochemistry, molecular biology, and proteomics have coevolved with our understanding of the p300/CBP enzyme. In this Review, part of the thematic issue on Epigenetics, we summarize the current understanding of p300/CBP including the novel technologies developed for these studies.

2 Background Information

Click to copy section linkSection link copied!

2.1 Epigenetics and Chromatin

While the central dogma of molecular biology describes how the DNA sequence dictates the cell’s functions, recent researchers have observed several intriguing phenomena that prove reality to be more complex. Identical twins inherit the same DNA sequence, but can have differences in appearance, intellect, and disease incidence. Multicellular organisms are composed of extremely diverse cell types, almost all of which contain the same DNA sequence. Mice with the same DNA sequence can have different coat colors and body weight. Calico cats have patches of fur with different colors, but the underlying skin cells have the same DNA sequences. Several disorders exist that have different outcomes depending on whether the mutation responsible was inherited from a female or a male parent. Also, the human genome encodes only twice as many genes as the fly genome, for example, so the number of genes cannot account for the greater complexity of humans.

These examples all illustrate the existence of mechanisms over and above the genome, which influence biology, and fall into the emerging field of epigenetics. The term “epigenetics” was coined by Waddington in 1942. (1) As was eloquently put, “Mendel’s gene is more than a DNA moiety.” (2) Several mechanisms exist in cells that contribute to epigenetic inheritance. In addition to the DNA inherited by a gamete during meiosis, the egg and embryo receive maternal RNAs. These serve various transient functions in the progeny’s cells before the RNAs are degraded. Similarly, the cytoplasm of the daughter cell contains many proteins that were made in the germline of the parent, constituting another mode of inheritance of traits not necessarily encoded by the DNA. Furthermore, the DNA inherited is not a naked sequence; it is packaged into chromatin, which is the topic of the rest of this section.

The human genome, a copy of which is contained in almost every human cell, is about 2 m in total length, if placed end-to-end, while the chomatinized genome is about 0.09 mm in total length, if placed end-to-end, which can fit into the cell nucleus, that is typically less than 0.01 mm in diameter. (3) Chromatin is made up of fundamental subunits called nucleosomes. A nucleosome consists of 146 base pairs of DNA wrapped around an octamer of histone proteins. The histone octamer consists of two copies each of histones H2A, H2B, H3, and H4. Furthermore, at least 20bp of DNA between each nucleosome can be packaged with the linker histone, H1. The histones, however, are not simply inert packaging, but rather they arrange the DNA in a way that the information can be stored and retrieved.

Chromatin can be assembled in different conformations, which are influenced by a variety of factors, including DNA sequence elements, DNA modifications, histone modifications, incorporation of histone variants, nucleosome occupancy and spacing, nucleosome sliding, and association of nonhistone proteins with the chromatin. The physical structure of chromatin has functional consequences for DNA templated processes, including gene expression, DNA replication, and DNA repair. Open, permissive, active chromatin promotes DNA transcription and replication, whereas closed, silenced, repressed chromatin is turned “off” to these processes. For example, telomeres and centromeres are generally silenced, and boundary elements prevent the silencing from spreading into regions that are turned “on”. Yet these distinctions are not static: enzymes that modify DNA and histones, chaperones that allow histones to be replaced, and enzymes that consume ATP to slide nucleosomes can alter the local chromatin structure. Through these actions, chromatin structure can be altered during one’s lifetime in response to a variety of environmental and internal conditions. In this way, the expression of genes can be altered in a cell or a cell lineage without changing the DNA sequence.

In addition to duplication of the DNA sequence, aspects of the chromatin conformation are passed down as the cell divides, as modifications to the DNA and histones distribute semiconservatively to the daughter strands during replication. For example, gene X could be transcriptionally silenced in a parent cell, and the progeny cell then inherits this silenced state along with the gene sequence. Thus, chromatin embodies an important level of epigenetic inheritance.

2.2 Post-Translational Modifications of Proteins

Once made, proteins can be regulated by an astounding variety of changes. Collectively, these changes are called post-translational modifications, or PTMs. PTMs can affect enzyme activity, protein–protein interactions, or other functions of the target protein.

Certain residue side chains can undergo chemical modifications, (4) which expand the building blocks of proteins from the 20 canonical amino acids to a growing list of interesting molecules, and expand the proteome to include differentially modified proteins. Without changing the atoms in a proline residue, reversible isomerization can change its structure. Arginine residue side chains can be deiminated, whereby a terminal nitrogen atom is replaced with oxygen. In rare cases, histidine can be modified to dipthamide. Several types of small groups, which are usually donated from coenzymes, can be covalently added to residue side chains. Serine, threonine, tyrosine, and histidine side chains (as well as arginine and lysine side chains in prokaryotes) can be reversibly phosphorylated. Lysine side chains’ epsilon amine (as well as protein N-terminal alpha amine and, in rare cases, serine and threonine side chains (5)) can be reversibly acetylated, and lysine side chains’ epsilon amine can also be formylated, crotonylated, propionylated, butyrylated, hydroxybutyrylated, glutarylated, succinylated, malonylated, or 3-phosphoglycerylated. (6) Arginine side chains can be mono- or dimethylated, while lysine side chains can be reversibly mono-, di-, or trimethylated. Tyrosine side chains can be hydroxylated. Serine and threonine side chains can be O-GlcNAcylated. Cysteine side chains can be prenylated (by the addition of a farnesyl or a geranyl–geranyl moiety). Serine side chains can be octanoylated. Arginine, glutamic acid, aspartic acid, asparagine, cysteine, and phosphoserine (and sometimes lysine and diphthamide) side chains can be mono- or poly-ADP-ribosylated. There are also different redox states of certain side chains, which can give rise to cysteine oxidation, cysteine disulfide formation, and histidine oxidation. Post-translational modifications can also be larger in size: target proteins can be covalently linked at their lysine side chains to small proteins like ubiquitin, SUMO, Rubb, and Nedd, either with one such addition or linkage in a chain. Finally, proteins can be modified by the removal of part of the sequence by proteolytic cleavage.

This field of post-translational modifications is best summarized by Cohen et al.: “one of the major goals in postgenomic biology is to unravel the molecular basis and the physiological role of covalent protein modifications... This has the potential to identify novel disease pathways and thereby new therapeutic targets as well as diagnostic markers.” (7)

This Review is focused on lysine acetylation. The acetyl group in question is donated by the cofactor, acetyl-coenzyme A. Coenzyme A, which is found in all characterized living organisms on earth, (8) is synthesized by cells from pantothenic acid (vitamin B5) and cysteine, (9) and its thiol moiety can react with the carboxylic acids of acyl groups to activate those groups with an energy-rich thioester bond. Acetyltransferase enzymes catalyze the covalent transfer of the acetyl group from acetyl-CoA to the epsilon amine of the lysine side chain, with the release of the free thiol, CoASH (see Figure 1). The resultant addition of atomic bulk to the side chain and loss of positive charge can change intramolecular protein conformation or change affinity for binding partners. Thus, this small modification can have a variety of possible influences on the function of the particular substrate protein.

Figure 1. Reversible acetylation of the epsilon amine group of lysine side chains.

One method of studing post-translational modifications is to measure the function of site-specifically modified proteins, but this has encountered challenges in the case of acetylation. Acetylation and deacetylation can be mimicked using site-specific glutamine and arginine mutations (respectively), which preserve the charge of the residue they are replacing but are not substrates for acetyl transfer or deacetylation. However, these are not perfect mimics and often do not phenocopy the acetylated or deacetylated protein in cells. Proteins can be purified from cells that lack deacetylases or acetyltransferases, generating populations that are hyper- or hypo-acetylated (respectively), but these alterations typically affect more than one substrate and/or residue. Third, purified proteins can be reacted with purified acetyltransferase enzyme and acetyl-CoA to generate acetylated products, but the site-specificity of acetyltransferases is often promiscuous and reactions rarely go to completion. (10) Acetyl-lyine can be installed in a site-specific manner to proteins using a nonsense-suppression methodology, (11, 12) but this typically generates only very small quantities of the desired protein. Fifth, acetyl-lysine can be installed in a site-specific manner to purified proteins using expressed protein ligation (13) or native chemical ligation, to generate a semisynthetic product, but this is restricted to proteins with acetylation close to one of the termini (or approachable by circular permutation (14)), and has additional structural and sequence requirements. Finally, cysteine alkylation chemistry can be performed on purified proteins to generate an acetyl-lysine or the corresponding lysine mimic, although any other cysteines present would similarly be modified. (15) This latter methodology produces an acetyl-lysine mimic that is not hydrolyzed by deacetylases (as demonstrated by reactions with two example deacetylases). This therefore addresses a further challenge in lysine acetylation research, which is that the acetyl group is rapidly hydrolyzed in experiments where deacetylase enzymes are present, such as lysates or other complex mixtures.

One group of proteins that undergo acetylation is histones. All histones, including the four canonical histones, their variants, and linker histones, can undergo acetylation, and this was first observed as early as the 1960s. (16, 17) Indeed, histones have served as a model system for the study of acetylation and other post-translational modifications, partially because of their abundance in cells and their high sequence conservation among eukaryotes. (18)

Several nonhistone proteins also have well-characterized acetylation sites, (19) including the tumor suppressor protein p53 and the tubulin components of the cytoskeleton. (20) The perception of the “acetylome” as being on a scale close to that of the phospho-proteome has only recently become appreciated. (21) Several reports of proteome-wide study of lysine acetylation have identified thousands of sites. (22-24) These proteins span many important cellular pathways, including chromatin remodeling, cell cycle, splicing, nuclear transport, actin nucleation, and mitochondrial metabolism. Interestingly, a great proportion of acetylated proteins seem to be included in large macromolecular complexes. For example, 61 of the 81 ribosomal subunits are acetylated, 11 of the 16 F₁F₀-ATP synthase subunits are acetylated, and 69 of the 143 spliceosome subunits are acetylated. These example complexes are found in the cytoplasm, mitochondrion, and nucleus (respectively), and this further illustrates the pervasiveness of acetylation throughout the cell.

The link between metabolism and acetylation is multifaceted. In addition to the acetylation of metabolic enzymes to regulate their activities, and regulation of the expression of metabolic enzymes by acetylation of histones and transcription factors, metabolic pathways influence the amount of acetyl-CoA available to lysine acetyltranferase enzymes (see Figure 2). (25) In general, a high energy balance leads to a higher level of acetyl-CoA in the cell, due to catabolism of glucose and fatty acids, while some acetyl-CoA is available during conditions of low energy balance from acetate. Although acetyl-CoA is membrane-impermeable, it can pass through the nuclear pore complex, and pyruvate can be imported to the mitochondrion or citrate exported to the cytoplasm for acetyl-CoA production. Recently, the pyruvate dehydrogenase complex subunits were found to be present in the nucleus, providing a mechanism for nuclear acetyl-CoA production. (26) Reactions that compete with lysine acetylation for the pool of acetyl-CoA include the synthesis of fatty acids, cholesterol, citrate, and ketone bodies. In fact, about 4% of cellular enzymes utilize coenzyme A and its thioesters as a cofactor. (27)

A further way in which lysine acetylation is linked to energy balance is through the sirtuin deacetylase enzymes, which require a nicotinamide adenine dinucleotide (NAD) cofactor, (28) and therefore low nutrient conditions can facilitate deacetylation. Acetylation is not the only PTM that is influenced by energy balance; for example, glycosylation of proteins is regulated by the availability of UDP-GlcNAc through the hexosamine pathway. These mechanisms help a cell make appropriate responses to nutrient conditions, (29) but might also provide mechanisms for disruption of post-translational modification states in diseased cells that have altered metabolism.

Figure 2. Major metabolic processes that produce or consume acetyl-CoA. Processes occurring in the cytoplasm are indicated using purple font, and processes occurring in the mitochondrion are indicated using orange font. Note that PDH can also be nuclear. This figure was adapted in part from Albaugh et al. (30)

2.3 Case Study: Histone H4 Tail

Between the 1960s and 1990s, histone lysine acetylation was found to correlate with transcriptional activation. (31-34) It is now known that this correlation is especially true for histone H4 lysines 5 and 8 (as well as histone H3 lysines 9 and 14), where acetylation is considered permissive to transcription, but there are exceptions, for example, histone H4 lysine 12, where acetylation may be repressive to transcription. (35)

One way that the post-translational modifications on the histone tail can influence chromatin structure is by weakening the interaction of positively charged residue side chains with the negatively charged phosphodiester backbone of DNA, thereby allowing easier access of the DNA by polymerase. (36) Indeed, of the 23 residues of the histone H4 tail, 10 residues are positively charged. However, recent reports reveal that disruption of these electrostatic interactions is not sufficient to cause the histone tails to dissociate from the DNA. (37)

In addition to altering affinity for DNA, protein function can be regulated by acetylation through altering affinity for other proteins. Bromodomains are domains with the special purpose of binding acetylated proteins, bearing different flanking sequence specificities. (38) Bromodomains are contained either singly or doubly in more than 40 human proteins. Although the binding affinity of each bromodomain with each acetylated lysine is generally weak, it is believed that it has major functional relevance in the cell, due in part to some proteins possessing more than one bromodomain in tandem that synergize to increase binding affinity, and also due to histones possessing multiple acetylated residue that can act combinatorially. In the example of the histone H4 tail, at least three bromodomain-containing proteins have been identified that interact with the various acetylated residues. Gcn5 has one bromodomain, while TAF1 and BRDT each have double bromodomains in tandem.

Acetylation is not the only post-translational modification that attracts proteins with a specifically tailored recognition domain. The list of proteins with domains that bind methylated, phosphorylated, or other modified residues is growing. (39) For example, with respect to the histone H4 tail, di-/trimethylated lysine 20 is specifically recognized by the tandem tudor domains of 53BP1, the tandem tudor domains of Crb2, (40) and the tandem tudor domains of JMJD2A, (41) while mono-/dimethylated lysine 20 is specifically recognized by the three MBT repeats of L3MBTL2. (42, 43) An interesting phenomenon of cooperativity in binding between two nearby histone molecules is illustrated by the protein BPTF, which has a bromodomain that binds acetylated histone H4 as well as a PHD-finger domain that binds methylated histone H3. (44)

Given the number of residues on each histone that can be post-translationally modified, and the variety of modifications possible, one can begin to envision the potential combinatorial complexity possible for each nucleosome. For every molecule of the histone H4 N-terminal tail, over 500 such combinations are possible! One way to frame this problem is the Allis lab’s “histone code hypothesis”, whereby the “marks” (PTMs) on histones are “written” (by enzymes like acetyltransferases and methyltransferases), “read” (by proteins with domains like bromodomains and tudor domains), and “erased” (by enzymes like deacetylases and demethylases) to encode information in each nucleosome to direct its functions. (45) A further extension of this scheme is the “nucleosome code hypothesis”, whereby histone H4 could be grouped with sequence variants of H3, H2A, and H2B to create another level of the information encoded by each nucleosome. (46)

While many combinations are theoretically possible for each nucleosome, it has been hypothesized that only a few functionally relevant patterns are prevalent in the cell, (47) and recent evidence supports this model. (48) Indeed, there are documented examples of crosstalk between different modified residues, which may be the mechanisms for how these combination states are established. In the example of histone H4, methylation of R3 could increase acetylation of K5 (because of the chromodomain in the acetyltranferase, yeast Esa1 (49)), methylation of K20 could increase acetylation of K16 (because of the chromodomain of Msl3 in the acetyltransferase complex, Mof (48)), acetylation of K5 could increase dimethylation of R3 and decrease monomethylation of R3 (by altering the activity of the methyltransferases, PRMT5 and PRMT1 (50)), lysine SUMOylation decreases lysine acetylation and ubiquitylation (because these modifications compete for the same residues (51)), and acetylation of K16 decreases possible lysine ADP-ribosylation. (52)

Furthermore, several acetyltransferases have bromodomains, (53) which could mediate further cooperativity between acetylation sites. This has been proposed to influence the histone H4 N-terminal tail acetylation by an an N-terminally progressing “zip” mechanism. In this model, K16 is the first to be acetylated, followed by K12, then K8, and finally K5. In this manner, acetylation on this tail may be an all-or-nothing phenomenon, where K16 acetylation sets off a cascade that results in hyperacetylation of all four lysines on each molecule of histone H4. (54, 55)

In the case of histone acetylation, the balance of addition and removal of the acetyl groups is thought to be highly dynamic, (56-58) which is especially true in regions of the chromatin with high levels of histone methylation, (59, 60) specifically histone H3 with trimethylated K4. (61, 62) This dynamic state is possible because of the action of histone deacetylase enzymes (HDACs), the first of which was cloned in 1996. (63) We now know that HDACs can act by a simple hydrolytic mechanism (the classical HDACs, which contain a crucial zinc ion), or a complex NAD-requiring mechanism (the sirtuins). At least one sirtuin, SIRT2, is known to deacetylate histone H4.

Several acetyltransferases are known to acetylate histone H4. Lysine acetyltransferase enzymes are classified according to sequence conservation into four families, GNAT family (Gcn5 and Pcaf), p300/CBP, Rtt109 (not present in humans), and the MYST family (includes MOZ/Morf, Ybf2/Sas3, Sas2, Tip60), and examples from more than one class are thought to acetylate histone H4, including p300/CBP. Specifically, when recombinantly expressed and purified, Pcaf can acetylate histone H4 K8 (64) and Tip60 can acetylate histone H4 K5/8/12/16. (65) Recombinantly expressed and purified p300 acetyltransferase domain efficiently acetylates H4 N-terminal tail when supplied as a synthetic peptide. (66) Purified full-length p300 also efficiently acetylates H4 N-terminal tail when supplied as full-length free histones or mononucleosomes, (67) with a preference for K5/K8. (68) To extend this to histones in a more native chromatin conformation, Cos7 cells were transiently transfected with p300 or CBP and analyzed for histone acetylation by immunofluorescence microscopy. In cells with increased p300/CBP levels, increased H4 K5/K8 acetylation was seen, as well as other sites. (69) In cells with p300/CBP knockout, reduced H4 acetylation at certain gene sequences was observed by chromatin IP with antibodies against acetylated K5, K8, K12, and K16. (70)

In the field of cancer therapeutic discovery, development of acetyltransferase inhibitors has lagged behind other epigenetic target classes. The deacetylase inhibitors Vorinostat and Romidepsin have proved useful in the clinic for treating cutaneous T cell lymphoma, and compounds that block the acetyl-binding pocket of BET bromodomains (in proteins like Brd2/3/4) are currently in clinical trials for midline carcinoma and other cancers. (71) To our knowledge, there have been no acetyltransferase inhibitors that have progressed to clinical trials, despite the sense that they might prove equally, or more, valuable as compared to deacetylase and bromodomain inhibitors. Acetyltransferase enzymes, in particular p300/CBP, their involvement in disease, and their inhibitor development is the topic of the rest of this Review.

2.4 Discovery of p300/CBP

p300 and CBP are two acetyltransferase enzymes in humans and most higher eukaryotes. p300 (also called EP300 or KAT3B) is so-named because it is about 300 kDa in size (with 2414 amino acids). p300 was reported in 1985 (72) and 1989 (73) (and cloned in 1994 (74)) in studies looking for proteins that bind E1A, an adenoviral oncogenic transcription factor. Meanwhile, CBP (also called CREBBP or KAT3A) was first reported and cloned in 1993 in a study of proteins that bind CREB, (75) a transcription factor that binds cAMP response elements (CREs). CBP is composed of 2441 amino acids, and because of the high sequence homology observed between it and p300, (76) the two proteins are now collectively referred to as p300/CBP. They are in a family of their own, with little sequence homology between them and other acetyltransferases in the human genome. (77)

Soon after the first known histone acetyltransferases (HATs) were cloned in 1995–1996, (78-80) p300/CBP was found to have HAT activity as well. (81, 82) Characterization of this acetyltransferase activity has been of ongoing interest since then, and significant contributions have been made by many laboratories.

The search for p300/CBP orthologs in a variety of living organisms has yielded several interesting observations. First, no orthologs have been found in prokaryotes, and within the domain of eukaryotes, only the “higher” eukaryotes appear to have p300/CBP orthologs. (83) Because nuclear (84) and chromatin (85) structures are largely conserved between “lower” and “higher” eukaryotes, this argues that the evolution of p300/CBP was not triggered by the evolution of the nucleus and chromatin, but later when metazoa evolved. Thus, p300/CBP function may be especially important in aspects of growth and development that are prevalent in multicellular organisms, such as cell-to-cell communication or organ morphogenesis. (86) That being said, crystallography studies have unveiled that p300/CBP has a structural homologue in yeast, called Rtt109, (87) although there is little sequence or apparent functional similarity between the two acetyltransferases.

Four genes that may be orthologs of p300/CBP have been identified in the plant Arabidopsis. (88) Within the animal kingdom, many different species have been found to possess p300/CBP, but with different copy numbers. Evolutionarity distant animals such as flies and roundworms possess one p300/CBP each, although flatworms seem to have acquired their own duplication of p300/CBP. Sea squirts, which are in the phylum chordata but are not in the subphylum vertebrates, also seem to possess one p300/CBP. When vertebrates evolved, the chromosomal region corresponding to p300/CBP, as well as eight nearby genes, seems to have undergone a duplication that resulted in the p300 gene (on human chromosome 22, at the locus 22q13) and the CBP gene (on human chromosome 16, at the locus 16p13). (89) Thus, chickens, opossums, mice, and humans all have one p300 gene and one CBP gene. However, even among the vertebrates there is some variation in copy number, as frogs appear to have lost their p300 gene, zebrafish appear to have lost their CBP gene, and puffer-fish appear to have duplicated their CBP gene.

After the duplication event, p300 and CBP have diverged in sequence somewhat, with 61% overall sequence identity. Interestingly, some domains have retained more similarity than others. Not surprisingly, sequence variation in the catalytic acetyltransferase domain has been selected against, resulting in 86% amino acid residue identity, in the region corresponding to the acetyltransferase domain and its two flanking domains, when comparing human p300 protein and human CBP protein sequence. (90) The acetyltransferase domain spans residues 1284–1673. (91) This conservation suggests an evolutionarily optimized function of the catalytic domain and underscores the importance of the acetyltransferase roles of p300 and CBP.

Furthermore, there is significant sequence homology in other noncatalytic domains of p300/CBP, including in several types of protein–protein interacting motifs (see Figure 3). At the N-terminal side there is a nuclear receptor interacting domain (NRID or RID), which is also one of two SPC domains (SPC-1 and SPC-2), that may bind PXXP motifs. SPC-2 is also a Sin3 interacting domain (SID). There are three cysteine/histidine-rich (C/H) domains. The C/H1 and C/H3 domains contain transcriptional adaptor zinc fingers (TAZ1 and TAZ2), and the C/H3 also contains a ZZ zinc finger. The C/H2, which is part of the catalytic domain, contains a plant homeo domain (PHD). Between the C/H1 and C/H2, there are an interferon binding homology domain (IHD), KIX domain, and a bromodomain. At the C-terminal side of p300/CBP there is an interferon binding domain (IBiD), which contains a nuclear coactivator binding domain (NCBD) and a glutamine-rich domain, followed by a proline-containing PxP motif. (92, 93)

Figure 3. Domain structure of p300/CBP. Exon–intron gene diagrams are shown for p300 and CBP (top). Below are example protein structures for the bromodomain (PDB 3I3J, 2.33 Å), catalytic HAT domain (PDB 3BIY, 1.7 Å), ZZ zinc finger (PDB 1TOT), and TAZ2 domain (PDB 3IO2, 2.5 Å). All structures were produced using purified p300, except the ZZ zinc finger, which used purified CBP. p300/CBP proteins are colored with a rainbow, with blue at the N-terminus and red at the C-terminus, and residues included in the structure are listed below each. Zinc ions are black spheres. All structures are based on X-ray crystallography, except the ZZ zinc finger structures from solution NMR. The p300 bromodomain structure shown here is remarkably similar to an independently generated CBP bromodomain structure (not shown, PDB 3DWY, 1.98 Å). Below is a model for full-length p300/CBP with all domains shown, and is a compilation based on several recent analyses.: (94, 95) three cysteine/histidine-rich (C/H) domains are shown in turquoise, three zinc fingers are shown in yellow, and the catalytic acetyltransferase domain is shown in orange, with its autoacetylated regulatory loop drawn above, which corresponds to residues 1523–1554. A few examples of proteins that bind p300/CBP are listed below the protein model, with the particular domain involved in binding indicated with a black line. Below that, amino acid similarity is indicated, for comparing p300 and CBP sequences within either the catalytic BHC region (from the bromodomain to the C/H3 domain) or the entire protein. At the bottom, commonly purified active p300 variants are indicated, including p300 acetyltransferase/HAT domain, BHC enzyme (bromodomain-HAT-C/H3), and full-length protein. It should be noted that p300 HAT has a deletion in residues 1529–1560.

Sequence homology in these domains helps explain why p300 and CBP have many overlapping functions. For example, p300 was first identified because of its ability to bind E1A, but CBP can also do this, (96) for which they both use their mutually conserved C/H3-TAZ2 region. (97) Also, CBP was first identified because of its capacity to bind CREB, but p300 also has this ability, (98) for which they both use their mutually conserved KIX domain. (99) However, despite these similarities, p300 and CBP appear to also have a handful of distinct functions, which may be due to slight differences in substrate specificity and/or in a subset of protein–protein binding interactions. (100)

2.5 p300/CBP Function in Signaling Pathways

As discussed in section 2.1, the cell must turn different subsets of genes on, in response to intracellular or extracellular signals, to regulate cellular functions, and this is accomplished partially by the acetylation of histone proteins to open the chromatin conformation and promote transcription. An intriguing collection of cellular signaling pathways have been dissected, and one striking finding is that p300/CBP is almost always a player. Examples of signals that ultimately use p300/CBP as downstream effectors include calcium signaling, response to hypoxia, Notch signaling, and NFκB signaling (see Figure 4).

Notch is a transmembrane protein that is involved in intercellular signaling. When neighboring cell proteins engage and activate Notch, this induces cleavage of Notch and release of the active intracellular domain (ICD). The ICD then binds CSL and Mastermind. CSL targets the complex to DNA elements, while Mastermind recruits coactivators including p300/CBP and Pcaf, and together this complex activates transcription of target genes. (101) For a more detailed description of this example, see section 5.2.

Another example is the cAMP pathway, which was mentioned because of its historical role in the first identification and naming of CBP. In this signaling pathway, growth factors or other extracellular signals are received by transmembrane G protein-coupled receptors (GPCRs), which activate heterotrimeric G proteins. The G proteins can then activate adenylyl cyclase, which produces cAMP, and this releases the active protein kinase A (PKA) from a complex with an inhibitory subunit. PKA then diffuses into the nucleus and phosphorylates CREB at serine 133. CREB dimers bind cAMP-response elements (CREs) in the genomic DNA and also recruit p300/CBP to activate transcription of an estimated 100 target genes. (102)

A third example is the estrogen pathway, which is important to hormone-dependent cancers (see section 6). Estrogen is a steroid hormone that diffuses into cells and binds to intracellular estrogen receptors. Estrogen receptor dimers bind estrogen-response elements (EREs) in the genomic DNA. Upon ligand binding, the complex recruits p300/CBP to activate transcription of around 1000 target genes. (103)

p300/CBP is also involved in stress response pathways, in which adaptation to conditions such as hyperosmolarity involves changes in gene expression. (104) For example, osmotic shock induces several kinase cascades, including those involving the kinases p38, JNK, and ERK. (105) Phosphorylation of p300/CBP can regulate its activity in different ways, depending on the phosphorylation site, (106) and thereby regulate transcription of target genes.

There are also several links between p300/CBP and the DNA damage response pathway. The DNA damage response is orchestrated mainly by the protein p53, and its expression and post-translational regulation are modulated by p300/CBP activity. p53 and other proteins in the DNA damage response are substrates for acetylation by p300/CBP. (107, 108) p300/CBP is also involved in the activation of genes following DNA damage, such as p21. (109)

Figure 4. p300/CBP is central to many important signaling pathways. These include pathways that respond to intracellular signals (turquoise), extracellular signals (purple), and intercellular signals (blue). These pathways control the key cellular functions via altering expression of target genes, through the action of p300/CBP in the nucleus.

One way in which p300/CBP is able to respond to signaling pathways is by the post-translational modifications of p300/CBP itself. Phosphorylation of p300/CBP occurs at several sites, catalyzed by kinases including PKC, (110) cyclin E/CDK-2, CaMKIV, IKK, and AKT, (111) that are reported to negatively or positively regulate p300/CBP acetyltransferase activity, protein–protein interactions, or protein stability, depending on the site. (112-114) p300/CBP also has two sites of methylation near the KIX domain, and one effect of an arginine methylation event by CARM1 is the decreased recruitment by CREB (115) but the increased recruitment by estrogen receptor. (116) p300/CBP can also be SUMOylated at three lysines near the bromodomain, which may influence p300/CBP subnuclear localization, (117) is antagonistic with acetylation at the same sites, and negatively regulates p300/CBP activity. (118) Acetylation of p300/CBP occurs on 17 lysine residues of a regulatory loop within the acetyltransferase domain, probably by a highly efficient and cooperative intermolecular reaction, (119) and stimulates its acetyltransferase activity (120, 121) and binding of proteins. (122) One regulatory mechanism that this autoacetylation could serve is by relieving the steric hindrance in the substrate binding site, with the regulatory loop acting as a pseudosubstrate.

Another way in which p300/CBP is able to respond to signaling pathways is due to the ability of p300/CBP to bind a multitude of different proteins, using its various protein-interacting domains. The number of proteins that p300/CBP can bind to, also referred to as the p300/CBP interactome, is a list that is ever growing. In 2006, the count was at 312, (123) and today at least 411 proteins are implicated in binding p300/CBP (see Supporting Information Table 2). (124) Some of these proteins interact directly with DNA, sometimes in response to a signal, recruiting p300/CBP to the target gene element. Genomic profiling of p300/CBP recruitment to DNA sequences has been analyzed by several groups using chromatin immunoprecipitation. At these DNA elements, p300/CBP nucleates a complex of many proteins that together allow for transcriptional activation. Transcriptome profiling of genes regulated by p300/CBP has been analyzed by one study, using treatment with a p300/CBP inhibitor and microarray analysis, which implicated 615 as being regulated by p300/CBP. (125) One limitation of these interactome and transcriptome studies of p300/CBP is that cryptic protein partners, DNA elements, and regulated genes might be missing from the lists, if certain signaling pathways need to be activated before p300/CBP can engage in a specific binding partnership, recruitment, or transcriptional event.

Many of the protein–protein interactions making up transcription complexes are mediated by the acetylation of lysines on the proteins, by p300/CBP or by other associated acetyltransferases, and the resultant binding to other proteins with bromodomains. To date, ∼100 proteins have been implicated as p300/CBP acetylation substrates (see Supporting Information Table 1). (126) Thus, p300/CBP helps supply acetylation as a glue to hold the complex together, while also serving as a scaffold to bring together many proteins, and a bridge to connect one protein-bound DNA element with another (see Figure 5). (127, 128)

Figure 5. p300/CBP functions as a scaffold, bridge, and acetyltransferase. The acetyltransferase reactions are illustrated by turquoise arrows, indicating acetylation of histone and nonhistone substrates (in yellow), as well as autoacetylation of the p300/CBP acetyltransferase domain. The bridge function is illustrated by turquoise squares, representing DNA-binding proteins that bring DNA elements into proximity with p300/CBP through their interactions. The scaffold function is illustrated by orange squares, representing a protein complex being recruited by p300/CBP. These functions together allow for gene expression.

In light of the astounding number of possibilities of complexes in which p300/CBP could participate, one may wonder how this is regulated. The first clue is that certain domains, such as the C/H3 domain, have many potential protein binding partners that compete for the same recognition sequence within p300/CBP. Another clue is CBP haploinsufficiency, where one wild-type CBP copy is not enough for normal mouse development, and, conversely, CBP overexpression is also lethal in the fruitfly Drosophila melanogaster, indicating a tightly controlled, limiting pool of p300/CBP in cells. (129) Therefore, in our current model, which protein any given molecule of p300/CBP might interact with would depend upon the relative nuclear concentrations of the potential partners and upon relative binding affinities of the potential partners. Therefore, information from an intracellular or extracellular signal would be relayed through a pathway to produce a change in a certain effector protein’s nuclear concentration or affinity for p300/CBP, altering p300/CBP cellular complexes. For example, upstream signaling pathways may enhance p300/CBP recruitment to a specific target gene by translocation of a certain protein to the nucleus, or post-translational modification of the protein to increase the binding affinity to p300/CBP.

What emerges is a fascinating picture of different signaling pathways competing for p300/CBP. (130) This hypothesis has been supported by several interesting studies. In one report, tumor necrosis factor-α (TNF-α) was used to stimulate the RelA subunit of NFκB binding to p300/CBP (via its zinc finger) and resultant induction of HIV gene expression, but this was inhibited when interferon-α (IFN-α) was used to stimulate STAT2 binding to p300/CBP (via the same zinc finger). (131) In another study, when AP-1 was bound to p300/CBP (via its C-terminal region (132)), this resulted in induction of TRE genes (involved in the antioxidant response), but this was inhibited when p53 was bound to p300/CBP (via the C/H1 and/or C/H3, resulting in induction of p53-regulated promoters), (133) and also inhibited when glucocorticoids were used to stimulate glucocorticoid receptor binding to p300/CBP (via the N-terminal nuclear receptor interacting domain). (134) Similarly, genotoxic stress stimulates p53 binding to p300/CBP and resultant induction of p53-dependent genes (resulting in cell cycle arrest), but this is inhibited when overexpressed E2F-1 is bound to p300/CBP (via its TAZ2 domain, (135) resulting in apoptosis). (136) In another study, cAMP stimulates CREB binding to p300/CBP (via its KIX domain) and resultant induction of cAMP-responsive genes, but this is inhibited when insulin or growth factors were used to stimulate S6 kinase pp90RSK binding to p300/CBP (via its C/H3 domain), which resulted in induction of Ras-responsive genes. (137)

Taken together, these and other studies demonstrate that p300/CBP is not only essential to many cellular signaling pathways, but utilizes its protein–protein interactions to integrate the different signals and determine how the cell will respond. In this manner, p300/CBP has a hand in controlling virtually all of the major cellular functions, including proliferation, differentiation, and response to stress (see Figure 4).

3 p300 Acetyltransferase Activity

Click to copy section linkSection link copied!

p300/CBP has a central acetyltransferase (also called HAT) domain that catalyzes the reaction in which the acetyl group from acetyl-CoA is transferred to a protein lysine side chain. p300/CBP has the ability to acetylate a wide variety of proteins (see Supporting Information Table 1). These substrate proteins are located principally in the nucleus (such as histones) but are also present in other parts of the cell (such as the cytosolic GAPDH). Immunofluorescence microscopy and subcellular fractionation studies have localized p300/CBP predominantly to the nucleus. It is not completely understood how p300/CBP shuttles in and out of the nucleus, and part of the answer may be its binding interactions with protein ligands that are themselves targeted to the nucleus or elsewhere.

3.1 p300 Acetyltransferase Domain Structure

One of the challenges for biochemical characterization of p300/CBP is the difficulty to express and purify active enzyme. This may be due to the large size of full-length protein (see Figure 3) and/or inappropriate hyperacetylation when the active acetyltransferase domain is overexpressed. This can be overcome by coexpression with the deacetylase Sir2. Alternately, for the acetyltransferase domain, it is possible to express an inactive protein followed by ligation to a synthetic peptide to generate the active enzyme. (138, 139) Purified p300 containing its acetyltransferase domain plus its two flanking domains can be prepared efficiently from insect cells. (140) The effect of the flanking domains on acetyltransferase activity will be discussed in further detail in section 5.1.

As transferase enzymes, acetyltransferases have two substrates (acetyl-CoA and a lysine-containing protein) and two products (CoASH and an acetyl-lysine-containing protein). For an enzyme with two substrates, a rational strategy to create a high potency inhibitor is to incorporate the major structural features of both substrates, and thereby allow binding to be tighter than for either substrate on its own. This idea sparked the generation of a variety of acetyltransferase inhibitors, starting with the minimalist bisubstrate analog Lys-CoA, and including various peptide sequences appended to the lysine. Discovery of Lys-CoA, in addition to enzymology applications that will be discussed in section 3.2, allowed for the crystallization of the p300 acetyltransferase domain active site in complex with the bisubstrate, with the structure solved at 1.7 Å resolution (see Figure 6). (141)

This crystal structure revealed six nucleophilic residues in sufficient proximity to be able to attack the carbonyl carbon of acetyl-CoA, but mutational analysis and the use of an electrophilic CoA labeling reagent (142) refuted a mechanism that p300 catalysis proceeds through a covalent enzyme intermediate.

Figure 6. p300 acetyltransferase domain structure bound to Lys-CoA. (A) Secondary structures of p300 acetyltransferase domain. (B) L1 loop and an acidic surface. (C) Parts of Lys-CoA bisubstrate analog (gray) and four p300 residues of interest (green). Generated in PyMol based on Protein Databank entry 3BIY, published by Liu et al. (143)

In contrast to other crystallized acetyltransferases like Gcn5 and yeast Esa1, the crystal structure of p300 revealed a shallow, acidic surface about 10 Å distance from the substrate lysine (see Figure 6). This surface is thought to interact with the substrate flanking sequence, and mutational analysis confirmed that E1505 and D1628, both found in this surface, are important for catalysis. (137) This provides insight into the broad peptide substrate specificity of p300, and the preference for nearby basic residues (usually a lysine or arginine, within 3 or 4 residues of the modified lysine). This contribution to catalysis was analyzed for histone H4, where the K8 substrate is flanked by basic residues at K5 and K12. Replacing K5 and K12 with alanine impaired acetylation at K8, but this was rescued if either alanine was changed to arginine to preserve the positive charge. Acetylation was not rescued if K5A was changed to citrulline, which can still be a hydrogen-bond donor but loses the potential for an electrostatic interaction associated with lysine, arguing that the positive charge is important in substrate recognition and catalysis. (65)

In addition to revealing this acidic surface, the crystal structure highlighted the importance of many residues involved in Lys-CoA binding (see Figures 6 and 7). Mutationally sensitive Y1467 was implicated in a hydrogen bond between its side chain hydroxyl and the sulfur of Lys-CoA. This may allow the Y1467 to function as a general acid, facilitating the protonation of the leaving group during catalysis. W1436 was implicated in a hydrogen bond between its main chain oxygen and epsilon nitrogen atom of the substrate lysine, as well as van der Waals interactions between its hydrophobic indole side chain and the aliphatic portion of the substrate lysine. This forms a hydrophobic tunnel in combination with two tyrosines, which may reduce the substrate lysine pK_a, such that the neutral amine required for attack is more favored. p300 acetyltransferase catalytic activity was sharply reduced by W1436A mutation. As the pH–rate profile of p300 reveals an important pK_a of 8.4, (137) it is proposed that this pK_a may correspond to this substrate amine in complex with p300. In addition, R1410 showed salt bridging interactions with the phosphates of CoA, whose importance was confirmed using 3′-dephospho-Lys-CoA and mutagenesis. (137) Interestingly, W1436 and R1410 p300 point mutations have been observed in patients with lung cancer, suggesting that p300 can be a tumor suppressor.

The crystal structure of the p300 acetyltransferase domain also showed that p300 has structural similarity, and hence a possibly ancient common ancestor, with the fungal acetyltransferase Rtt109. (144) Furthermore, although p300/CBP has little sequence similarity with other acetyltransferases, p300 has a conserved CoA binding region in common with other crystallized acetyltransferases like Gcn5, yeast Esa1, and yeast Rtt109. (145) In this CoA binding region, the pantetheine arms of CoA adopts similar positions surrounded by several integral beta strands and alpha helices that overlap in superposition models, but the adenosine rings of CoA occupy differing conformations, with Gcn5 (146) and Esa1 (147) structures being more flexible. In the p300 structure, a specialized substrate-binding loop, called the L1 loop, interacts with the entire length of the lysine and CoA, and locks them in place (see Figure 6). (137) This is consistent with the tight binding observed with p300 and acetyl-CoA, as well as the reduced inhibition seen for Lys-CoA varieties with longer peptide sequences, as there may be a steric clash between the peptide and the L1 loop. Assays with bisubstrate analogs containing various length linkers between the peptidyl-Lys and the CoA showed that linker length correlated with potency, although these compounds never exceeded the potency of the original Lys-CoA. This suggests that the crystal structure is of p300 trapped in the conformation of a late step in catalysis, where the acetylated peptide substrate is rapidly ejected from the active site. (148)

3.2 p300 Acetyltransferase Reaction Chemistry

There are several kinetic mechanisms possible for a two-substrate two-product “bi bi” scheme like the reaction catalyzed by p300/CBP. We now know that most acetyltransferases follow an ordered binding, ternary complex mechanism, but p300 appears to proceed through a Theorell–Chance mechanism, in which there is no stable ternary complex, and the peptide substrate associates only very transiently with the enzyme, leaving as soon as the reaction is complete. (149)

One of the first insights into the catalysis by p300 was derived from solvent viscosity studies. Initial velocities were measured in the presence of different concentrations of sucrose, and a significant dose-dependent loss in catalysis was observed. Moreover, substrate analogs that were poor substrates did not have as large a solent viscosity effect. These data argue that release of at least one of the products is the rate-limiting step in the reaction with a normal substrate, as opposed to the chemical step(s). (65) Binding studies with CoASH and substrate analog acetonyl-CoA helped characterize the tight binding properties. p300 binds acetyl-CoA with an affinity in the high nanomolar or low micromolar range. (140)

To distinguish among several possible p300 kinetic mechanisms, two-substrate kinetics was performed and reported in 2001. (65) The steady-state kinetic parameters, using initial velocities, were determined for acetyl-CoA at different concentrations of a H4–20 peptide substrate. In double-reciprocal plots (E/V versus 1/[acetyl-CoA]), parallel lines were observed, which was originally interpreted as support for a ping-pong kinetic mechanism rather than a ternary complex mechanism involving direct transfer of the acetyl group from acetyl-CoA to a lysine-containing peptide. (65, 150)

These steady-state kinetics of p300 confounded researchers for some time, because a covalent enzyme intermediate could not be identified, and because the bisubstrate analog Lys-CoA was a potent p300 inhibitor. Once the crystal structure of the p300 acetyltransferase domain was elucidated, a Theorell–Chance, also known as hit-and-run, catalytic mechanism was considered. Implicit in this model (151) was a relatively high affinity for acetyl-CoA, which was consistent with the observed low K_i of the substrate analog acetonyl-CoA. The Theorell–Chance mechanism was further investigated using product inhibition studies. This included four separate experiments, with inhibition by either CoASH or Ac-peptide (K8Ac H4–12 with K5R and K12R), and varied substrate as either acetyl-CoA or peptide (H4–12 with K5R and K12R). The observed pattern was fully consistent with a Theorell–Chance mechanism, but not ping-pong or ordered bi bi mechanisms. (137)

The Theorell–Chance mechanism helps account for why Lys-CoA is a ∼20-fold better p300 inhibitor than the longer peptide-CoA conjugate H4-CoA-20, even though Ac-Lys is a ∼15-fold worse p300 substrate than H4–20. In contrast, Gcn5 and Pcaf acetyltransferases obey classical ternary complex mechanisms, and are more potently inhibited by the longer peptide-CoA conjugate bisubstrate analogs. (152) A further application of Lys-CoA and the cocrystal structure was to facilitate in silico modeling of small molecules in the p300 active site. The understanding of the features that distinguish p300/CBP from other acetyltransferases, including the Theorell–Chance catalytic mechanism and the key role that acetyl-CoA binding plays in the reaction, led to interest in designing inhibitors that would bind in the same tunnel as acetyl-CoA, acting as competitive inhibitors that would be expected to be specific for p300/CBP versus other acetyltransferases. These studies resulted in the discovery of C646, a small molecule inhibitor of p300/CBP that is relatively potent, specific, and cell permeable. In agreement with the rationale behind this inhibitor, it is competitive for acetyl-CoA and selective for p300/CBP. (153) This and other inhibitors of p300/CBP will be discussed in further detail in section 4.

Figure 7. Acetyl transfer catalysis by p300. (A) The p300 active site is drawn in green, and histone H4 substrate in blue, with important residues indicated. CoA is drawn in black, and binds in a specific tunnel. (B) Four steps in a proposed p300 mechanism. acetyl-CoA binds, then peptidyl-lysine binds. The hydrophobic indole of W1436 promotes an uncharged lysine and positions it for attack. The lysine attacks the carbonyl of acetyl-CoA, while Y1467 acts as a general acid to protonate the leaving group. Acetyl-lysine-containing product leaves quickly, then CoASH departs slowly.

4 Inhibitors of p300 Acetyltransferase Activity

Click to copy section linkSection link copied!

Especially for the p300/CBP field, a challenge faced interpreting gene knockdowns or knockouts is that the resultant phenotypes can be attributed to the disruption of either the enzymatic acetylation activity of p300/CBP or the protein–protein binding activities. One way that the two properties of p300/CBP can be deciphered in cells is through the application of inhibitors that only block the catalytic activity and not the protein–protein binding. Acetyltransferase inhibitors may therefore be useful as tool compounds in understanding acetyltransferase functions and also have the potential to treat a variety of diseases (which will be described in section 6). Therefore, the identification and characterization of pharmacologic acetyltransferase inhibitors are ongoing.

4.1 Bisubstrate Acetyltransferase Inhibitors

The first potent acetyltransferase inhibitor identified is Lys-CoA, (154) which is a covalent fusion between an acetyl-lysine and coenzyme A, with an extra methylene in between (see Figure 8). Structure–activity relationship studies have subsequently attempted to improve potency of Lys-CoA and probe p300 catalysis. (155-157) Lys-CoA proved a powerful tool in studies of the p300 mechanism by crystallography and kinetics. (65, 137, 158)

The rationale behind the bisubstrate design is that features of the acetyltransferase that engage each individual substrate (the lysine and the CoA) can be simultaneously engaged by a compound that mimics both. A similar bisubstrate strategy has also been employed to generate potent inhibitors of carnitine acetyltransferase, (159) gentamycin acetyltransferase, (160) spermidine acetyltransferase, (161, 162) serotonin acetyltransferase, (163-165) GNAT acetyltransferases, (166) aminoglycoside acetyltransferase, (167-170) ghrelin O-acyltransferase, (171, 172) and protein kinases. (173, 174) Lys-CoA is potent against p300, with a K_i of 19 nM, (175) and is between 50- and 400-fold tighter binding than CoASH alone. (176, 177) Because the inhibition by Lys-CoA follows slow, tight-binding kinetics, (137) the measured IC₅₀ can vary depending on whether a preincubation step with enzyme is included.

Lys-CoA is specific for p300 (and CBP, which has a near-identical acetyltransferase domain sequence). This selectivity can be explained by its Theorell–Chance kinetic mechanism, whereby p300 interacts with the substrate protein weakly using a broad, promiscuous surface (see Figures 6 and 7). This is in contrast to other acetyltransferases, many of which employ a ternary complex mechanism, (178-182) in which protein substrate interactions are more important for enzyme engagement. For non-p300/CBP acetyltransferases, it can be deduced that the simple Lys-CoA molecule does not engage enough of their active site to confer high affinity. This explains why Lys-CoA inhibits other acetyltransferases with lower potency as compared to p300.

However, with its Theorell–Chance kinetic mechanism, p300 does not naturally engage the substrate protein for a long period of time, ejecting it from the active site soon after acetyl transfer. This explains why adding flanking peptide sequences in the Lys-CoA design actually reduces potency against p300. Even though H2A, H3, and H4 tail peptides are substrates for p300, embedding Lys-CoA in these sequences reduces potency against p300. (183)

By appending different peptide sequences flanking the lysine residue in Lys-CoA, bisubstrate inhibitors were generated with varying specificity profiles with other acetyltransferases (see Figure 8). These acetyltransferases are more substrate selective, and thus the inhibitor selectivity comes from matching the flanking sequences to that of the natural substrate. For example, H3-CoA-20 (20-mer peptide with K14 as the site of CoA conjugation) is potent (K_i of around 28 nM) and selective for Pcaf. (184, 185) An H3-CoA-20 derivative proved useful in generating a cocrystal structure with Gcn5. (186) Additional studies on peptide-CoA conjugates have explored the broader potential of these bisubstrate analogs against a range of acetyltransferases. (187)

One major limitation of these bisubstrate inhibitors is that they are not efficiently cell permeable. Cell delivery by microinjection allowed the study of p300 acetyltransferase functions in a variety of systems, including the nematode Caenorhabditis elegans, (188) frog oocytes, (189) and cultured mammalian cells, (190, 191) although these methods are labor-intensive. Delivery by cell permeabilization allowed the introduction of Lys-CoA into muscle cells (192) and melanocytes, (193) but the lipid-based detergent used has some cytotoxicity.

Because the negative charges on the three phosphates of the phosphoadenosine moiety may be responsible for reduced cell permeability, analogs were explored that lack some of these groups, but most had no detectable p300 inhibition, and the best was 3′-dephospho-Lys-CoA, which had a 32-fold worse potency (IC₅₀ of 1.6 μM). (194) Prodrug strategies have been suggested to mask the phosphate groups. (193) Some success has been achieved by appending positively charged arginines and lysines in peptides appended to the target lysine moiety. Appending the Tat peptide sequence (see Figure 8), which originates from the well-established cell-penetrating HIV Tat protein, resulted in a mere 5-fold worse IC₅₀ for p300, but also made it less selective for p300, with 91-fold better potency for Pcaf (IC₅₀ of 2.2 μM for Pcaf, which is only 8.8-fold that of p300). (195) A similar Tat-conjugate was employed to generate H3-CoA-20-Tat, which retained 300-fold selectivity for Pcaf over p300, and these were used to study the functional interaction of acetyltransferases and the protein PZLF in cells. (196)

Figure 8. Bisubstrate inhibitors of acetyltransferases.

4.2 Natural Product Acetyltransferase Inhibitors

There is much interest in the identification of nonpeptidic small molecule inhibitors of acetyltransferases. Many natural products have been isolated and tested for acetyltransferase inhibitory properties. It should be noted that as these were studied by different laboratories employing varying methodologies, the IC₅₀ numbers included here might not all be directly comparable. It is also notable that most of those described here are conveniently commercially available. The first natural product that was found to have acetyltransferase inhibitory properties is anacardic acid (see Figure 9). (197)

Anacardic acid can be isolated from cashew nutshell oil, mangos, and geraniums. It consists of a salicylic acid substituted with an alkyl chain. It is partially miscible in ethanol and ether, but immiscible in water. It is known to be toxic to Gram-positive bacteria and causes an allergic skin rash in humans. (198) A PubMed search for “anacardic acid” yields 117 articles, spanning the years 1976–2013.

The inhibition of acetyltransferases by anacardic acid was first described in 2003, and it appeared to be fairly potent against p300 (IC₅₀ of 8.5 μM) and Pcaf (IC₅₀ of 5 μM), showing noncompetitive inhibition kinetics. (199) However, an independent analysis of anacardic acid suggested inhibitory action against Tip60 (IC₅₀ of 64 μM) and MOF (IC₅₀ of 43 μM) but not against p300 or Pcaf (IC₅₀ > 200 μM), (200) while a third study measured IC₅₀ above 200 μM for yeast Esa1, Tip60, p300, and Pcaf. (201) Certain benzamide analogs of anacardic acid have increased potency against acetyltransferases. (202) Intriguingly, modification of anacardic acid by adding a phenyl ring, to produce the benzamide analog called CTPB (see Figure 9), was reported to confer p300 activation. (203-205) In addition to its likely modulation of other nonacetyltransferase targets in the cell, a major limitation of anacardic acid is its poor solubility. (206)

Another natural product found to have acetyltransferase inhibitory properties is curcumin (see Figure 9). (207) Curcumin can be isolated from tumeric, which is a root spice in the ginger family. It consists of two phenols connected by two carbonyls. It is soluble in oil and DMSO, but not in water. It is a commonly used yellow food dye, and it is nontoxic: a daily dose of 12 g for 3 months is safe. (208) A PubMed search for “curcumin” yields an astounding 5400 articles, spanning the years 1949–2013. The use of curcumin in food and ethnic medicines has a long history. (209) In addition to acetyltransferases, curcumin is thought to affect a variety of other targets in cells, including several kinases, COX2, phosphatases, and Bcl proteins. (210-213)

Its inhibition of acetyltransferases includes p300 and acetyltransferases in the MYST family, (214) and may occur via the electrophilic unsaturated ketone in curcumin being attacked by a acetyltransferase cysteine thiol group, to produce a covalent adduct. (215) The IC₅₀ against p300 is 25 μM. (216) Despite many clinical observations of a variety of positive effects, curcumin showed unacceptably poor absorption, rapid metabolism, and elimination in Phase I clinical trials. (217, 218) Several curcumin analogs have been described, (219, 220) but a pharmacologically useful acetyltransferase-specific inhibitor has yet to be derived from curcumin.

In the same year that curcumin was found to have acetyltransferase inhibitory properties, the natural product garcinol was also found to have acetyltransferase-inhibitory properties (see Figure 9). (221, 222) Garcinol can be isolated from Garcinia indica, also known as kokum, which is a plant in the mangosteen family that produces edible fruit. Garcinol consists of a polyisoprenylated benzophenone. It is soluble in DMSO, ethanol, or DMF, but not in water. A PubMed search for “garcinol” yields 76 articles, spanning the years 1987–2013. It is a fairly potent acetyltransferase inhibitor, hitting p300 (IC₅₀ of 7 μM) and Pcaf (IC₅₀ of 5 μM), and has mixed-type inhibition kinetics. (223) Unfortunately, garcinol (and the related isogarcinol) is fairly toxic in cells. An analog of garcinol, called LTK-14 (see Figure 9), improves toxicity and selectivity, with retained p300 potency (IC₅₀ around 6 μM) but has no detectable inhibition of Pcaf. (224, 225) Garcinol and LTK-14 are poorly soluble and unstable, and this has been attempted to be corrected through further investigation of structural analogs. (226-228) One intriguing garcinol analog is nemorosone, which was found to have a modest (1.5–2-fold at 10 μM) activation of p300. (227)

Also in 2004, certain γ-butyrolactone analogs, including one named MB-3 (see Figure 9), were found to have acetyltransferase inhibitory properties. (229) Although the γ-butyrolactones used in that study were rationally designed and of synthetic origin, γ-butyrolactones can be isolated from wine, and have therefore been included in this section on natural products. MB-3 is soluble in DMSO or methanol. γ-Butyrolactones were developed with varying specificities against Pcaf and a Gcn5-like acetyltransferase, although potencies were modest (for example, the Gcn5 inhibitor has an IC₅₀ of 100 μM (228)) and cellular activity remains to be demonstrated. (230)

Another natural product that was found to have acetyltransferase-inhibitory properties is plumbagin (see Figure 9). (231) Plumbagin can be isolated from the plant genera Plumbago (leadwort), Drosera, and Nepenthes. Plumbagin is a napthoquinone derivative. It is soluble in DMSO and ethanol, but only slightly in water. A PubMed search for “plumbagin” yields 370 articles, spanning the years 1968–2013. Plumbagin is fairly safe at low doses but toxic at high doses. (232) Plumbagin is thought to undergo redox cycling, which has effects on reactive oxygen species and the chelating of metals in cells. It also affects the drug efflux mechanism in cells and the conjugative transfer of antibiotic-resistance plasmids in bacteria. (233) The effect of plumbagin on acetyltransferases was revealed in 2009, with modest inhibition of p300 (IC₅₀ of 25 μM) and Pcaf (IC₅₀ of 50 μM). Further analysis of structural analogs of plumbagin did not result in improved potency or specificity with p300 or Pcaf. (234)

Also in 2009, the natural product epigallocatechin-3-gallate (EGCG) was found to have acetyltransferase inhibitory properties (see Figure 9). (235) EGCG can be isolated from tea plants. It consists of an epigallocatechin linked to a gallic acid via an ester linkage. It is soluble in water, DMSO, ethanol, and DMF. A PubMed search for “epigallocatechin-3-gallate” yields 3434 articles, spanning the years 1985–2013. EGCG appears to be a broad-spectrum acetyltransferase inhibitor, with modest potency against p300 (IC₅₀ of 30 μM), CBP (IC₅₀ of 50 μM), Pcaf (IC₅₀ of 60 μM), and Tip60 (IC₅₀ of 70 μM), and uncompetitive inhibition kinetics. (234) EGCG has several targets in cells, including topoisomerase. (236-239) EGCG appears to negate the effects of other compounds when combination therapies were attempted, suggesting potentially detrimental contraindications. (240, 241) EGCG, like other topoisomerase poisons, may be carcinogenic. (242)

Also in 2009, the natural product quercetin was found to have acetyltransferase-inhibitory properties (see Figure 9). (243) Quercetin can be isolated from a wide variety of plants, including the oak tree for which it is named, Quercus, as well as tea leaves, honey, fruits, and vegetables. Quercetin is a polyphenolic flavonoid, is insoluble in water, and is soluble in DMSO. A PubMed search for “quercetin” yields an astounding 9568 articles, spanning the years 1948–2013. Quercetin also has other effects in cells, including scavenging reactive oxygen species (244) and inhibiting cytochromes p450, (245) monoamine-oxidase, (246) and DNA gyrase. (247) Although the effects of quercetin on acetyltransferases have not yet been fully analyzed, an IC₅₀ for p300 was measured at 100 μM. However, they isolated p300 from cells that were treated with the compound, and tested the purified enzyme for acetyltransferase activity, and therefore the effects of quercetin on p300 activity could be indirectly mediated by another factor, such as by altering p300 phosphorylation. (248)

Another natural product found to have acetyltransferase inhibitory properties is ochratoxin A. Ochratoxin A is produced by certain bacteria in the Aspergillus and Penicillium genuses, it is poisonous, and humans are believed to be exposed to substantial amounts of ochratoxin A in their environment and food. (249) It is a bicyclic lactone and is soluble in water and organic solvents. A PubMed search for “ochratoxin A” yields 2410 articles, spanning the years 1965–2013. Although detailed analysis of its acetyltransferase target or its mode of action has not been done, it appears to inhibit acetyltransferase(s) with moderate potency (IC₅₀ of 25 μM). (250)

The final natural product discussed here, which was found to have acetyltransferase-inhibitory properties, is a prostaglandin, specifically Δ12-PG-J2 (see Figure 9). (251) Prostaglandins are fatty acids with important functions in the human body, and Δ12-PG-J2 is a decomposition product of PG-D2, which is a major prostaglandin produced by mast cells, and is found in mast cells and brain cells. The “Δ12” indicates that it is unsaturated at the twelfth carbon along the chain, and the “J” refers to the α,β-unsaturated cyclopentanone moiety. Prostaglandins are slightly soluble in ethanol and insoluble in water. PG-J2 derivatives are natural activating ligands of the nuclear receptor PPARγ. (252) The electrophilic carbon in the cyclopentanone moiety appears to be attacked by the p300 cysteine 1438 to form a covalent adduct with reduced acetyltransferase activity. (253) It is relatively potent against p300 (IC₅₀ of 750 nM) but not Pcaf (no detectable inhibition at 5 μM), and also inhibits acetylation in cells (ED₅₀ of 5 μM by immunoblotting against acetyl-K9/K14 H3 in HepG2 cells).

Figure 9. Natural products implicated as modulators of acetyltransferases.

4.3 Synthetic Acetyltransferase Inhibitors

Apart from natural products, several small molecules and other synthetic compounds have been found to have acetyltransferase-inhibitory activity through various chemical screens. Isothiazolones with acetyltransferase-inhibitory properties were identified in 2005 (see Figure 10). (254) A series of isothiazolone analogs were compared for potency against Pcaf (which was as low as an IC₅₀ of 1 μM (255, 256)) and p300 (which was as low as an IC₅₀ of ∼30 μM), and many were Pcaf-specific. Interestingly, no inhibition was observed in the presence of 1 mM DTT, (253) implying that these compounds may not work well in reducing intracellular conditions, and also implying a possible mechanism. The nitrogen–sulfur bond is thought to be weak and susceptible to cleavage by thiols, such as via reaction with an acetyltransferase cysteine, to produce a disulfide adduct. (257) Consistent with this, isothiazolones also inhibit the cysteine protease cathepsin B, although certain structural analogs exhibit >20-fold selectivity for Pcaf over cathepsin B. (258) Intriguingly, the isothiazolone Kathon CG, an ingredient in cosmetics, was found to have potent inhibition of Pcaf and caused decreased cell growth. (259)

Also in 2005, quinoline compounds were found to have acetyltransferase-inhibitory properties (see Figure 10). Inhibition of Gcn5 by the quinoline MC1626 was first implicated by chemical genetic studies, (260) but the effects observed were subsequently thought to occur via a Gcn5-independent mechanism in cells. (261) However, several quinoline analogs were determined to have bona fide modest potency against p300 and CBP (IC₅₀ as low as 25 μM) but little or no inhibition of Pcaf or Gcn5. (262, 263) Intriguingly, the quinoline HCQ (hydroxychloroquine, an antimalarial drug) and a structurally unrelated all-trans retinoic acid were found to stimulate Pcaf activity (1.5–2-fold at 1 μM). (264) A larger molecule that contains a quinoline moiety, called montelukast, which is a leukotriene receptor antagonist and used to treat asthma and allergies, was found to inhibit cellular NFkB-associated acetyltransferase activity with submicromolar potency, although potentially indirectly. (265)

Another class of compounds found to have acetyltransferase-inhibitory properties is the thiazoles (see Figure 10), including the compound CPTH2, which has weak potency (high-mM IC₅₀) against Gcn5. (266) A compound that bears some structural similarities to the thiazoles is the so-called compound a (see Figure 10), found by the Zheng lab to have acetyltransferase-inhibitory properties. (267) This compound appears to have weak potency against several acetyltransferases, including Tip60 (IC₅₀ of 149 μM), yeast Esa1 (IC₅₀ of 190 μM), and p300 (IC₅₀ of 150 μM).

Virtual screening of a commercially available library of ∼500 000 compounds started with in silico docking to the acetyl-CoA binding pocket of the p300 acetyltransferase domain. (152) Compounds with predicted binding affinity were then screened by various assays with purified p300 acetyltransferase domain. This led to the identification of three inhibitors of p300, which all shared a linear arrangement of 3 or 4 aromatic rings terminating in a benzoic acid. Despite this apparent structural similarity, the steady-state kinetic mechanism of each inhibitor was distinct. Compound C646 appeared to act by competition with acetyl-CoA but not with peptide substrate, which was consistent with the original docking model and further validated by site-directed mutagenesis (of the residues highlighted in Figure 11). Although C646 contains a potentially electrophilic group, its inhibition of p300 appeared to be noncovalent. C646 was fairly potent against p300 (K_i of 400 nM) and had at least 8-fold selectivity versus Pcaf, Gcn5, yeast Rtt109, Sas histone acetyltransferase, MOZ histone acetyltransferase, and serotonin N-acetyltransferase. C646 was also proven to inhibit acetylation in cells, making it an attractive probe for p300/CBP acetyltransferase studies.

An analog of C646, C107, retains potency as a p300 acetyltransferase inhibitor, as measured against purified enzyme and in cells by acid-urea gel analysis. In assays where C646-induced fluorescence interferes with measurements, C107 appears to be a valid substitute as it lacks the intrinsic fluorescence properties of C646. (140) It also lacks the pharmacologic liabilities commonly associated with furan rings, but still retains most of the same structural features of C646, including a five-membered heterocycle that may cause off-target effects. (268, 269)

Figure 10. Synthetic inhibitors of acetyltransferases.

Figure 11. C646 modeled in the acetyltransferase active site. (A) C646 is shown in magenta, computationally docked in the crystal structure of the acetyltransferase active site, which was generated as a cocrystal with Lys-CoA. Several residues that coordinate CoA binding are predicted to similarly coordinate C646 binding, as shown in aqua stick representations of the side chains. (B) The structure of C646, shown in an orientation similar to that in the docked model above.

5 Protein Ligands of p300/CBP

Click to copy section linkSection link copied!

5.1 Structures of p300/CBP with Bound Protein Ligands

Another factor in the functions, catalysis, and inhibition of p300 is interactions of domains that flank that catalytic domain. On the N-terminal side of the p300 catalytic domain is a bromodomain, and on the C-terminal side is a cysteine-histidine rich (C/H3) domain. Many proteins have been identified that bind to these domains (see Supporting Information Table 2). These ligands include acetylated proteins that interact with the p300 bromodomain, such as histones (for example, histone H4 acetylated at K20, (270) and H3 in the context of chromatin (271)), MyoD (acetylated at K99, K102), (272, 273) STAT3 (acetylated at K49, K87), (274) p53 (acetylated at K382), (275) CtBP, (276) and HIV Tat (acetylated at K50). Many proteins bind the C/H3 domain, including NUT, (277) adenoviral E1A, FOS, Pcaf, (278) Gcn5, TFIIB, p53, FOXO3a, STAT1, and MEF2. (279) There are some ligands that seem to bind both the bromodomain and the C/H3 domain, such as p53 and MyoD. Furthermore, there may be crosstalk between ligand-binding domains, for example, between the p300 bromodomain and PHD finger in the C/H2 domain. (280)

Some of the p300–ligand interactions have been studied in structural detail by cocrystal X-ray diffraction (281) and solution binding NMR (282-286) analysis. Bromodomain binding typically occurs on one side of the four-helical bundle, and is mediated by the two loops between helices, although one crystal structure had an additional ligand bound against the side of the helix (see Figure 12). A recent study reports that the histone chaperone Asf1 binds the p300/CBP bromodomain in a noncanonical way. (287) A recent structure from Daniel Panne and colleagues reveals a potential intramolecular regulatory interaction between the p300 bromodomain and its neighboring acetyltransferase domain. (288) Structural features of these protein ligand interactions have been replicated by several recent synthetic ligands for the p300/CBP bromodomain, which will be discussed in section 5.3.

The TAZ2 region of the C/H3 domain appears to bind ligands in diverse conformations (see Figure 13). C/H3 binding to the N-terminal region of MEF2 appears to be via any of three distinct surfaces on the TAZ2 domain. The crystal structure had a MEF2 dimer with three bound TAZ2 domains, each in a different conformation. (289) C/H3 binding to the p53 TAD1 appears to be via extended interactions across a large part of the TAZ2 domain. (290) C/H3 binding to E1A appears to induce a helical structure in the CR1 region of E1A, which is otherwise unstructured. (291) A structure of C/H3 TAZ2 binding to STAT1 helps explain why TAZ2 binds STAT1 while TAZ1 binds STAT2, which occurs when the STAT1/STAT2 heterodimer engages p300 through both contacts. (292)

Figure 12. Structures of CBP bromodomain bound to ligands. The purified CBP bromodomain (residues 1081–1197, shown in a rainbow blue to red) is shown bound to (A) histone H4 residues 14–28 acetylated at K20 (PDB 2RNY); (B) p53 residues 367–386 acetylated at K382 (PDB 1JSP); (C) the compound ischemin (PDB 2L84); and (D) the compound dimethylisoxazole (PDB 3SVH). Peptide ligands are shown in gray (A,B) or stick models colored by atom (C,D and acetyl-lysines in A,B). All structures are based on solution NMR except for (D), which is from X-ray crystallography (1.8 Å).

Figure 13. Structures of p300/CBP TAZ2 domain bound to ligands. The TAZ2 domain is shown colored in a rainbow (blue to red, residues included listed below each) bound to various ligands: STAT1 (A, PDB 2KA6); E1A (B, PDB 2KJE); p53 (C, PDB 2K8F); MEF2-DNA complex (D, PDB 3P57), and C/EBPε (PDB 3T92). All structures are based on solution NMR except for two from X-ray crystallography: that in (D) (2.192 Å) and that in (E) (1.5 Å). All structures were produced using purified p300, except the (A) and (B), which used purified CBP. Zinc ions are black spheres, protein ligands are gray, and DNA is yellow. The crystal structure with MEF2 revealed binding in three possible conformations with TAZ2, and one example is shown here.

5.2 Flanking Domains on p300/CBP Acetyltransferase Activity

One well-documented effect of these p300–ligand binding interactions is to facilitate the formation of a transcriptionally activating complex. DNA-binding ligands could recruit p300 to gene elements. p300 could nucleate complex formation by serving as a scaffold, also interacting with general transcriptional machinery. Some p300 ligands are effector proteins that modulate chromatin or have other activities, which are brought into proximity with their chromatin substrate by the bridging p300. (293) Some p300 ligands have activities that are inhibitory to transcription, for example, HDAC1, which binds the p300 C/H3 domain, (294) and these corepressors could be relieved by competing interaction with an alternate ligand. By these mechanisms, regulated ligand binding changes the subnuclear targeting of p300 and other proteins, without necessarily influencing the catalytic function of p300 (see Figure 14).

Figure 14. Models for targeting influenced by p300-ligand binding. In these models, p300 is shown in green, the histone octamer is shown in yellow, DNA is shown with a red strand, and p300 ligands are indicated with an “L”. In (A), a ligand targets p300 to a gene or other DNA element due to the DNA binding affinity of the ligand. In (B), a ligand targets p300 to a protein complex due to the protein binding affinity of the ligand. In (C), two ligands bridged by p300 allow for chromatin (bound by the purple ligand) to come into proximity with a chromatin-modifying enzyme (the orange ligand). In (D), two ligands compete for the same site within p300, and the one ligand could be seen as a competitive inhibitor for the p300 association with the other.

One naturally occurring p300 ligand of interest is the protein Mastermind. Mastermind binds to the C/H3 domain of p300. (295) Mastermind received its name from researchers studying the Drosophila gene, and when describing the human homologue, it can also be known as Mastermind-like protein 1, MAM, MAM1, MAML, or MAML1, but these are all the same gene. Mastermind first became a gene of interest in C. elegans (where it has been called sel-8, lag-3, or pqn-17) when its mutation was found to suppress a mutation in lin-12 (human Notch3) (296) and subsequently found to function in the Notch pathway by binding LAG-1 (human CSL, a DNA-binding protein) and activating transcription. (297) When protein sequence homology was found between the human genes and those in model organisms, (298) this allowed researchers to understand how the Notch pathway works in humans. (299, 300) The first crystal structure of Mastermind was from C. elegans, and was in complex with Notch, CSL, and DNA, in which the Mastermind N-terminal region forms a long α helix resembling an arm, with a bend or elbow in the middle, that hugs around Notch and CSL. (301) Subsequent crystallography of the human proteins showed a comparable structure. (302-304)

We now know that when activated, Notch binds CSL and Mastermind, and this complex associates with DNA via CSL (see Figure 15). The core complex then recruits transcriptional coactivators, including p300 and Pcaf. In addition to nucleating a transcriptional complex and being recruited to chromatin associated with Notch regulation, it was hypothesized that there are additional synergistic effects of the Mastermind–p300 interaction.

Figure 15. Mastermind-Notch-CSL-DNA core complex. The complex formed by DNA, CSL, Notch (ANK repeats and RAM region purified separately), and Mastermind N-terminal helix is shown with two different view angles. The X-ray crystal structure was generated at 3.85 Å, and this figure was produced in PyMol using Protein Databank entry 3V79. Proteins are shown as ribbons, with the surfaces at 70% transparency. DNA is shown as stick models colored by atom.

Interestingly, it was shown that Mastermind can activate p300 acetyltransferase catalysis. (305) The effect of Mastermind on p300 acetyltransferase catalysis was dose-dependent and appeared to enhance the maximal acetylation rate of p300 and not the binding of p300 to peptide substrate. In cells, Mastermind increased p300 autoacetylation, measured using immunoblotting, and increased transcriptional coactivation, measured using a luciferase reporter. Mastermind and p300 were recruited to nuclear bodies, (306) and these nuclear bodies had enhanced histone H3 and H4 acetylation. A remaining question is how the events are timed. A simple model would be that first Mastermind binds to the C/H3 domain of p300, and this promotes activation of p300 acetyl transfer, leading to its increased autoacetylation, acetylation of histones, acetylation of Mastermind, p300–Mastermind targeting to nuclear bodies, and transcriptional coactivation (see Figure 16). This is supported by the loss of Mastermind activation of p300 autoacetylation when the C/H3 domain is deleted. (313) A further observation is that the activation loop (residues 1523–1554) is not required for Mastermind effects on p300 autoacetylation (at lysine 1499) or transcriptional activation. However, some of the data argue against this simple model; for example, p300 lacking the C/H3 domain still gets targeted to nuclear bodies by Mastermind. (313) It is also still unknown how and when these steps are reversed, and one clue is that acetylation decreases the binding affinity between Mastermind and p300. (307) Therefore, Mastermind may first associate with p300, turn it on, and then dissociate. (308)

It also remains to be seen whether these trends observed with Mastermind will extend to other p300 ligands. Because there are more than one ligand that interact with the C/H3 domain, there may be a common mechanism by which they influence p300 catalysis, or it may vary entirely depending on the specific ligand in question. Interestingly, a ligand of the p300 bromodomain, called CtBP, appears to change p300 acetyltransferase activity via steric hindrance that blocks other substrates. (309) Furthermore, many ligands of other p300 domains, and their effects on p300 catalysis, are still being uncovered and investigated. It could be hypothesized that ligand binding could influence substrate specificity through direct competition for the same binding site or conformational changes in the binding pockets of p300/CBP or the multiprotein complex. Ligand binding could also theoretically change the catalysis itself via long-range conformational changes in the region that binds acetyl-CoA or the residues involved in catalysis.

In purified p300, the flanking bromodomain and C/H3 domain have a significant effect on catalysis in the absence of ligands. p300 BHC (a construct containing the bromodomain, catalytic acetyltransferase domain, and C/H3 domain) is considerably more efficient as a histone acetyltransferase than the p300 acetyltransfarase domain, with a 5-fold higher k_cat. (140) Even more dramatic, p300 BHC has a 10-fold lower K_m for acetyl-CoA. Interestingly, the small molecule inhibitors C646 and C107 appeared to show about 4–5-fold reduced potency against BHC acetyltransferase activity versus the isolated acetyltransferase domain. However, another study showed different results. (310) The bromodomain-HAT crystal structure suggests the potential for intramolecular interactions that can be communicated between the domains. (311)

Figure 16. Model for Mastermind activation of p300. In this model, p300 (green) initially has inhibited acetyltransferase activity due to an autoinhibitory loop (orange, left). This is relieved upon recruitment by the Notch-Mastermind-CSL complex. Mastermind (purple) binds to the p300 C/H3 domain, and also to Notch intracellular domain (magenta) and CSL (red). p300 autoacetylation, Mastermind acetylation, and histone acetylation are then catalyzed by p300 (turquoise ▲).

5.3 Compounds That Block or Mimic p300/CBP Ligand Binding

Recent progress has been made in developing inhibitors of bromodomain interactions (reviewed by Filippakopoulos et al. (312)). Several compounds have been identified that inhibit BET bromodomains, such as I-BET762/GSK525762A, (313) I-BET151/GSK1210151A, (314, 315) JQ1, (316) PFI-1, (317, 318) and various isoxazoles. (319-321) These have proven useful in a variety of exciting biological applications, including in HIV, (322-325) merkel cell polyomavirus, (326) leukemia, (327-331) lymphoma, (332) multiple myeloma, (333) lung adenocarcinoma, (334) inflammation, (335-337) kidney disease, (338) and fertility (339) research. Low micromolar inhibitors of other bromodomains have also been reported. (340) In general, bromodomain inhibitors may block the binding interactions of many different protein ligands, often complicating analysis of single ligand interactions in cells. (341-345)

Compounds that target the p300/CBP bromodomain have been identified by the Structural Genomics Consortium (SGC) and Ming–Ming Zhou’s group (see Figure 17). MS7972 appears to inhibit the p300/CBP bromodomain with an affinity of around 20 μM and undetermined specificity for other bromodomain-containing proteins. (346) The compound ischemin was identified that also appears to inhibit the p300/CBP bromodomain with affinity of around 20 μM and undetermined specificity for other bromodomain-containing proteins. (347) Cyclic peptides containing acetyl-lysine were designed to inhibit the p300/CBP bromodomain with an affinity of as low as 8 μM and undetermined specificity for other bromodomain-containing proteins. (348) Further compounds were identified that have an affinity for the p300/CBP bromodomain of around 0.39 μM and affinity for a BET bromodomain of around 1.4 μM. (349) The Brennan group tested a collection of [1,2,4]triazolo[4,3-a]phthalazines against a panel of bromodomains, and found several with submicomolar affinity for p300/CBP bromodomain, although all had relatively strong affinities for BET bromodomains. (350) The widely used analgesic acetaminophen (paracetamol) was also found to bind the CBP bromodomain, probably by a weak nonspecific interaction. (351) A series of 3,5-dimethylisoxazoles were found to have varying micomolar inhibitory properties against the p300/CBP bromodomain, although all still retained relatively potent inhibitory activity against BET bromodomains. (352) There is structural evidence that several of these inhibitors bind the bromodomain in a manner similar to that of the natural protein ligands (see Figure 12).

More recently, the compound named 59 was identified with affinity of around 32 and 21 nM for p300 and CBP bromodomains, respectively, and reported 40-fold or greater selectivity versus all 10 other bromodomains tested. Although promising, this compound did show some pan-inhibitory properties against several unrelated enzymes including adrenergic receptors, phosphodiesterase-5, and platelet-activating factor. (353)

Figure 17. Inhibitors of the p300/CBP bromodomain.

For the C/H3 domain, no inhibitors have been carefully studied to our knowledge, although there is some evidence to suggest that the drug Roscovitine (see Figure 18), also known as Seliciclib, which is an inhibitor of cyclin-dependent kinase (CDK), may in fact inhibit the interaction of p300 C/H3 and CDK. (354)

The KIX domain (located before the N-terminus of the bromodomain) is the target of several small molecules. The compound napthol AS-E (see Figure 18) appears to bind the KIX domain with an affinity of 8.6 μM and undetermined specificity. (355) The NMR structure was obtained of the KIX domain in complex with the phosphorylated compound, known as KG-501 (identical to napthol AS-E except the hydroxyl group is replaced with a phosphate group). This compound was the first KIX inhibitor identified, (356) and was subsequently reported to be converted to more-active napthol AS-E in the cell medium prior to cellular entry. (362) In the costructure, KG-501 does not directly compete for ligand binding. Rather, it binds at a site that is known to dynamically regulate binding interactions at the distal groove. (363) It is likely that the active dephosphorylated compound binds in a similar manner. The effect of binding allosterically inhibits the binding of the CREB KID domain, inhibits CREB-mediated gene induction, but appears to increase histone acetylation. (362, 363) At around the same time, a series of isoxazolidine-containing molecules named iTADs were described (357) that bind in the same binding site of KIX as transactivation domains of proteins such as MLL, c-Jun, and Tat. (358) iTAD1 (see Figure 18) binds KIX with an affinity of around 38 μM and promiscuously binds other proteins known to also interact with transactivation domains, such as TRRAP and Med23. Binding of iTAD to KIX competitively inhibits endogenous transactivation domain-containing ligands from binding the same site, while activating CBP activities that are normally induced by protein ligand binding. (359) The addition of a DNA-binding moiety to iTAD can allow activation of the associated gene by recruiting the active CBP. (360) The CBP KIX domain may also be the target of the compound ICG-001 (see Figure 18), which appears to block the association of CBP with β-catenin, and decrease expression of genes usually induced in the Wnt/β-catenin/CBP pathway. Although the specificity of this compound is not known, nor the exact binding mechanism, it does show promising effects in animal models of colon cancer, myocardial infarction, pulmonary fibrosis, and fibrotic kidney disease. (361-364)

More recently, two natural products from lichen, sekikaic acid and lobaric acid (see Figure 18), were found to have KIX-binding properties, in addition to their other known activities. (365) Sekikaic acid and lobaric acid inhibit the KIX interaction with the ligand MLL with IC₅₀ values of 34 and 17 μM, respectively. Interestingly, they also inhibit the binding of the KID domain of CREB, at a distinct binding site within KIX, with IC₅₀ values of 64 and 25 μM, respectively. Furthermore, the interaction appears to have some specificity, because the binding of Med15 and its cognate transactivation domain within VP16 was not inhibited by sekikaic acid. The effect is a downregulation of p300/CBP-mediated gene expression, including the Cyclin D1 gene normally induced by c-Jun through its interaction with KIX.

The binding of the C/H1 region of p300/CBP with the protein ligand HIF-1α has also been the target of inhibition studies. Several epidithiodiketopiperazine (ETP) compounds have been found to inhibit this interaction, including the fungal natural products chaetocin and chetomin, (366) as well as the synthetic ETP 3 (see Figure 18). (367) Chetomin and ETP 3 both bind to C/H1 (K_D values of 540 and 750 nM, respectively) and inhibit HIF-1α binding (IC₅₀ values of 540 and 1500 nM, respectively), probably by disrupting the global folding of the domain, which prevented hypoxia-induced gene induction in cultured cells. The specificity of these compounds for the p300/CBP C/H1 has not yet been studied, but it will be interesting to see whether the promising effects that these compounds have on animal models are due to the p300/CBP inhibition or another target. Another compound, called KCN1 (see Figure 18), appears to inhibit p300/CBP interaction with HIF-1α, although by an unknown mechanism. (368)

Figure 18. Inhibitors of the other p300/CBP domains.

6 Potential Applications for Inhibitors and Activators of p300/CBP

Click to copy section linkSection link copied!

6.1 Loss of p300/CBP Activity in Human Disease

Given the pivotal role of p300/CBP in essential cellular functions, it is not surprising that p300 homozygous knockout, CBP homozygous knockout, p300/CBP double homozygous knockout, and p300/CBP double heterozygous knockout are lethal in mammals. (369, 370) These gene dosage effects provide further evidence for the existence of a limiting pool of p300/CBP that may allow for differential p300/CBP recruitment depending on signaling pathway activation.

Furthermore, single heterozygous loss-of-function mutations, in p300 or CBP, are one of the known causes of Rubinstein–Taybi syndrome (abbreviated RTS or RSTS), a congenital developmental disorder. The frequency of RTS is approximately one affected individual out of every 100 000 newborns. (371) p300/CBP mutations that cause RTS are usually de novo mutations (i.e., not inherited from either parent), but in the extremely rare cases of vertical transmission, inheritance is Mendelian autosomal dominant. (372)

p300/CBP mutations that cause RTS are found in the germline of the patient, can occur in any of several p300/CBP exons (and disrupt any of several p300/CBP protein domains), and are usually point mutations or small deletions or insertions (which can cause truncations (371, 373)), but can also be translocations, inversions, or large deletions. (374)

40% of RTS patients either have unknown RTS etiology, or may be more appropriately diagnosed with a different (but phenotypically similar) syndrome, such as Saethre–Chotzen syndrome (caused by mutations in TWIST1) or Mowat–Wilson syndrome (caused by mutations in ZEB2). (375) Approximately 55% of RTS patients have germline mutations in CBP, and approximately 5% of RTS patients have germline mutations in p300. (374) RTS patients with p300 mutations often have milder phenotypes than those with CBP mutations. (376-378) In RTS patients, CBP mutations are more common than p300 mutations, but in the human population, single-nucleotide polymorphisms in general are more common in the p300 gene than the CBP gene. (379) It has therefore been hypothesized that p300 germline mutations could be associated with a disorder or phenotype other than classical RTS, which has yet to be found.

RTS is characterized by postnatal growth deficiency, mental retardation, skeletal and cardiac abnormalities, psychomotor development delay, and a dysmorphology involving broad thumbs and big toes, short stature, and characteristic facial features. (380) Cells taken from these patients have reduced acetylation of histones, particularly H2A and H2B, as compared to control cells, (381) further implicating the loss of function of p300/CBP in the disease etiology. Another phenotype of RTS is an increased likelihood to develop cancer. About 5% of children with RTS develop tumors of neural crest origin. (382) It has been hypothesized that such tumors might have somatic mutations in the remaining p300/CBP allele. (383)

Apart from RTS-associated tumors, loss-of-function in p300/CBP has been implicated in several additional cancers with somatic mutations in p300 or CBP. One study, which screened 103 cancer cell lines, examined loss of heterozygosity (LOH) and found that 51% of the cell lines had LOH at the p300 locus and 35% had LOH at the CBP locus (with 19% of the cell lines having LOH at both loci), (384) and these numbers are consistent with another study of 203 cancer samples, which found 35–50% of primary ovarian, colon, and breast tumors had LOH at the p300 locus. (385) In another study, 222 cancer samples were examined, and while only 1% of the samples had mutations in CBP (heterozygous truncations), 3.6% of the samples had LOH at the p300 locus (either by mutation or by silencing of one p300 allele) combined with a truncation in the remaining p300 allele. Similarly, in a study of colorectal and gastric carcinomas, LOH at the p300 locus was combined with missense mutations in the remaining p300 allele. (386) These data are consistent with a “two-hit” inactivation model, which is characteristic of tumor suppressors. However, other genes are also located within the regions lost in many of these large deletions, so that LOH may only be part of the story.

Furthermore, p300 mutations identified in primary tissues were found in solid tumors of colorectal, breast, and gastric tissue, while p300 mutations identified in cell lines were found in colorectal, breast, ovarian, pancreatic, oral squamous cell, and cervical cancers. (387) A recent study of B-cell non-Hodgkin’s lymphoma identified CBP (or more rarely p300) heterozygous loss of function mutations in 40% of samples, (388) while another study of 154 lung cancer samples identified mutations in 5–10% of samples. (389) These cancer-associated p300/CBP mutations were found in several p300/CBP exons, without any obvious connection between the p300/CBP protein domain disrupted in each case and the phenotypes observed.

While these mutation screening studies may be largely correlative, several experiments have helped establish the p300/CBP mutation as being causative. In one study, carcinoma cell lines with p300 truncation mutations (but not cancer cell lines without p300 mutations) acquired a reduction in proliferation when transfected with full-length, wild-type p300 (although not CBP), further implicating the p300 mutation in the cancerous phenotypes of this cancer. (390) In a recent study of acute lymphoblastic leukemia (ALL), cells were taken from 71 ALL patients at the time of diagnosis and again at the time of relapse, and CBP loss of function mutation was found to correlate with patients acquiring resistance to therapy. (391)

In addition to p300/CBP mutation, another mechanism by which p300/CBP may experience loss of function in cancer is through decreased expression, selective degradation, or both. This was explored in a study in which prolonged activation of Ras signaling and platelet-derived growth factor (PDGF) signaling, which are known to cause cancer, also causes reduced p300/CBP expression and proteasomal degradation. These experiments were performed in NIH 3T3 fibroblasts, but the decreased p300/CBP protein levels might be relevant in cancers involving Ras, PDGF, and possibly other pathways. (392) Another observation of decreased p300/CBP expression was made in certain breast and colorectal carcinomas (but not in bladder, renal, or ovarian tumors) (393) and in a similar study finding decreased p300 expression in breast and prostate cancer (but not in cervical cancer). (394) A third example was observed in instances of acute myeloid leukemia that were caused by a translocation in which MOZ is fused with TIF2, (395, 396) and this oncogenic chimeric protein bound to p300/CBP and resulted in decreased p300/CBP protein levels by an unknown mechanism. (397)

In summary, p300/CBP partial loss of function can contribute to cancer in humans. This result may seem paradoxical, becausep300/CBP total loss of function prevents cell growth, but one explanation is that p300/CBP acts in concert with tumor suppressor proteins. One such example is in the TGF-β pathway, which involves the tumor suppressors TGF-β, Smad2, Smad4, and RUNX. (398) In this pathway, TGF-β signaling results in the transcriptional activation of target genes, and this transcriptional regulation requires p300/CBP in cooperation with Smads and RUNX. Another example of a tumor suppressor protein is p53, (399) which is acetylated by p300/CBP, contributing to its stability. In addition, p53 binds to p300/CBP to form a coactivator complex with DNA, and utilizes the acetyltransferase activity of p300/CBP to activate target gene expression. Another tumor suppressor protein that is regulated by p300/CBP is retinoblastoma protein Rb, whose acetylation decreases its phosphorylation, (400) and the acetylation of the associated E2F increases its ubiquitylation. (401)

To further explore p300/CBP loss-of-function in RTS and cancer, several mouse models have been developed. Mouse models of RTS with heterozygous truncation in CBP (402) or p300 (403) have phenotypes that mimic RTS, and consistent with observations in humans, the p300 mutants had milder phenotypes. Mice with heterozygous knockout of CBP also had hematopoeitic failure and hematological malignancy. (404) The role for p300/CBP in hematopoiesis is not surprising, considering that over 56 proteins that bind p300/CBP are known to be essential for T and B cell production in mice. (405) Furthermore, in these malignant cells, there was often somatic loss of heterozygosity (LOH) at the CBP locus, which inactivated the wild-type allele, similar to LOH seen in human cancers.

Although embryonic lethal, homozygotes were successfully generated from these mice using a chimera strategy, and p300 or CBP knockout caused hematological malignancy. Interestingly, the type of hematological malignancy was different depending on whether p300 or CBP was mutated. (406) Another strategy to generate homozygous knockouts of p300 and/or CBP utilized flanking LoxP sites to create conditional deletions, dependent on the presence of Cre recombinase, that was used to inactivate p300 and/or CBP in thymocytes. In this study, loss of CBP (but not p300) occasionally caused T cell lymphoma, but neither loss consistently resulted in drastic T-cell phenotypes, while loss of both p300 and CBP caused T cells to die. (407)

Taken together, these studies using mouse genetics validate the role of p300/CBP loss-of-function in RTS and cancer, confirm our understanding of p300/CBP gene dosage and a limiting pool of p300/CBP protein, and provide further evidence of subtle functional differences between the p300 and CBP paralogs. Diseases involving loss-of-function of p300/CBP could theoretically be treated using compounds that chemically complement point mutations in the acetyltransferase active site, (408) stimulate p300/CBP activity, or inhibit deacetylase activity. Studies of loss-of-function serve as a caution that activity inhibitors might be contraindicated in certain patients, and correct dosing would need to be optimized to minimize harmful consequences of too little p300/CBP activity.

6.2 Overexpression, Inappropriate Activation, or Mistargeting of p300/CBP

While loss-of-function in p300/CBP is deleterious, gain-of-function in p300/CBP also contributes to human disease, because the correct balance of acetylation and deacetylation, in the right time and place, is required for normal cell functioning. This section explores cases of gain-of-function in p300/CBP, either by direct mutation or overexpression of p300/CBP or by the involvement of p300/CBP in the disease etiology, as well as additional instances where disruption of p300/CBP activity would be therapeutically advantageous (see Figure 19).

Figure 19. Diseases of potential therapeutic application for a p300/CBP inhibitor. No p300/CBP inhibitor has yet made it into clinical trials, but the biology of p300/CBP action and documented effects of p300/CBP disruption lead us to hypothesize a beneficial therapeutic potential for a p300/CBP inhibitor in many diseases.

There are several instances where p300/CBP overexpression has been found to correlate with cancer. In one study of 209 normal nasopharyngeal mucosa and nasopharyngeal carcinoma samples, p300 expression correlated with malignancy, aggressive behavior of the carcinoma, and poor patient prognosis. (409) Furthermore, in a study of 123 hepatocellular carcinoma samples, plus 123 matching adjacent nonmalignant liver tissue samples, p300 expression correlated with malignancy, tumor size, poor differentiation, tumor progression, and poor prognosis. (410)

Overexpression of p300 is also present in many hormone-dependent cancers. In one study of 183 breast cancer samples, (411) and another that included matched normal breast tissue, (412) p300 expression correlated with malignancy, activation of the hypoxia response, and dominant-negative mutant p53 levels. In a study of 95 prostate cancer samples, (413) and another of 92 prostate cancer samples, (414) p300 expression correlated with phenotypes of malignancy, including proliferation, tumor volume, extraprostatic extension, seminal vesicle involvement, tumor progression, nuclear alterations, and poor prognosis. Furthermore, p300 knockdown resulted in decreased prostate cancer cell proliferation. Targeting p300 in these cancers could also decrease hormone receptor acetylation, which would modulate sensitivity to hormones and drugs like tamoxifen. (415)

Genomic profiling in 101 melanoma samples provides evidence for p300 overexpression in this cancer. (416) Subsequently, profiling of samples from 358 melanoma patients revealed that p300 levels were increased in the cytoplasm while decreased in the nucleus, (417) and that the increase in the cytoplasm correlates with melanoma progression, tumor size, and ulceration status. (418) Furthermore, in normal melanocytes, decreased p300/CBP protein levels correlate with activation of replicative senescence, and because senescence is broadly tumor-suppressive, this prompted the study of p300/CBP inhibitors in melanoma. Indeed, inhibition of p300/CBP reduced proliferation and induced senescence in melanoma cells, (419) as well as sensitizing cells to DNA damage, which increases the interest in potential combination therapies of p300/CBP inhibition plus DNA damaging agents. (420)

This advantageous combination with DNA damage has also been demonstrated for colorectal cancer. In one report using colorectal cancer cells, p300 knockout strains were generated, and they responded to DNA damage by undergoing apoptosis at a greater rate than cells expressing p300. Moreover, xenografts of the p300 knockout cells were hypersensitive to doxorubicin, a cancer therapeutic that induces DNA damage. (421)

In the case of certain hematological malignancies, part of p300 or CBP is translocated such that it becomes fused with another protein, creating an oncogenic fusion protein with inappropriate p300/CBP activity. These translocations are more common for CBP than p300, and this is thought to be due to an unstable genomic element near the 5′ end of the CBP gene, (422) although breakpoints in the second intron have also been described as occurring often. (423) Truncations near the 5′ end of the CBP gene result in loss of the regulatory N-terminal portion of CBP, may activate the catalytic acetyltransferase domain, and may target the fusion protein to inappropriate genes or substrates.

One example fuses the monocytic leukemia zing-finger (MOZ) gene with CBP (or in rare cases, with p300), (424-426) and is found in acute myeloid leukemia (AML). Another example fuses the gene for MOZ-related factor (MORF), with CBP, and is also found in AML, but less frequently than for MOZ. (427-430) A third example fuses the mixed lineage leukemia (MLL) gene with p300 or CBP, (431-434) is found in patients with infantile acute leukemia and patients with treatment-related leukemia, and has been studied using a conditional knockin mouse model. (435)

A further avenue of gain-of-function in p300/CBP is through the action of oncogenes that misappropriate p300/CBP in their transformation of cells. One such example is in acute myeloid leukemia, which can be caused by an oncogenic fusion of AML1 and ETO genes. Leukemogenesis induced by AML1-ETO involves binding of this fusion protein with p300/CBP, acetylation of the fusion protein by p300/CBP, and the activation of target genes. (436) Another example is in NUT midline carcinoma, which is caused by oncogenic fusions of the NUT protein, including BRD4-NUT and BRD3-NUT. Malignant cell transformation by BRD4-NUT involves binding of this fusion protein with p300/CBP, translocation of this complex to nuclear foci, and stimulation of p300/CBP catalytic activity at these foci. (437) Another way that p300/CBP can be required for the activity of oncogenes is by controlling the transcription of those oncogenes, which is true for the immediate early proto-oncogenes c-jun and c-fos. (438) These are oncogenic transcription factors, and they, as well as c-myb, (439) utilize the action of p300/CBP in activating target genes in their oncogenic pathways.

Another example of gain-of-function in p300/CBP is in viral transformation. Transformation occurs when a virus usurps the cell’s p300/CBP to promote the viral life cycle, and in so doing confers inappropriate activities on p300/CBP, and as a result the cell becomes immortalized. p300 was first identified because of its ability to bind the adenoviral E1A protein, and subsequent experiments have elucidated the essential role of the interaction with p300/CBP in transformation of the host cell. Likewise, the papillomaviral E6 protein and the viral SV40 large T antigen protein require interaction with p300/CBP for cellular transformation. (440)

Chromatin modifiers, including p300/CBP, are also being explored as therapeutic targets for treating retroviral infections, such as HIV. Part of this is because the viral genome expression is impacted by host chromatin dynamics, (441) including in HIV LTR transcription initiation and the reversal of viral latency. (442) To that end, targets that have been investigated include the lysine demethylase Lsd1, (443) lysine deacetylases, and lysine acetyltransferases. Furthermore, p300/CBP might be dually useful for HIV treatment because the HIV lifecycle involves p300/CBP acetylating the HIV Tat (444) and integrase proteins. (445, 446) There is also evidence that HIV Tat expression could cause the induction of p300 overexpression, (447) further demonstrating the potential benefit for testing p300/CBP inhibition in HIV treatment.

Genetic studies suggest a role for p300/CBP in platelet cell production, where disruption of p300/CBP can cause a high platelet count in a normal animal, or stimulate platelet production in a diseased animal. This is likely due to the involvement of p300/CBP in transcriptional control of genes involved in platelet and megakaryocyte production. p300/CBP disruption has proved a promising therapeutic option for several animal models of different types of thrombocytopenia. (448, 449)

Additionally, p300/CBP inhibition may prove therapeutic for heart disease. As mentioned above, patients with RTS and mice with p300 deleted have cardiac abnormalities, which is consistent with the role of p300/CBP in transcriptional control by cardiac factors such as MyoD, MEF2, and GATA4/5/6. (450) On the other hand, overexpression of p300 has been shown to induce hypertrophy in cardiomyocytes. Treatment of cardiomyocytes with the hypertrophic agent phenylephrine has been shown to activate p300, and genetic knockdown of p300 or CBP inhibited the hypertrophy. (451)

p300/CBP is also a potential therapeutic target in diabetes. Hepatic gluconeogenesis is controlled at the transcriptional level by p300/CBP as cAMP signaling results in the activation of genes that drive glucose production. In the fed state, insulin signaling leads to p300/CBP phosphorylation, preventing its association with CREB and down-regulating glucose production. (452) In diabetic patients with decreased insulin or insulin insensitivity, disruption of p300/CBP activity could therefore reduce the transcription of CREB-controlled genes, and result in lower glucose production. In a related pathway that leads to type 2 diabetes, obesity, and nonalcoholic fatty liver disease, p300/CBP plays a role in transcriptional activation of genes in lipogenesis and fat accumulation in the liver. High glucose levels result in activation of p300/CBP, acetylation of carbohydrate-responsive element-binding protein (ChREBP), formation of a complex including p300/CBP and ChREBP, acetylation of promoter histone H4, and activation of target gene transcription. (453) p300 overexpression results in fat accumulation, insulin resistance, and inflammation of the liver, thus providing a further potential role for p300/CBP inhibition in the treatment of type 2 diabetes, obesity, and nonalcoholic fatty liver disease. (454)

In summary, p300/CBP is involved in a variety of different human diseases, including several where p300/CBP acetyltransferase inhibition may be of therapeutic value. Thus, understanding p300/CBP function, developing assays to measure p300/CBP activity in cells, and developing small molecule agents that target p300/CBP are of pharmacologic interest.

6.3 Cell-Based Assays of p300/CBP Activity and Inhibition

This section deals with studies in cultured cells of inhibitor target validation, pharmacodynamics, and studying the phenotypes downstream of p300/CBP modulation. A variety of techniques have been developed to study post-translational modifications; however, the understanding of acetylation has lagged behind some of the better-characterized PTMs, such as ubiquitylation and phosphorylation. In many cases, this may be due to technical challenges faced when studying acetylation.

For the separation and/or detection of acetylation states of proteins from cells and cell lysates, typical methods can involve acetyl-specific antibodies, specially formulated acid-urea gel electrophoresis, or mass spectrometry. Acid-urea gel electrophoresis and mass spectrometry require fixed time points of bulk populations of cells, and are conducted after cells are killed and lysed. Assays that involve antibodies include immunoblotting (also known as western blotting), immunoprecipitation (also known as pulldowns), chromatin immunoprecipitation (also known as ChIP), and immunohistochemistry (also known as immunofluorescence microscopy). Several antibodies have been developed that recognize either acetyl-lysine in general, or acetyl-lysine in the context of specific neighboring sequences. These antibodies have been, and continue to be, useful for a variety of studies, but their poor affinities and imperfect specificities are often a limitation. Of these techniques, only immunocytochemistry makes single cell analysis possible, which allows analysis of heterogeneity within a cell population, and also makes it possible to visualize subcellular spatial distribution of the signal. For conventional immunofluorescence, the cells must be fixed and permeabilized, which are known to be associated with disruptions to the sensitive structures in the cell. (455)

Each of these traditional techniques involves several steps between harvesting the cells and analyzing the signal, during which time the acetylation state could theoretically be altered. Acetyl-lysine-specific antibodies could be used in living cells via two possible methods. First, the antibody can be labeled with a dye and introduced into cells by microinjection or bead loading, (456-460) which are disruptive to cells, although less drastic than killing and lysing cells. Bead loading of antibodies or antibody fragments is less laborious and results in higher sample numbers than microinjection. In a second method for using antibodies in living cells, genetically encoded single-chain antibodies can be fused to fluorescent proteins, (461, 462) which is a promising strategy that has yet to be demonstrated for the study of p300/CBP. Both of these methods would theoretically be able to track the localization of acetylated proteins and any redistribution that might occur when p300/CBP is disrupted, but would not be capable of measuring changes in the total amount of acetyl-protein or the ratio of acetyl- to unmodified-protein, because the fluorescence level is constitutive.

To follow acetyltransferase-deacetylase activity in living cells, one potential method that has been applied to methylation is using bimolecular fluorescence complementation (BiFC). (463) Another approach is with bimolecular Förster resonance energy transfer (FRET). (464, 465) One group tagged bromodomain-containing proteins BRD2, TAFII250, and Pcaf with YFP, tagged histones with CFP, and measured the CFP–YFP interaction by flow cytometry. (466) The major limitation of this flow cytometry approach is that changes in acetylation dynamics within a single cell cannot be monitored in real-time. Also, the apparent changes in acetylation could be on an untagged substrate, providing it is in close enough proximity to the tagged subunit, and therefore the target site determination requires inference from mutagenesis studies.

As an improvement on these techniques, the Minoru Yoshida and colleagues developed a unimolecular FRET-based assay that allows the analysis of acetylation and deacetylation in single, living cells. (140, 467, 468) This methodology has proved useful for the dynamic analysis of other post-translational modifications, (469-473) including on histones, (474, 475) and has only recently been expanded to study acetylation, by the creation of reporters based on histone H4 lysine substrates and BRDT (binds acetyl-K5/K8) or BRD2 (binds acetyl-K12) bromodomains. These FRET experiments can show dynamics in real-time; for example, a baseline with normal acetyltransferase/deacetylase activity levels is established, followed by addition of drug, and the time-course of drug response is thereby followed in each cell. As a first demonstration of the technique, dose-dependent FRET decreases of about 20% (Y/C emission) after 2 h of treatment with trichostatin A (TSA), a deacetylase inhibitor, (476) were observed for the K5/K8 and K12 reporters. This could be reversed upon washout and the response of the K12 reporter (and to a lesser degree the K5/K8 reporter) could be blocked by BIC1, a compound that weakly disrupts the bromodomain that the reporter depends upon. Dose-dependent FRET increases of about 10% after 5 min of treatment with 20 μM C107, a p300/CBP acetyltransferase inhibitor, were observed for the K5/K8 reporter. (140) Similarly, FRET was increased by about 20% in cells with stably knocked down p300 or CBP as compared to control cells, for the K5/K8 reporter. Limitations of this assay include potential signal from intermolecular FRET such as in dense chromatin, disruptions to the cells from transfection agents and expression of a tagged histone, potential phototoxicity and photobleaching after long time-courses, and the inability to do time-courses for genetic disruption of p300/CBP as opposed to pharmacologic disruption. An exciting extension of this methodology would be to adapt it for high-throughput drug screening, such as by epifluorescence imaging in 96-well glass-bottomed culture dish format, with robotics to control the field of view in each well, and employing a microfluidic device for precise timing of drug delivery in each well.

In addition to target validation, an important question in drug discovery is whether disease phenotypes can be reversed by pharmacologic inhibition of p300/CBP. As discussed in section 6.2, overexpression or dysregulation of p300/CBP can contribute to cell transformation. Hallmarks of cancer include increased malignant cell growth (and evasion of pathways that could block growth or induce cell death such as apoptosis), increased blood vessel growth (angiogenesis), ability to multiply indefinitely (immortality), movement to distant sites and invasion of surrounding tissues (metastasis), aberrant metabolism, evasion of the immune system, chromosome abnormalities and DNA instability, and inflammation. (477, 478) Genetic knockout or knockdown of p300 has implicated p300 in pathways that favor growth and angiogenesis. However, as discussed in section 2.5, p300 has diverse functions as a scaffold and bridge, and thus it is unclear how significantly the acetyltransferase function of p300 contributes to these cellular phenotypes. p300 inhibitors can therefore also be used as tools to dissect the role of the catalytic activity in cellular pathways.

For these reasons, the various acetyltransferase inhibitors have been utilized in a variety of experiments aimed at measuring their biological effects. In fact, the anticancer properties of several natural products were described before their acetyltransferase-inhibitory properties were known. Because, to date, C646 is the most potent, specific, cell-permeable, small molecule inhibitor of p300/CBP that has been reported, we will focus on its applications in this section, but it should be noted that many of the effects have been phenocopied in studies with other acetyltransferase inhibitors such as curcumin.

One biological effect of acetyltransferase inhibition that can be measured is changes in gene expression, including genes involved in cancer. One study of a carcinoma caused by a BRD4-NUT fusion protein found that C646 interferes with the changes in gene expression seen with different expression levels of BRD4-NUT. (479) Another study found that C646 interferes with the c-jun and c-fos oncogene expression induced by growth factor. (480) A study of prostate cancer cell lines found that C646 interfered with expression of an NFκB subunit, (481) and a study of a hepatocellular carcinoma cell line found that C646 interfered with expression of microRNA-224. (482) When examining melanoma cell lines, C646 interfered with the expression of several genes involved in cell cycle regulation, DNA damage repair, and nucleosome assembly, while enhancing expression of the tumor suppressor protein p53. (483)

Other cancerous phenotypes have also been examined in the presence of p300 inhibition. C646 was observed to induce apoptosis and increase prostate-specific antigen secretion in prostate cancer cell lines. (484) C646 was observed to decrease the growth of leukemia cells but not control cells, and in a mouse model of leukemia, C646 was observed to improve white blood cell count, anemia, thrombocytopenia, and survival. (485) Inhibition of p300/CBP by genetic or small molecule approaches blocked regulatory T cells and enhanced immune surveillance of tumors. (486)

Other effects, unrelated to cancer, of C646 treatment in cells have been recorded. C646 was observed to interfere with tau phosphorylation, an event involved in neurodegeneration. (487) C646 was observed to interfere with the reprogramming of fibroblasts to produce induced pluripotent stem (iPS) cells. (488) In explants, C646 was observed to decrease hepatoblast production, while at the same time changing gene expression levels that relate to liver and pancreas cell fate. (489) In mice, C646 was observed to enhance the consolidation of fear extinction memory and long-term memory potentiation. (490)

6.4 Overlap between Genetic and Pharmacologic Disruption of p300/CBP

In contrast to small molecules, which have been developed that target less than 5% of the proteome, (491) RNAi strategies have allowed for comparatively straightforward specific targeting of virtually every gene in the transcriptome, and, more recently, CRISPR/TALEN technology has made genomic editing even more accessible. As discussed in sections 6.1 and 6.2, genetic studies of p300/CBP have been useful in identifying phenotypes of p300/CBP knockdown or overexpression and understanding human diseases where p300/CBP has loss- or gain-of-function. However, there are examples in the biochemical literature where genetics and pharmacology specifically targeting the same gene or protein have led to different phenotypes. (490)

Phenomena that can cause apparent discrepancy between genetic and pharmacologic effects include protein level thresholds, compound allosteric effects, protein–protein binding independent of enzyme activity, and cellular compensation over time. (490) All of these could be expected to play a part in p300/CBP function, and it could be predicted that p300/CBP would present such a dichotomy. For example, inhibitors target a particular function or activity, while genetic knockdowns and knockout target the total protein levels.

However, in general, the phenotypes of cells treated with p300/CBP inhibitors, RNAi-based knockdowns, and conditional knockouts all have common features. For the live-cell studies of histone hyperacetylation dynamics, a similar FRET increase was observed for C107 and shRNA against p300 or CBP. The real-time response to C107 was rapid and peaked at around 45 min after addition of C107, while the response to knockdown was measured after several passages of cells stably expressing the shRNA and compared to empty vector control cells. (140)

Cells with stable knockdown could compensate for prolonged p300/CBP deficiency by overexpressing another acetyltransferase with overlapping activity, (492) by downregulating deacetylase activity to restore the acetylation balance, or through other mechanisms. Indeed, the Brindle lab observed partial compensation through CRTC2 overexpression in their p300/CBP knockout cells. (493) Another acetyltransferase that could compensate is Gcn5, because mice with heterozygous mutation in Gcn5 and heterozygous mutation in p300 have greater lethality and phenotypic defects than either heterozygous mutation alone, arguing for functional overlap between Gcn5 and p300. (494) However, we observed that a chronic defect in acetylation was present in cells with p300 or CBP stable knockdown.

7 Future Directions

Click to copy section linkSection link copied!

Although many substrates, protein ligands, and target genes have been identified for p300/CBP, it is still unclear what fraction of the acetylome is catalyzed by p300/CBP and under what circumstances each occurs. Mutagenesis and methods to artificially introduce acetylated lysines (or their mimics) into proteins have been used to study some specific acetylation events, but others still have unknown functions. Another area of current investigation is the flanking domain interactions of p300/CBP, and determining how specific ligands regulate acetyltransferase activity and/or substrate specificity. Further studies with natural and synthetic ligands will prove useful to determine the effects of various protein ligand interactions. Finally, it remains possible that there are additional protein lysine acetyltransferases that have yet to be discovered, the identification of which may require high throughput screening and CoA capture compounds.

Recent progress has been made toward developing high-throughput assays to measure p300/CBP inhibition against purified enzyme and in cells, screening of natural product and synthetic compound libraries, and developing candidate molecules that could be active in vivo. Although several small molecule probes are available for research, there remains a need for better compounds with varied structures and improved pharmacokinetics that can be used in live animals.

Of the many theoretical medical applications of p300/CBP inhibitors, a few have been supported by encouraging data using cultured cells, such as certain models of solid tumors. A new era of p300/CBP biomedical research will emerge as new p300/CBP inhibitors are tested in animal disease models. Important questions will be what level of inhibition of p300/CBP defines an effective therapeutic window, and what the main toxicities of this inhibition will be.

It will be interesting to see whether future p300-specific and CBP-specific inhibitors have therapeutic value in distinct and/or overlapping disease states. Developing inhibitors for other acetyltransferases besides p300/CBP is also an area of potential significance to biomedicine.

Because epigenetic marks can function combinatorially (see section 2.3), it is possible that acetyltransferase inhibitors will be highly useful in combination therapies with other epigenetic modulators, in specific cases. In the cell, different post-translational modifications on the same segment of chromatin can combine to fine-tune the functional readout, and PTM reader domains are often found together in a large macromolecular complex. Furthermore, multiple PTM-altering abnormalities can be present in the same disease state. To exploit this, combination therapies have been explored for other epigenetic modulators, (495-497) but not yet for acetyltransferases. Also, along the lines of combination therapies, there is reason to believe that p300/CBP inhibitors will synergize in cancer cells with drugs that act by inducing DNA damage. (498) Furthermore, bifunctional drugs or “codrugs” that have two individual active moieties linked covalently may offer therapeutic advantages. (499)

8 Conclusion

Click to copy section linkSection link copied!

Three decades of research into p300/CBP, since the first report in 1985, have revealed its importance to normal cell health and etiology of disease. p300/CBP is a key enzyme in higher eukaryotes, where it acts as an effector in myriad major cellular signaling pathways, which modulate protein functions and gene expression in response to a variety of signals. This is accomplished by binding of over 400 protein ligands to its various protein interaction-mediating domains and the acetylation of ∼100 protein substrates. The unusual hit-and-run kinetic mechanism has permitted the identification of p300/CBP-specific acetyltransferase inhibitors, which have shown promising effects in studies in living cells. The protein acetylation and protein binding functions of p300/CBP are intricately interrelated, and both are targets of pharmacological interventions that may have considerable therapeutic applications.

Supporting Information

Click to copy section linkSection link copied!

Table of 98 protein acetylation substrates of p300/CBP and table of 411 protein binding partners of p300/CBP. This material is available free of charge via the Internet at http://pubs.acs.org.

cr500452k_si_001.pdf (254.15 kb)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!

Corresponding Authors
- Beverley M. Dancy - Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Hunterian 316, Baltimore, Maryland 21205, United States ; Email: [email protected]
- Philip A. Cole - Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Hunterian 316, Baltimore, Maryland 21205, United States ; Email: [email protected]
Notes
The authors declare the following competing financial interest(s): P.A.C. is a cofounder, advisor, and equity owner in the company Acylin Therapeutics that is developing HAT inhibitors. B.M.D. declares no competing financial interest.

Biographies

Click to copy section linkSection link copied!

Acknowledgment

Click to copy section linkSection link copied!

We thank the National Institutes of Health (NIH) and Flight Attendant Medical Research Institute (FAMRI) Foundation for funding.

Abbreviations

Click to copy section linkSection link copied!

Ac	acetyl
CBP	CREB (cAMP response element-binding) binding protein
CoA	coenzyme A
ED₅₀	half-maximal effective dose in a cell, tissue, or organism
HAT	histone acetyltransferase
HDAC	histone deacetylase
IC₅₀	half-maximal inhibitory concentration in solution with a purified enzyme
K	lysine
NAD	nicotinamide adenine dinucleotide
p300	E1A binding protein p300
PTM	post-translational modification
TSA	trichostatin A

References

Click to copy section linkSection link copied!

This article references 499 other publications.

1
Waddington, C. H. Endeavour 1942, 18
Google Scholar
There is no corresponding record for this reference.
2
Klar, A. J. Trends Genet. 1998, 14, 299
Google Scholar
2
Propagating epigenetic states through meiosis: where Mendel's gene is more than a DNA moiety
Klar, Amar J. S.
Trends in Genetics (1998), 14 (8), 299-301CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)
A review, with 21 refs., on epigenetic inheritance as illustrated by Drosophila and Schizosaccharomyces pombe.
3
Redon, C.; Pilch, D.; Rogakou, E.; Sedelnikova, O.; Newrock, K.; Bonner, W. Curr. Opin. Genet. Dev. 2002, 12, 162
Google Scholar
There is no corresponding record for this reference.
4
Dawson, M. A.; Kouzarides, T. Cell 2012, 150, 12
Google Scholar
4
Cancer Epigenetics: From Mechanism to Therapy
Dawson, Mark A.; Kouzarides, Tony
Cell (Cambridge, MA, United States) (2012), 150 (1), 12-27CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
A review. The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biol. processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clin. and preclin. results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.
5
Mukherjee, S.; Hao, Y. H.; Orth, K. Trends Biochem. Sci. 2007, 32, 210
Google Scholar
There is no corresponding record for this reference.
6
Moellering, R. E.; Cravatt, B. F. Science 2013, 341, 549
Google Scholar
There is no corresponding record for this reference.
7
Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
Google Scholar
7
Histone modifiers in cancer: friends or foes?
Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
8
Xing, S.; Poirier, Y. Trends Plant Sci. 2012, 17, 423
Google Scholar
8
The protein acetylome and the regulation of metabolism
Xing, Shufan; Poirier, Yves
Trends in Plant Science (2012), 17 (7), 423-430CODEN: TPSCF9; ISSN:1360-1385. (Elsevier Ltd.)
A review. Acetyl-CoA (CoA) is a central metabolite involved in numerous anabolic and catabolic pathways, as well as in protein acetylation. Beyond histones, a large no. of metabolic enzymes are acetylated in both animal and bacteria, and the protein acetylome is now emerging in plants. Protein acetylation is influenced by the cellular level of both acetyl-CoA and NAD+, and regulates the activity of several enzymes. Acetyl-CoA is thus ideally placed to act as a key mol. linking the energy balance of the cell to the regulation of gene expression and metabolic pathways via the control of protein acetylation. Better knowledge over how to influence acetyl-CoA levels and the acetylation process promises to be an invaluable tool to control metabolic pathways.
9
Daugherty, M.; Polanuyer, B.; Farrell, M.; Scholle, M.; Lykidis, A.; de Crécy-Lagard, V.; Osterman, A. J. Biol. Chem. 2002, 277, 21431
Google Scholar
There is no corresponding record for this reference.
10
Robinson, P. J.; An, W.; Routh, A.; Martino, F.; Chapman, L.; Roeder, R. G.; Rhodes, D. J. Mol. Biol. 2008, 381, 816
Google Scholar
10
30 nm Chromatin Fibre Decompaction Requires both H4-K16 Acetylation and Linker Histone Eviction
Robinson, Philip J. J.; An, Woojin; Routh, Andrew; Martino, Fabrizio; Chapman, Lynda; Roeder, Robert G.; Rhodes, Daniela
Journal of Molecular Biology (2008), 381 (4), 816-825CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
The mechanism by which chromatin is decondensed to permit access to DNA is largely unknown. Here, using a model nucleosome array reconstituted from recombinant histone octamers, we have defined the relative contribution of the individual histone octamer N-terminal tails as well as the effect of a targeted histone tail acetylation on the compaction state of the 30 nm chromatin fiber. This study goes beyond previous studies as it is based on a nucleosome array that is very long (61 nucleosomes) and contains a stoichiometric concn. of bound linker histone, which is essential for the formation of the 30 nm chromatin fiber. We find that compaction is regulated in two steps: Introduction of H4 acetylated to 30% on K16 inhibits compaction to a greater degree than deletion of the H4 N-terminal tail. Further decompaction is achieved by removal of the linker histone.
11
Neumann, H.; Peak-Chew, S. Y.; Chin, J. W. Nat. Chem. Biol. 2008, 4, 232
Google Scholar
11
Genetically encoding Nε-acetyllysine in recombinant proteins
Neumann, Heinz; Peak-Chew, Sew Y.; Chin, Jason W.
Nature Chemical Biology (2008), 4 (4), 232-234CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
Nε-acetylation of lysine is a reversible post-translational modification with a regulatory role that rivals that of phosphorylation in eukaryotes. No general methods exist to synthesize proteins contg. Nε-acetyllysine at defined sites. The site-specific incorporation of Nε-acetyllysine in recombinant proteins produced in Escherichia coli was achieved via the evolution of an orthogonal Nε-acetyllysyl-tRNA synthetase/tRNACUA pair. This strategy should find wide applications in defining the cellular role of this modification.
12
Guo, J.; Wang, J.; Lee, J. S.; Schultz, P. G. Angew. Chem., Int. Ed. 2008, 47, 6399
Google Scholar
There is no corresponding record for this reference.
13
Muir, T. W.; Sondhi, D.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6705
Google Scholar
13
Expressed protein ligation: A general method for protein engineering
Muir, Tom W.; Sondhi, Dolan; Cole, Philip A.
Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 6705-6710CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
A protein semisynthesis method-expressed protein ligation-is described that involves the chemoselective addn. of a peptide to a recombinant protein. This method was used to ligate a phosphotyrosine peptide to the C terminus of the protein tyrosine kinase C-terminal Src kinase (Csk). By intercepting a thioester generated in the recombinant protein with an N-terminal cysteine contg. synthetic peptide, near quant. chem. ligation of the peptide to the protein was achieved. The semisynthetic tail-phosphorylated Csk showed evidence of an intramol. phosphotyrosine-Src homol. 2 interaction and an unexpected increase in catalytic phosphoryl transfer efficiency toward a physiol. relevant substrate compared with the non-tail-phosphorylated control. This work illustrates that expressed protein ligation is a simple and powerful new method in protein engineering to introduce sequences of unnatural amino acids, posttranslational modifications, and biophys. probes into proteins of any size.
14
Karukurichi, K. R.; Wang, L.; Uzasci, L.; Manlandro, C. M.; Wang, Q.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 1222
Google Scholar
There is no corresponding record for this reference.
15
Huang, R.; Holbert, M. A.; Tarrant, M. K.; Curtet, S.; Colquhoun, D. R.; Dancy, B. M.; Dancy, B. C.; Hwang, Y.; Tang, Y.; Meeth, K.; Marmorstein, R.; Cole, R. N.; Khochbin, S.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 9986
Google Scholar
There is no corresponding record for this reference.
16
Johns, E. W.; Phillips, D. M.; Simson, P.; Butler, J. A. Biochem. J. 1961, 80, 189
Google Scholar
There is no corresponding record for this reference.
17
Phillips, D. M. Biochem. J. 1963, 87, 258
Google Scholar
There is no corresponding record for this reference.
18
Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
Google Scholar
18
Histone modifiers in cancer: friends or foes?
Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
19
Close, P.; Creppe, C.; Gillard, M.; Ladang, A.; Chapelle, J. P.; Nguyen, L.; Chariot, A. Cell. Mol. Life Sci. 2010, 67, 1255
Google Scholar
19
The emerging role of lysine acetylation of non-nuclear proteins
Close, Pierre; Creppe, Catherine; Gillard, Magali; Ladang, Aurelie; Chapelle, Jean-Paul; Nguyen, Laurent; Chariot, Alain
Cellular and Molecular Life Sciences (2010), 67 (8), 1255-1264CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
A review. The acetylation of protein Lys residues is a post-translational modification that critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. More recent reports have also demonstrated that numerous proteins located outside the nucleus are also acetylated and that this modification has profound consequences on their functions. This review describes the latest findings on the protein substrates acetylated outside the nucleus and on the acetylases and deacetylates that catalyze these modifications. Protein acetylation is emerging as a major mechanism by which key proteins are regulated in many physiol. processes such as migration, metab., and aging as well as in pathol. circumstances such as cancer and neurodegenerative disorders.
20
Glozak, M. A.; Sengupta, N.; Zhang, X.; Seto, E. Gene 2005, 363, 15
Google Scholar
There is no corresponding record for this reference.
21
Norris, K. L.; Lee, J. Y.; Yao, T. P. Sci. Signaling 2009, 2, pe76
Google Scholar
21
Acetylation goes global: the emergence of acetylation biology
Norris Kristi L; Lee Joo-Yong; Yao Tso-Pang
Science signaling (2009), 2 (97), pe76 ISSN:.
For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the acetylome that potentially rivals that of the phosphoproteome. The remarkably ubiquitous and conserved nature of protein acetylation revealed by these new studies suggests the regulatory power of this dynamic modification. The establishment of comprehensive acetylomes will change the landscape of protein acetylation, where an exciting research frontier awaits.
22
Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman, M.; Walther, T. C.; Olsen, J. V.; Mann, M. Science 2009, 325, 834
Google Scholar
22
Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
Choudhary, Chunaram; Kumar, Chanchal; Gnad, Florian; Nielsen, Michael L.; Rehman, Michael; Walther, Tobias C.; Olsen, Jesper V.; Mann, Matthias
Science (Washington, DC, United States) (2009), 325 (5942), 834-840CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technol. limitations have so far prevented a global anal. of lysine acetylation's cellular roles. We used high-resoln. mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromol. complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.
23
Chen, Y.; Zhao, W.; Yang, J. S.; Cheng, Z.; Luo, H.; Lu, Z.; Tan, M.; Gu, W.; Zhao, Y. Mol. Cell. Proteomics 2012, 11, 1048
Google Scholar
23
Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways
Chen, Yue; Zhao, Wenhui; Yang, Jeong Soo; Cheng, Zhongyi; Luo, Hao; Lu, Zhike; Tan, Minjia; Gu, Wei; Zhao, Yingming
Molecular and Cellular Proteomics (2012), 11 (10), 1048-1062CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
Despite the progress in identifying many Lys acetylation (Kac) proteins, Kac substrates for Kac-regulatory enzymes remain largely unknown, presenting a major knowledge gap in Kac biol. Here, we identified and quantified 4623 Kac sites in 1800 Kac proteins in SIRT1+/+ and SIRT1-/- MEF cells, representing the first study to reveal an enzyme-regulated Kac subproteome and the largest Lys acetylome reported to date from a single study. Four hundred eighty-five Kac sites were enhanced by more than 100% after SIRT1 knockout. Our results indicate that SIRT1 regulates the Kac states of diverse cellular pathways. Interestingly, we found that a no. of acetyltransferases and major acetyltransferase complexes are targeted by SIRT1. Moreover, we showed that the activities of the acetyltransferases are regulated by SIRT1-mediated deacetylation. Taken together, our results reveal the Lys acetylome in response to SIRT1, provide new insights into mechanisms of SIRT1 function, and offer biomarker candidates for the clin. evaluation of SIRT1-activator compds.
24
Zhao, S.; Xu, W.; Jiang, W.; Yu, W.; Lin, Y.; Zhang, T.; Yao, J.; Zhou, L.; Zeng, Y.; Li, H.; Li, Y.; Shi, J.; An, W.; Hancock, S. M.; He, F.; Qin, L.; Chin, J.; Yang, P.; Chen, X.; Lei, Q.; Xiong, Y.; Guan, K. L. Science 2010, 327, 1000
Google Scholar
There is no corresponding record for this reference.
25
Albaugh, B. N.; Arnold, K. M.; Denu, J. M. ChemBioChem 2011, 12, 290
Google Scholar
There is no corresponding record for this reference.
26
Sutendra, G.; Kinnaird, A.; Dromparis, P.; Paulin, R.; Stenson, T. H.; Haromy, A.; Hashimoto, K.; Zhang, N.; Flaim, E.; Michelakis, E. D. Cell 2014, 158, 84
Google Scholar
There is no corresponding record for this reference.
27
Begley, T. P.; Kinsland, C.; Strauss, E. Vitam. Horm. 2001, 61, 157
Google Scholar
27
The biosynthesis of coenzyme A in bacteria
Begley, Tadhg P.; Kinsland, Cynthia; Strauss, Erick
Vitamins and Hormones (San Diego, CA, United States) (2001), 61 (), 157-171CODEN: VIHOAQ; ISSN:0083-6729. (Academic Press)
A review with 50 refs. CoA (I) and enzyme-bound phosphopantetheine (II) function as acyl carriers and as carbonyl activating groups for Claisen reactions as well as for amide-, ester-, and thioester-forming reactions in the cell. These cofactors play a key role in the biosynthesis and breakdown of fatty acids and in the biosynthesis of polyketides and nonribosomal peptides. CoA is biosynthesized in bacteria in nine steps. The biosynthesis begins with the decarboxylation of aspartate to give β-alanine. Pantoic acid is formed by the hydroxymethylation of α-ketoisovalerate followed by redn. These intermediates are then condensed to give pantothenic acid. Phosphorylation of pantothenic acid followed by condensation with cysteine and decarboxylation gives 4'-phosphopantetheine. Adenylation and phosphorylation of 4'-phosphopantetheine completes the biosynthesis of CoA. This review will focus on the mechanistic enzymol. of CoA biosynthesis in bacteria. (c) 2001 Academic Press.
28
Xing, S.; Poirier, Y. Trends Plant Sci. 2012, 17, 423
Google Scholar
28
The protein acetylome and the regulation of metabolism
Xing, Shufan; Poirier, Yves
Trends in Plant Science (2012), 17 (7), 423-430CODEN: TPSCF9; ISSN:1360-1385. (Elsevier Ltd.)
A review. Acetyl-CoA (CoA) is a central metabolite involved in numerous anabolic and catabolic pathways, as well as in protein acetylation. Beyond histones, a large no. of metabolic enzymes are acetylated in both animal and bacteria, and the protein acetylome is now emerging in plants. Protein acetylation is influenced by the cellular level of both acetyl-CoA and NAD+, and regulates the activity of several enzymes. Acetyl-CoA is thus ideally placed to act as a key mol. linking the energy balance of the cell to the regulation of gene expression and metabolic pathways via the control of protein acetylation. Better knowledge over how to influence acetyl-CoA levels and the acetylation process promises to be an invaluable tool to control metabolic pathways.
29
Wellen, K. E.; Thompson, C. B. Nat. Rev. Mol. Cell Biol. 2012, 13, 270
Google Scholar
29
A two-way street: reciprocal regulation of metabolism and signalling
Wellen, Kathryn E.; Thompson, Craig B.
Nature Reviews Molecular Cell Biology (2012), 13 (4), 270-276CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
A review. It is becoming increasingly clear that cellular signaling and metab. are not just sep. entities but rather are tightly linked. Although nutrient metab. is known to be regulated by signal transduction, an emerging paradigm is that signaling and transcriptional networks can be modulated by nutrient-sensitive protein modifications, such as acetylation and glycosylation, which depend on the availability of acetyl-CoA and sugar donors such as UDP-N-acetylglucosamine (UDP-GlcNAc), resp. The integration of metabolic and signaling cues allows cells to modulate activities such as metab., cell survival and proliferation according to their intracellular metabolic resources.
30
Albaugh, B. N.; Arnold, K. M.; Denu, J. M. ChemBioChem 2011, 12, 290
Google Scholar
There is no corresponding record for this reference.
31
Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Proc. Natl. Acad. Sci. U.S.A. 1964, 51, 786
Google Scholar
31
Acetylation and methylation of histones and their possible role in the regulation of ribonucleic acid (RNA) synthesis
Allfrey, V. G.; Faulkner, R.; Mirsky, A. E.
Proceedings of the National Academy of Sciences of the United States of America (1964), 51 (5), 786-94CODEN: PNASA6; ISSN:0027-8424.
Isolated calf thymus nuclei was incubated with 14C-labeled Na acetate. Evidence that acetate was incorporated as acetyl groups attached to histones included: (1) following chromatography the label was eluted together with basic proteins; (2) acetyl-labeled histones were sepd. by electrophoresis; (3) acetate-14C was not removed from histones by org. solvents; (4) over 75% of the label remained after histones were treated with trichloroacetic acid. Most extensive acetate uptake occurred with arginine-rich histones. Puromycin did not inhibit the acetylation, indicating histones were modified by acetylation after completion of the polypeptide chain. Acetylation lowered the histone effectiveness as inhibitor of the RNA polymerase reaction, and a dynamic and reversible mechanism was suggested for activation as well as repression of RNA synthesis.
32
Hebbes, T. R.; Thorne, A. W.; Crane-Robinson, C. EMBO J. 1988, 7, 1395
Google Scholar
There is no corresponding record for this reference.
33
Hebbes, T. R.; Clayton, A. L.; Thorne, A. W.; Crane-Robinson, C. EMBO J. 1994, 13, 1823
Google Scholar
There is no corresponding record for this reference.
34
Braunstein, M.; Rose, A. B.; Holmes, S. G.; Allis, C. D.; Broach, J. R. Genes Dev. 1993, 7, 592
Google Scholar
34
Transcriptional silencing in yeast is associated with reduced nucleosome acetylation
Braunstein, Miriam; Rose, Alan B.; Holmes, Scott G.; Allis, C. David; Broach, James R.
Genes & Development (1993), 7 (4), 592-604CODEN: GEDEEP; ISSN:0890-9369.
Two classes of sequences in the yeast Saccharomyces cerevisiae are subject to transcription silencing: the silent mating-type cassettes and telomers. The silencing of these regions is shown to be strictly assocd. with acetylation of the ε-amino groups of lysines in the N-terminal domains of 3 of the 4 core histones. Both the silent mating-type cassettes and the Y domains of telomeres are packaged in nucleosomes in vivo that are hypoacetylated relative to those packaging active genes. This difference in acetylation is eliminated by genetic inactivation of silencing:. The silent cassettes from sir2, sir3, or sir4 cells show the same level of acetylation as other active genes. The correspondence of silencing and hypoacetylation of the mating-type cassettes is obsd. even for an allele lacking a promoter, indicating that silencing per se, rather than the absence of transcription, is correlated with hypoacetylation. Finally, overexpression of Sir2p, a protein required for transcriptional silencing in yeast, yields substantial histone deacetylation in vivo. These studies fortify the hypothesis that silencing in yeast results from heterochromatin formation and argue that the silencing proteins participate in this formation.
35
Turner, B. M.; Birley, A. J.; Lavender, J. Cell 1992, 69, 375
Google Scholar
There is no corresponding record for this reference.
36
Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Proc. Natl. Acad. Sci. U.S.A. 1964, 51, 786
Google Scholar
36
Acetylation and methylation of histones and their possible role in the regulation of ribonucleic acid (RNA) synthesis
Allfrey, V. G.; Faulkner, R.; Mirsky, A. E.
Proceedings of the National Academy of Sciences of the United States of America (1964), 51 (5), 786-94CODEN: PNASA6; ISSN:0027-8424.
Isolated calf thymus nuclei was incubated with 14C-labeled Na acetate. Evidence that acetate was incorporated as acetyl groups attached to histones included: (1) following chromatography the label was eluted together with basic proteins; (2) acetyl-labeled histones were sepd. by electrophoresis; (3) acetate-14C was not removed from histones by org. solvents; (4) over 75% of the label remained after histones were treated with trichloroacetic acid. Most extensive acetate uptake occurred with arginine-rich histones. Puromycin did not inhibit the acetylation, indicating histones were modified by acetylation after completion of the polypeptide chain. Acetylation lowered the histone effectiveness as inhibitor of the RNA polymerase reaction, and a dynamic and reversible mechanism was suggested for activation as well as repression of RNA synthesis.
37
Mutskov, V.; Gerber, D.; Angelov, D.; Ausio, J.; Workman, J.; Dimitrov, S. Mol. Cell. Biol. 1998, 18, 6293
Google Scholar
37
Persistent interactions of core histone tails with nucleosomal DNA following acetylation and transcription factor binding
Mutskov, Vesco; Gerber, Delphine; Angelov, Dimitri; Ausio, Juan; Workman, Jerry; Dimitrov, Stefan
Molecular and Cellular Biology (1998), 18 (11), 6293-6304CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
In this study, we examd. the effect of acetylation of the NH2 tails of core histones on their binding to nucleosomal DNA in the absence or presence of bound transcription factors. To do this, we used a novel UV laser-induced protein-DNA crosslinking technique, combined with immunochem. and mol. biol. approaches. Nucleosomes contg. one or five GAL4 binding sites were reconstituted with hypo-acetylated or hyper-acetylated core histones. Within these reconstituted particles, UV laser-induced histone-DNA crosslinking was found to occur only via the non-structured histone tails and thus presented a unique tool for studying histone tail interactions with nucleosomal DNA. Importantly, these studies demonstrated that the NH2 tails were not released from nucleosomal DNA upon histone acetylation, although some weakening of their interactions was obsd. at elevated ionic strengths. Moreover, the binding of up to five GAL4-AH dimers to nucleosomes occupying the central 90 bp occurred without displacement of the histone NH2 tails from DNA. GAL4-AH binding perturbed the interaction of each histone tail with nucleosomal DNA to different degrees. However, in all cases, greater than 50% of the interactions between the histone tails and DNA was retained upon GAL4-AH binding, even if the tails were highly acetylated. These data illustrate an interaction of acetylated or non-acetylated histone tails with DNA that persists in the presence of simultaneously bound transcription factors.
38
Zeng, L.; Zhou, M. M. FEBS Lett. 2002, 513, 124
Google Scholar
There is no corresponding record for this reference.
39
Taverna, S. D.; Li, H.; Ruthenburg, A. J.; Allis, C. D.; Patel, D. J. Nat. Struct. Mol. Biol. 2007, 14, 1025
Google Scholar
39
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
Taverna, Sean D.; Li, Haitao; Ruthenburg, Alexander J.; Allis, C. David; Patel, Dinshaw J.
Nature Structural & Molecular Biology (2007), 14 (11), 1025-1040CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
A review. Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), esp. on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their assocd. complexes, has been predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here, the authors summarize key features in the mol. recognition of histone PTMs by a diverse family of 'reader pockets' (including bromodomains, Royal superfamily modules, PHD fingers, WD40 protein repeats, 14-3-3 proteins, and BRCT domains), highlighting specific readout mechanisms for individual marks, common themes, and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biol. and disease, notably cancer.
40
Botuyan, M. V.; Lee, J.; Ward, I. M.; Kim, J. E.; Thompson, J. R.; Chen, J.; Mer, G. Cell 2006, 127, 1361
Google Scholar
There is no corresponding record for this reference.
41
Lee, J.; Thompson, J. R.; Botuyan, M. V.; Mer, G. Nat. Struct. Mol. Biol. 2008, 15, 109
Google Scholar
41
Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor
Lee, Joseph; Thompson, James R.; Botuyan, Maria Victoria; Mer, Georges
Nature Structural & Molecular Biology (2008), 15 (1), 109-111CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
The lysine demethylase JMJD2A has the unique property of binding trimethylated peptides from two different histone sequences (H3K4me3 and H4K20me3) through its tudor domains. Here we show using X-ray crystallog. and calorimetry that H3K4me3 and H4K20me3, which are recognized with similar affinities by JMJD2A, adopt radically different binding modes, to the extent that we were able to design single point mutations in JMJD2A that inhibited the recognition of H3K4me3 but not H4K20me3 and vice versa.
42
Guo, Y.; Nady, N.; Qi, C.; Allali-Hassani, A.; Zhu, H.; Pan, P.; Adams-Cioaba, M. A.; Amaya, M. F.; Dong, A.; Vedadi, M.; Schapira, M.; Read, R. J.; Arrowsmith, C. H.; Min, J. Nucleic Acids Res. 2009, 37, 2204
Google Scholar
There is no corresponding record for this reference.
43
Li, H.; Fischle, W.; Wang, W.; Duncan, E. M.; Liang, L.; Murakami-Ishibe, S.; Allis, C. D.; Patel, D. J. Mol. Cell 2007, 28, 677
Google Scholar
There is no corresponding record for this reference.
44
Li, H.; Ilin, S.; Wang, W.; Duncan, E. M.; Wysocka, J.; Allis, C. D.; Patel, D. J. Nature 2006, 442, 91
Google Scholar
There is no corresponding record for this reference.
45
Jenuwein, T.; Allis, C. D. Science 2001, 293, 1074
Google Scholar
45
Translating the histone code
Jenuwein, Thomas; Allis, C. David
Science (Washington, DC, United States) (2001), 293 (5532), 1074-1080CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
The review. Chromatin, the physiol. template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-assocd. proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all; chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathol. development.
46
Bernstein, E.; Hake, S. B. Biochem. Cell Biol. 2006, 84, 505
Google Scholar
46
The nucleosome: a little variation goes a long way
Bernstein, Emily; Hake, Sandra B.
Biochemistry and Cell Biology (2006), 84 (4), 505-517CODEN: BCBIEQ; ISSN:0829-8211. (National Research Council of Canada)
A review. Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing no. of mammalian histone variants, their particular biol. functions and unique features, and how they may affect the structure of the nucleosome. The authors propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that the authors refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.
47
Schreiber, S. L.; Bernstein, B. E. Cell 2002, 111, 771
Google Scholar
There is no corresponding record for this reference.
48
Ernst, J.; Kellis, M. Nat. Biotechnol. 2010, 28, 817
Google Scholar
There is no corresponding record for this reference.
49
Jenuwein, T.; Allis, C. D. Science 2001, 293, 1074
Google Scholar
49
Translating the histone code
Jenuwein, Thomas; Allis, C. David
Science (Washington, DC, United States) (2001), 293 (5532), 1074-1080CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
The review. Chromatin, the physiol. template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-assocd. proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all; chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathol. development.
50
Feng, Y.; Wang, J.; Asher, S.; Hoang, L.; Guardiani, C.; Ivanov, I.; Zheng, Y. G. J. Biol. Chem. 2011, 286, 20323
Google Scholar
There is no corresponding record for this reference.
51
Nathan, D.; Ingvarsdottir, K.; Sterner, D. E.; Bylebyl, G. R.; Dokmanovic, M.; Dorsey, J. A.; Whelan, K. A.; Krsmanovic, M.; Lane, W. S.; Meluh, P. B.; Johnson, E. S.; Berger, S. L. Genes Dev. 2006, 20, 966
Google Scholar
There is no corresponding record for this reference.
52
Messner, S.; Altmeyer, M.; Zhao, H.; Pozivil, A.; Roschitzki, B.; Gehrig, P.; Rutishauser, D.; Huang, D.; Caflisch, A.; Hottiger, M. O. Nucleic Acids Res. 2010, 38, 6350
Google Scholar
There is no corresponding record for this reference.
53
Dhalluin, C.; Carlson, J. E.; Zeng, L.; He, C.; Aggarwal, A. K.; Zhou, M. M. Nature 1999, 399, 491
Google Scholar
There is no corresponding record for this reference.
54
Thorne, A. W.; Kmiciek, D.; Mitchelson, K.; Sautiere, P.; Crane-Robinson, C. Eur. J. Biochem. 1990, 193, 701
Google Scholar
54
Patterns of histone acetylation
Thorne, Alan W.; Kmiciek, Daniel; Mitchelson, Keith; Sautiere, Pierre; Crane-Robinson, Colyn
European Journal of Biochemistry (1990), 193 (3), 701-13CODEN: EJBCAI; ISSN:0014-2956.
The N-terminal domains of all four core histones are subject to reversible acetylation at certain lysine residues. This modification has been functionally linked to transcription, histone deposition at replication, and to histone removal during spermatogenesis. To increase understanding of the significance of this modification the specificity of site utilization in the monoacetyl, diacetyl, and triacetyl forms of histones H3, H4, and H2B (histone H2A has only a single modification site) was studied using pig thymus and HeLa cells as the source. The HeLa histones were extd. from cells grown both with and without butyrate treatment. For histone H3 there is a fairly strict order of site occupancy: Lys14, followed by Lys23, followed by Lys18 in both pig and HeLa histones. Since the order and specificity is the same when butyrate is added to the HeLa cell cultures, it is concluded that addn. of the fatty acid does not scramble the specificity of site utilization, but merely allows more of the natural forms of modified histone to accumulate. For histone H4, the monoacetyl form is exclusively modified at Lys16, but further addn. of acetyl groups is less specific and progresses through sites 12, 8 and 5 in an N-terminal direction. Similar results were obtained for H4 from both pig thymus and butyrate-treated HeLa cells. Histone H2B could be studied in detail only from butyrate-treated HeLa cells and a much lower level of site specificity was found: sites 12 and 15 were preferred to the more N- and C-terminal sites at Lys5 and Lys20. The data reinforces the view that lysine acetylation in core histones is a very specific phenomenon that plays several functionally distinct roles. The high degree of site specificity makes it unlikely that the structural effects of acetylation are mediated merely by a generalized redn. of charge in the histone N-terminal domains.
55
Zhang, K.; Williams, K. E.; Huang, L.; Yau, P.; Siino, J. S.; Bradbury, E. M.; Jones, P. R.; Minch, M. J.; Burlingame, A. L. Mol. Cell. Proteomics 2002, 1, 500
Google Scholar
55
Histone acetylation and deacetylation: identification of acetylation and methylation sites of HeLa histone H4 by mass spectrometry
Zhang, Kangling; Williams, Katherine E.; Huang, Lan; Yau, Peter; Siino, Joseph S.; Bradbury, E. Morton; Jones, Patrick R.; Minch, Michael J.; Burlingame, Alma L.
Molecular and Cellular Proteomics (2002), 1 (7), 500-508CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology, Inc.)
The acetylation isoforms of histone H4 from butyrate-treated HeLa cells were sepd. by C4 reverse-phase high pressure liq. chromatog. and by PAGE. Histone H4 bands were excised and digested in-gel with the endoprotease trypsin. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to characterize the level of acetylation, and nanoelectrospray tandem mass spectrometric anal. of the acetylated peptides was used to det. the exact sites of acetylation. Although there are 15 acetylation sites possible, only four acetylated peptide sequences were actually obsd. The tetra-acetylated form is modified at lysines 5, 8, 12, and 16, the tri-acetylated form is modified at lysines 8, 12, and 16, and the di-acetylated form is modified at lysines 12 and 16. The only significant amt. of the mono-acetylated form was found at position 16. These results are consistent with the hypothesis of a "zip" model whereby acetylation of histone H4 proceeds in the direction of from Lys-16 to Lys-5, and deacetylation proceeds in the reverse direction. Histone acetylation and deacetylation are coordinated processes leading to a non-random distribution of isoforms. Our results also revealed that lysine 20 is dimethylated in all modified isoforms, as well as the nonacetylated isoform of H4.
56
Clayton, A. L.; Hazzalin, C. A.; Mahadevan, L. C. Mol. Cell 2006, 23, 289
Google Scholar
There is no corresponding record for this reference.
57
Waterborg, J. H. Biochem. Cell Biol. 2002, 80, 363
Google Scholar
57
Dynamics of histone acetylation in vivo. A function for acetylation turnover?
Waterborg, Jakob H.
Biochemistry and Cell Biology (2002), 80 (3), 363-378CODEN: BCBIEQ; ISSN:0829-8211. (National Research Council of Canada)
A review. Histone acetylation discovered more than 40 yr ago is a reversible modification of lysines within the amino-terminal domain of core histones. Amino-terminal histone domains contribute to the compaction of genes into repressed chromatin fibers. It is thought that their acetylation causes localized relaxation of chromatin as a necessary but not sufficient condition for processes that repackage DNA such as transcription, replication, repair, recombination, and sperm formation. While increased histone acetylation enhances gene transcription and loss of acetylation represses and silences genes, the function of the rapid continuous or repetitive acetylation and deacetylation reactions with half-lives of just a few minutes remains unknown. Thirty years of in vivo measurements of acetylation turnover and rates of change in histone modification levels have been reviewed to identify common chromatin characteristics measured by distinct protocols. It has now become possible to look across a wider spectrum of organisms than ever before and identify common features. The rapid turnover rates in transcriptionally active and competent chromatin are one such feature. While ubiquitously obsd., we still do not know whether turnover itself is linked to chromatin transcription beyond its contribution to rapid changes towards hyper- or hypoacetylation of nucleosomes. However, recent expts. suggest that turnover may be linked directly to steps in gene transcription, interacting with nucleosome remodeling complexes.
58
Katan-Khaykovich, Y.; Struhl, K. Genes Dev. 2002, 16, 743
Google Scholar
There is no corresponding record for this reference.
59
Annunziato, A. T.; Eason, M. B.; Perry, C. A. Biochemistry 1995, 34, 2916
Google Scholar
There is no corresponding record for this reference.
60
Hendzel, M. J.; Davie, J. R. Biochem. J. 1991, 273, 753
Google Scholar
There is no corresponding record for this reference.
61
Hazzalin, C. A.; Mahadevan, L. C. PLoS Biol. 2005, 3, e393
Google Scholar
There is no corresponding record for this reference.
62
Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
Google Scholar
There is no corresponding record for this reference.
63
Taunton, J.; Hassig, C. A.; Schreiber, S. L. Science 1996, 272, 408
Google Scholar
63
A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p
Taunton, Jack; Hassig, Christian A.; Schreiber, Stuart L.
Science (Washington, D. C.) (1996), 272 (5260), 408-11CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a human Jurkat T cell library. As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p, these results support a role for histone deacetylase as a key regulator of eukaryotic transcription.
64
Schiltz, R. L.; Mizzen, C. A.; Vassilev, A.; Cook, R. G.; Allis, C. D.; Nakatani, Y. J. Biol. Chem. 1999, 274, 1189
Google Scholar
There is no corresponding record for this reference.
65
Kimura, A.; Horikoshi, M. Genes Cells 1998, 3, 789
Google Scholar
65
Tip60 acetylates six lysines of a specific class in core histones in vitro
Kimura, Akatsuki; Horikoshi, Masami
Genes to Cells (1998), 3 (12), 789-800CODEN: GECEFL; ISSN:1356-9597. (Blackwell Science Ltd.)
Tip60, an HIV-1-Tat interactive protein, is a nuclear histone acetyltransferase (HAT) with unique histone substrate specificity. Since the acetylation of core histones at particular lysines mediates distinct effects on chromatin assembly and gene regulation, the identification of Lys site specificity of the HAT activity of Tip60 is an initial step in the anal. of its mol. function. Tip60 significantly acetylates N-terminal tail peptides of histones H2A, H3 and H4, but not H2B, consistent with substrate preference on intact histones. Preferred acetylation sites for Tip60 are Lys-5 of histone H2A, Lys-14 of histone H3, and Lys-5, Lys-8, Lys-12, Lys-16 of histone H4, detd. by a method which combined matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) measurements and Lys-C endopeptidase digestion, or a method detecting the incorporation of radiolabeled acetate into synthetic peptides. The Lys site specificity of Tip60 in histone N-terminal tail peptides in vitro was characterized by an assay measuring the mol. wt. of endopeptidase-digested peptides, or a previously described assay. These results agree well with the authors' proposed classification of Lys residues in core histones. The classification may be useful for an anal. of the relations between HATs and the substrates of other uncharacterized HATs.
66
Thompson, P. R.; Kurooka, H.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2001, 276, 33721
Google Scholar
There is no corresponding record for this reference.
67
Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
Google Scholar
There is no corresponding record for this reference.
68
Schiltz, R. L.; Mizzen, C. A.; Vassilev, A.; Cook, R. G.; Allis, C. D.; Nakatani, Y. J. Biol. Chem. 1999, 274, 1189
Google Scholar
There is no corresponding record for this reference.
69
McManus, K. J.; Hendzel, M. J. Mol. Cell. Biol. 2003, 23, 7611
Google Scholar
69
Quantitative analysis of CBP- and P300-induced histone acetylations in vivo using native chromatin
McManus, Kirk J.; Hendzel, Michael J.
Molecular and Cellular Biology (2003), 23 (21), 7611-7627CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
In vivo, histone tails are involved in numerous interactions, including those with DNA, adjacent histones, and other, nonhistone proteins. The N-termini are also the substrates for a no. of enzymes, including histone acetyltransferases (HATs), histone deacetylases, and histone methyltransferases. Traditional biochem. approaches defining the substrate specificity profiles of HATs have been performed using purified histone tails, recombinant histones, or purified mononucleosomes as substrates. It is clear that the in vivo presentation of the substrate cannot be accurately represented by using these in vitro approaches. Because of the difficulty in translating in vitro results into in vivo situations, the authors developed a novel single-cell HAT assay that provides quant. measurements of endogenous HAT activity. The HAT assay is performed under in vivo conditions by using the native chromatin structure as the physiol. substrate. The assay combines the spatial resolving power of laser scanning confocal microscopy with simple statistical analyses to characterize CREB binding protein (CBP)- and P300-induced changes in global histone acetylation levels at specific lysine residues. Here the authors show that CBP and P300 exhibit unique substrate specificity profiles, consistent with the developmental and functional differences between the two HATs.
70
Kasper, L. H.; Lerach, S.; Wang, J.; Wu, S.; Jeevan, T.; Brindle, P. K. EMBO J. 2010, 29, 3660
Google Scholar
There is no corresponding record for this reference.
71
Dawson, M. A.; Kouzarides, T. Cell 2012, 150, 12
Google Scholar
71
Cancer Epigenetics: From Mechanism to Therapy
Dawson, Mark A.; Kouzarides, Tony
Cell (Cambridge, MA, United States) (2012), 150 (1), 12-27CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
A review. The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biol. processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clin. and preclin. results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.
72
Yee, S. P.; Branton, P. E. Virology 1985, 147, 142
Google Scholar
There is no corresponding record for this reference.
73
Whyte, P.; Williamson, N. M.; Harlow, E. Cell 1989, 56, 67
Google Scholar
There is no corresponding record for this reference.
74
Eckner, R.; Ewen, M. E.; Newsome, D.; Gerdes, M.; DeCaprio, J. A.; Lawrence, J. B.; Livingston, D. M. Genes Dev. 1994, 8, 869
Google Scholar
There is no corresponding record for this reference.
75
Chrivia, J. C.; Kwok, R. P.; Lamb, N.; Hagiwara, M.; Montminy, M. R.; Goodman, R. H. Nature 1993, 365, 855
Google Scholar
There is no corresponding record for this reference.
76
Arany, Z.; Sellers, W. R.; Livingston, D. M.; Eckner, R. Cell 1994, 77, 799
Google Scholar
There is no corresponding record for this reference.
77
Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
Google Scholar
There is no corresponding record for this reference.
78
Brownell, J. E.; Zhou, J.; Ranalli, T.; Kobayashi, R.; Edmondson, D. G.; Roth, S. Y.; Allis, C. D. Cell 1996, 84, 843
Google Scholar
78
Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation
Brownell, James E.; Zhou, Jianxin; Ranalli, Tamara; Kobayashi, Ryuji; Edmondson, Diane G.; Roth, Sharon Y.; Allis, C. David
Cell (Cambridge, Massachusetts) (1996), 84 (6), 843-51CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
We report the cloning of a transcription-assocd. histone acetyltransferase type A (HAT A). This Tetrahymena enzyme is strikingly homologous to the yeast protein Gcn5, a putative transcriptional adaptor, and we demonstrate that recombinant Gcn5p possesses HAT activity. Both the ciliate enzyme and Gcn5p contain potential active site residues found in other acetyltransferases and a highly conserved bromodomain. The presence of this domain in nuclear A-type HATs, but not in cytoplasmic B-type HATs, suggests a mechanism whereby HAT A is directed to chromatin to facilitate transcriptional activation. These findings shed light on the biochem. function of the evolutionarily conserved Gcn5p-Ada complex, directly linking histone acetylation to gene activation, and indicate that histone acetylation is a targeted phenomenon.
79
Brownell, J. E.; Allis, C. D. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6364
Google Scholar
There is no corresponding record for this reference.
80
Kleff, S.; Andrulis, E. D.; Anderson, C. W.; Sternglanz, R. J. Biol. Chem. 1995, 270, 24674
Google Scholar
There is no corresponding record for this reference.
81
Bannister, A. J.; Kouzarides, T. Nature 1996, 384, 641
Google Scholar
There is no corresponding record for this reference.
82
Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
Google Scholar
There is no corresponding record for this reference.
83
Eckner, R. Biol. Chem. 1996, 377, 685
Google Scholar
There is no corresponding record for this reference.
84
Taddei, A.; Gasser, S. M. Genetics 2012, 192, 107
Google Scholar
There is no corresponding record for this reference.
85
Rando, O. J.; Chang, H. Y. Annu. Rev. Biochem. 2009, 78, 245
Google Scholar
85
Genome-wide views of chromatin structure
Rando, Oliver J.; Chang, Howard Y.
Annual Review of Biochemistry (2009), 78 (), 245-271CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)
A review. Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin, which affects most processes that occur on DNA. Along with genetic and biochem. studies of resident chromatin proteins and their modifying enzymes, mapping of chromatin structure in vivo is one of the main pillars in our understanding of how chromatin relates to cellular processes. In this review, we discuss the use of genomic technologies to characterize chromatin structure in vivo, with a focus on data from budding yeast and humans. The picture emerging from these studies is the detailed chromatin structure of a typical gene, where the typical behavior gives insight into the mechanisms and deep rules that establish chromatin structure. Important deviation from the archetype is also obsd., usually as a consequence of unique regulatory mechanisms at special genomic loci. Chromatin structure shows substantial conservation from yeast to humans, but mammalian chromatin has addnl. layers of complexity that likely relate to the requirements of multicellularity such as the need to establish faithful gene regulatory mechanisms for cell differentiation.
86
Bordoli, L.; Netsch, M.; Lüthi, U.; Lutz, W.; Eckner, R. Nucleic Acids Res. 2001, 29, 589
Google Scholar
There is no corresponding record for this reference.
87
Tang, Y.; Holbert, M. A.; Wurtele, H.; Meeth, K.; Rocha, W.; Gharib, M.; Jiang, E.; Thibault, P.; Verreault, A.; Cole, P. A.; Marmorstein, R. Nat. Struct. Mol. Biol. 2008, 15, 998
Google Scholar
87
Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. [Erratum to document cited in CA149:217962]
Tang, Yong; Holbert, Marc A.; Wurtele, Hugo; Meeth, Katrina; Rocha, Walter; Gharib, Marlene; Jiang, Eva; Thibault, Pierre; Verreault, Alain; Cole, Philip A.; Marmorstein, Ronen
Nature Structural & Molecular Biology (2008), 15 (9), 998CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
On page 738, the author name "Verreault" was mistakenly spelled as "Verrault". The error has been cor. in the HTML and PDF versions of the article.
88
Bordoli, L.; Netsch, M.; Lüthi, U.; Lutz, W.; Eckner, R. Nucleic Acids Res. 2001, 29, 589
Google Scholar
There is no corresponding record for this reference.
89
Giles, R. H.; Dauwerse, H. G.; van Ommen, G. J.; Breuning, M. H. Am. J. Hum. Genet. 1998, 63, 1240
Google Scholar
89
Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins?
Giles R H; Dauwerse H G; van Ommen G J; Breuning M H
American journal of human genetics (1998), 63 (4), 1240-2 ISSN:0002-9297.
There is no expanded citation for this reference.
90
Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
Google Scholar
90
p300/CBP proteins: HATs for transcriptional bridges and scaffolds
Chan, Ho Man; La Thangue, Nicholas B.
Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
91
Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
Google Scholar
There is no corresponding record for this reference.
92
Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
Google Scholar
There is no corresponding record for this reference.
93
Bedford, D. C.; Brindle, Ph. Aging (N. Y.) 2012, 4, 247
Google Scholar
93
Is histone acetylation the most important physiological function for CBP and p300?
Bedford David C; Brindle Paul K
Aging (2012), 4 (4), 247-55 ISSN:.
Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription.
94
Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
Google Scholar
There is no corresponding record for this reference.
95
Bedford, D. C.; Brindle, P. K. Aging (N. Y.) 2012, 4, 247
Google Scholar
95
Is histone acetylation the most important physiological function for CBP and p300?
Bedford David C; Brindle Paul K
Aging (2012), 4 (4), 247-55 ISSN:.
Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription.
96
Arany, Z.; Newsome, D.; Oldread, E.; Livingston, D. M.; Eckner, R. Nature 1995, 374, 81
Google Scholar
There is no corresponding record for this reference.
97
Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
Google Scholar
There is no corresponding record for this reference.
98
Lundblad, J. R.; Kwok, R. P.; Laurance, M. E.; Harter, M. L.; Goodman, R. H. Nature 1995, 374, 85
Google Scholar
There is no corresponding record for this reference.
99
Radhakrishnan, I.; Pérez-Alvarado, G. C.; Parker, D.; Dyson, H. J.; Montminy, M. R.; Wright, P. E. Cell 1997, 91, 741
Google Scholar
There is no corresponding record for this reference.
100
Kalkhoven, E. Biochem. Pharmacol. 2004, 68, 1145
Google Scholar
There is no corresponding record for this reference.
101
Nam, Y.; Sliz, P.; Song, L.; Aster, J. C.; Blacklow, S. C. Cell 2006, 124, 973
Google Scholar
There is no corresponding record for this reference.
102
Mayr, B.; Montminy, M. Nat. Rev. Mol. Cell Biol. 2001, 2, 599
Google Scholar
102
Transcriptional regulation by the phosphorylation-dependent factor CREB
Mayr, Bernhard; Montminy, Marc
Nature Reviews Molecular Cell Biology (2001), 2 (8), 599-609CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
A review. The transcription factor CREB - for 'cAMP response element-binding protein' - functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signaling pathways.
103
Bourdeau, V.; Deschênes, J.; Métivier, R.; Nagai, Y.; Nguyen, D.; Bretschneider, N.; Gannon, F.; White, J. H.; Mader, S. Mol. Endocrinol. 2004, 18, 1411
Google Scholar
103
Genome-wide identification of high-affinity estrogen response elements in human and mouse
Bourdeau, Veronique; Deschenes, Julie; Metivier, Raphael; Nagai, Yoshihiko; Nguyen, Denis; Bretschneider, Nancy; Gannon, Frank; White, John H.; Mader, Sylvie
Molecular Endocrinology (2004), 18 (6), 1411-1427CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)
Although estrogen receptors (ERs) recognize 15-bp palindromic estrogen response elements (EREs) with maximal affinity in vitro, few near-consensus sequences have been characterized in estrogen target genes. Here we report the design of a genome-wide screen for high-affinity EREs and the identification of approx. 70,000 motifs in the human and mouse genomes. EREs are enriched in regions proximal to the transcriptional start sites, and approx. 1% of elements appear conserved in the flanking regions (-10 kb to +5 kb) of orthologous human and mouse genes. Conserved and nonconserved elements were also found, often in multiple occurrences, in more than 230 estrogen-stimulated human genes previously identified from expression studies. In genes contg. known EREs, we also identified addnl. distal elements, sometimes with higher in vitro binding affinity and/or better conservation between the species considered. Chromatin immunopptn. expts. in breast cancer cell lines indicate that most novel elements present in responsive genes bind ERα in vivo, including some EREs located up to approx. 10 kb from transcriptional start sites. Our results demonstrate that near-consensus EREs occur frequently in both genomes and that whereas chromatin structure likely modulates access to binding sites, far upstream elements can be evolutionarily conserved and bind ERs in vivo.
104
Saito, H.; Posas, F. Genetics 2012, 192, 289
Google Scholar
There is no corresponding record for this reference.
105
Sheikh-Hamad, D.; Di Mari, J.; Suki, W. N.; Safirstein, R.; Watts, B. A., III; Rouse, D. J. Biol. Chem. 1998, 273, 1832
Google Scholar
There is no corresponding record for this reference.
106
Chen, Y. J.; Wang, Y. N.; Chang, W. C. J. Biol. Chem. 2007, 282, 27215
Google Scholar
There is no corresponding record for this reference.
107
Jang, E. R.; Choi, J. D.; Lee, J. S. FEBS Lett. 2011, 585, 47
Google Scholar
There is no corresponding record for this reference.
108
Sakaguchi, K.; Herrera, J. E.; Saito, S.; Miki, T.; Bustin, M.; Vassilev, A.; Anderson, C. W.; Appella, E. Genes Dev. 1998, 12, 2831
Google Scholar
There is no corresponding record for this reference.
109
Iyer, N. G.; Chin, S. F.; Ozdag, H.; Daigo, Y.; Hu, D. E.; Cariati, M.; Brindle, K.; Aparicio, S.; Caldas, C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 7386
Google Scholar
There is no corresponding record for this reference.
110
Yuan, L. W.; Gambee, J. E. J. Biol. Chem. 2000, 275, 40946
Google Scholar
There is no corresponding record for this reference.
111
Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
Google Scholar
There is no corresponding record for this reference.
112
Legube, G.; Trouche, D. EMBO Rep. 2003, 4, 944
Google Scholar
There is no corresponding record for this reference.
113
Schwartz, C.; Beck, K.; Mink, S.; Schmolke, M.; Budde, B.; Wenning, D.; Klempnauer, K. H. EMBO J. 2003, 22, 882
Google Scholar
There is no corresponding record for this reference.
114
Poizat, C.; Puri, P. L.; Bai, Y.; Kedes, L. Mol. Cell. Biol. 2005, 25, 2673
Google Scholar
114
Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells
Poizat, Coralie; Puri, Pier Lorenzo; Bai, Yan; Kedes, Larry
Molecular and Cellular Biology (2005), 25 (7), 2673-2687CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
P300 and CBP are general transcriptional coactivators implicated in different cellular processes, including regulation of the cell cycle, differentiation, tumorigenesis, and apoptosis. Posttranslational modifications such as phosphorylation are predicted to select a specific function of p300/CBP in these processes; however, the identification of the kinases that regulate p300/CBP activity in response to individual stimuli and the physiol. significance of p300 phosphorylation have not been elucidated. Here we demonstrate that the cardiotoxic anticancer agent doxorubicin (adriamycin) induces the phosphorylation of p300 in primary neonatal cardiomyocytes. Hyperphosphorylation precedes the degrdn. of p300 and parallels apoptosis in response to doxorubicin. Doxorubicin-activated p38 kinases α and β assoc. with p300 and are implicated in the phosphorylation-mediated degrdn. of p300, as pharmacol. blockade of p38 prevents p300 degrdn. P38 phosphorylates p300 in vitro at both the N and C termini of the protein, and enforced activation of p38 by the constitutively active form of its upstream kinase (MKK6EE) triggers p300 degrdn. These data support the conclusion that p38 mitogen-activated protein kinase regulates p300 protein stability and function in cardiomyocytes undergoing apoptosis in response to doxorubicin.
115
Xu, W.; Chen, H.; Du, K.; Asahara, H.; Tini, M.; Emerson, B. M.; Montminy, M.; Evans, R. M. Science 2001, 294, 2507
Google Scholar
There is no corresponding record for this reference.
116
Ceschin, D. G.; Walia, M.; Wenk, S. S.; Duboé, C.; Gaudon, C.; Xiao, Y.; Fauquier, L.; Sankar, M.; Vandel, L.; Gronemeyer, H. Genes Dev. 2011, 25, 1132
Google Scholar
There is no corresponding record for this reference.
117
Ryan, C. M.; Kindle, K. B.; Collins, H. M.; Heery, D. M. Biochem. Biophys. Res. Commun. 2010, 391, 1136
Google Scholar
There is no corresponding record for this reference.
118
Kuo, H. Y.; Chang, C. C.; Jeng, J. C.; Hu, H. M.; Lin, D. Y.; Maul, G. G.; Kwok, R. P.; Shih, H. M. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 16973
Google Scholar
There is no corresponding record for this reference.
119
Karanam, B.; Jiang, L.; Wang, L.; Kelleher, N. L.; Cole, P. A. J. Biol. Chem. 2006, 281, 40292
Google Scholar
There is no corresponding record for this reference.
120
Karukurichi, K. R.; Wang, L.; Uzasci, L.; Manlandro, C. M.; Wang, Q.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 1222
Google Scholar
There is no corresponding record for this reference.
121
Thompson, P. R.; Wang, D.; Wang, L.; Fulco, M.; Pediconi, N.; Zhang, D.; An, W.; Ge, Q.; Roeder, R. G.; Wong, J.; Levrero, M.; Sartorelli, V.; Cotter, R. J.; Cole, P. A. Nat. Struct. Mol. Biol. 2004, 11, 308
Google Scholar
121
Regulation of the p300 HAT domain via a novel activation loop
Thompson, Paul R.; Wang, Dongxia; Wang, Ling; Fulco, Marcella; Pediconi, Natalia; Zhang, Dianzheng; An, Woojin; Ge, Qingyuan; Roeder, Robert G.; Wong, Jiemin; Levrero, Massimo; Sartorelli, Vittorio; Cotter, Robert J.; Cole, Philip A.
Nature Structural & Molecular Biology (2004), 11 (4), 308-315CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is crit. for regulating gene expression in mammalian cells. However, the mol. events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to det. its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.
122
Karanam, B.; Wang, L.; Wang, D.; Liu, X.; Marmorstein, R.; Cotter, R.; Cole, P. A. Biochemistry 2007, 46, 8207
Google Scholar
There is no corresponding record for this reference.
123
Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
Google Scholar
123
Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
124
Personal communication with Paul Brindle, see: http://www.stjude.org/stjude/v/index.jsp?vgnextoid=c30215f204294210VgnVCM1000001e0215acRCRD.
Google Scholar
There is no corresponding record for this reference.
125
Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
Google Scholar
There is no corresponding record for this reference.
126
Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
Google Scholar
126
Histone modifiers in cancer: friends or foes?
Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
127
Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
Google Scholar
127
p300/CBP proteins: HATs for transcriptional bridges and scaffolds
Chan, Ho Man; La Thangue, Nicholas B.
Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
128
Pan, C. Q.; Sudol, M.; Sheetz, M.; Low, B. C. Cell. Signalling 2012, 24, 2143
Google Scholar
128
Modularity and functional plasticity of scaffold proteins as p(l)acemakers in cell signaling
Pan, Catherine Qiurong; Sudol, Marius; Sheetz, Michael; Low, Boon Chuan
Cellular Signalling (2012), 24 (11), 2143-2165CODEN: CESIEY; ISSN:0898-6568. (Elsevier Inc.)
A review. Cells coordinate and integrate various functional modules that control their dynamics, intracellular trafficking, metab. and gene expression. Such capacity is mediated by specific scaffold proteins that tether multiple components of signaling pathways at plasma membrane, Golgi app., mitochondria, endoplasmic reticulum, nucleus and in more specialized subcellular structures such as focal adhesions, cell-cell junctions, endosomes, vesicles and synapses. Scaffold proteins act as "pacemakers" as well as "placemakers" that regulate the temporal, spatial and kinetic aspects of protein complex assembly by modulating the local concns., proximity, subcellular dispositions and biochem. properties of the target proteins through the intricate use of their modular protein domains. These regulatory mechanisms allow them to gate the specificity, integration and crosstalk of different signaling modules. In addn. to acting as phys. platforms for protein assembly, many professional scaffold proteins can also directly modify the properties of their targets while they themselves can be regulated by post-translational modifications and/or mech. forces. Furthermore, multiple scaffold proteins can form alliances of higher-order regulatory networks. Here, we highlight the emerging themes of scaffold proteins by analyzing their common and distinctive mechanisms of action and regulation, which underlie their functional plasticity in cell signaling. Understanding these mechanisms in the context of space, time and force should have ramifications for human physiol. and for developing new therapeutic approaches to control pathol. states and diseases.
129
Tanaka, Y.; Naruse, I.; Maekawa, T.; Masuya, H.; Shiroishi, T.; Ishii, S. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10215
Google Scholar
There is no corresponding record for this reference.
130
Kamei, Y.; Xu, L.; Heinzel, T.; Torchia, J.; Kurokawa, R.; Gloss, B.; Lin, S. C.; Heyman, R. A.; Rose, D. W.; Glass, C. K.; Rosenfeld, M. G. Cell 1996, 85, 403
Google Scholar
There is no corresponding record for this reference.
131
Hottiger, M. O.; Felzien, L. K.; Nabel, G. J. EMBO J. 1998, 17, 3124
Google Scholar
There is no corresponding record for this reference.
132
Yin, X.; Warner, D. R.; Roberts, E. A.; Pisano, M. M.; Greene, R. M. Biochem. Biophys. Res. Commun. 2005, 329, 1010
Google Scholar
There is no corresponding record for this reference.
133
Avantaggiati, M. L.; Ogryzko, V.; Gardner, K.; Giordano, A.; Levine, A. S.; Kelly, K. Cell 1997, 89, 1175
Google Scholar
There is no corresponding record for this reference.
134
Kamei, Y.; Xu, L.; Heinzel, T.; Torchia, J.; Kurokawa, R.; Gloss, B.; Lin, S. C.; Heyman, R. A.; Rose, D. W.; Glass, C. K.; Rosenfeld, M. G. Cell 1996, 85, 403
Google Scholar
There is no corresponding record for this reference.
135
Goodman, R. H.; Smolik, S. Genes Dev. 2000, 14, 1553
Google Scholar
135
CBP/p300 in cell growth, transformation, and development
Goodman, Richard H.; Smolik, Sarah
Genes & Development (2000), 14 (13), 1553-1577CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)
A review with several refs. This review discusses the involvement of CBP/p300 in cell growth and transformation, chromosomal translocations, involvement of cellular oncogenes, assocn. with viral oncoproteins, involvement with DNA and RNA tumor viruses, the regulation of CBP/p300 by phosphorylation, and usage in development of model systems.
136
Lee, C. W.; Sørensen, T. S.; Shikama, N.; La Thangue, N. B. Oncogene 1998, 16, 2695
Google Scholar
There is no corresponding record for this reference.
137
Nakajima, T.; Fukamizu, A.; Takahashi, J.; Gage, F. H.; Fisher, T.; Blenis, J.; Montminy, M. R. Cell 1996, 86, 465
Google Scholar
There is no corresponding record for this reference.
138
Thompson, P. R.; Wang, D.; Wang, L.; Fulco, M.; Pediconi, N.; Zhang, D.; An, W.; Ge, Q.; Roeder, R. G.; Wong, J.; Levrero, M.; Sartorelli, V.; Cotter, R. J.; Cole, P. A. Nat. Struct. Mol. Biol. 2004, 11, 308
Google Scholar
138
Regulation of the p300 HAT domain via a novel activation loop
Thompson, Paul R.; Wang, Dongxia; Wang, Ling; Fulco, Marcella; Pediconi, Natalia; Zhang, Dianzheng; An, Woojin; Ge, Qingyuan; Roeder, Robert G.; Wong, Jiemin; Levrero, Massimo; Sartorelli, Vittorio; Cotter, Robert J.; Cole, Philip A.
Nature Structural & Molecular Biology (2004), 11 (4), 308-315CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is crit. for regulating gene expression in mammalian cells. However, the mol. events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to det. its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.
139
Muir, T. W.; Sondhi, D.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6705
Google Scholar
139
Expressed protein ligation: A general method for protein engineering
Muir, Tom W.; Sondhi, Dolan; Cole, Philip A.
Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 6705-6710CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
A protein semisynthesis method-expressed protein ligation-is described that involves the chemoselective addn. of a peptide to a recombinant protein. This method was used to ligate a phosphotyrosine peptide to the C terminus of the protein tyrosine kinase C-terminal Src kinase (Csk). By intercepting a thioester generated in the recombinant protein with an N-terminal cysteine contg. synthetic peptide, near quant. chem. ligation of the peptide to the protein was achieved. The semisynthetic tail-phosphorylated Csk showed evidence of an intramol. phosphotyrosine-Src homol. 2 interaction and an unexpected increase in catalytic phosphoryl transfer efficiency toward a physiol. relevant substrate compared with the non-tail-phosphorylated control. This work illustrates that expressed protein ligation is a simple and powerful new method in protein engineering to introduce sequences of unnatural amino acids, posttranslational modifications, and biophys. probes into proteins of any size.
140
Dancy, B. M.; Crump, N. T.; Peterson, D. J.; Mukherjee, C.; Bowers, E. M.; Ahn, Y. H.; Yoshida, M.; Zhang, J.; Mahadevan, L. C.; Meyers, D. J.; Boeke, J. D.; Cole, P. A. ChemBioChem 2012, 13, 2113
Google Scholar
There is no corresponding record for this reference.
141
Liu, X.; Wang, L.; Zhao, K.; Thompson, P. R.; Hwang, Y.; Marmorstein, R.; Cole, P. A. Nature 2008, 451, 846
Google Scholar
There is no corresponding record for this reference.
142
Hwang, Y.; Thompson, P. R.; Wang, L.; Jiang, L.; Kelleher, N. L.; Cole, P. A. Angew. Chem., Int. Ed. 2007, 46, 7621
Google Scholar
142
A selective chemical probe for coenzyme A-requiring enzymes
Hwang, Yousang; Thompson, Paul R.; Wang, Ling; Jiang, Lihua; Kelleher, Neil L.; Cole, Philip A.
Angewandte Chemie, International Edition (2007), 46 (40), 7621-7624CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A CoA-based affinity probe with a sulfoxycarbamate functionality can selectively identify several acetyltransferases relative to other enzymes and proteins. It leaves behind a desthiobiotin tag that can be used for western blotting and mass spectrometric characterization.
143
Liu, X.; Wang, L.; Zhao, K.; Thompson, P. R.; Hwang, Y.; Marmorstein, R.; Cole, P. A. Nature 2008, 451, 846
Google Scholar
There is no corresponding record for this reference.
144
Tang, Y.; Holbert, M. A.; Wurtele, H.; Meeth, K.; Rocha, W.; Gharib, M.; Jiang, E.; Thibault, P.; Verreault, A.; Cole, P. A.; Marmorstein, R. Nat. Struct. Mol. Biol. 2008, 15, 998
Google Scholar
144
Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. [Erratum to document cited in CA149:217962]
Tang, Yong; Holbert, Marc A.; Wurtele, Hugo; Meeth, Katrina; Rocha, Walter; Gharib, Marlene; Jiang, Eva; Thibault, Pierre; Verreault, Alain; Cole, Philip A.; Marmorstein, Ronen
Nature Structural & Molecular Biology (2008), 15 (9), 998CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
On page 738, the author name "Verreault" was mistakenly spelled as "Verrault". The error has been cor. in the HTML and PDF versions of the article.
145
Wang, L.; Tang, Y.; Cole, P. A.; Marmorstein, R. Curr. Opin. Struct. Biol. 2008, 18, 741
Google Scholar
145
Structure and chemistry of the p300/CBP and Rtt109 histone acetyltransferases: implications for histone acetyltransferase evolution and function
Wang, Ling; Tang, Yong; Cole, Philip A.; Marmorstein, Ronen
Current Opinion in Structural Biology (2008), 18 (6), 741-747CODEN: COSBEF; ISSN:0959-440X. (Elsevier B.V.)
A review. The recent crystal structure and assocd. biochem. studies of the metazoan-specific p300/CBP and fungal-specific Rtt109 histone acetyltransferases (HATs) have provided new insights into the ancestral relation between HATs and their functions. These studies point to a common HAT ancestor that has evolved around a common structural framework to form HATs with divergent catalytic and substrate-binding properties. These studies also point to the importance of regulatory loops within HATs and autoacetylation in HAT function. Implications for future studies are discussed.
146
Poux, A. N.; Cebrat, M.; Kim, C. M.; Cole, P. A.; Marmorstein, R. Proc. Natl. Acad. Sci. U.S.A. 2009, 99, 14065
Google Scholar
There is no corresponding record for this reference.
147
Yuan, H.; Rossetto, D.; Mellert, H.; Dang, W.; Srinivasan, M.; Johnson, J.; Hodawadekar, S.; Ding, E. C.; Speicher, K.; Abshiru, N.; Perry, R.; Wu, J.; Yang, C.; Zheng, Y. G.; Speicher, D. W.; Thibault, P.; Verreault, A.; Johnson, F. B.; Berger, S. L.; Sternglanz, R.; McMahon, S. B.; Côté, J.; Marmorstein, R. EMBO J. 2012, 31, 58
Google Scholar
There is no corresponding record for this reference.
148
Karukurichi, K. R.; Cole, P. A. Bioorg. Chem. 2011, 39, 42
Google Scholar
148
Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs
Karukurichi, Kannan R.; Cole, Philip A.
Bioorganic Chemistry (2011), 39 (1), 42-47CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biol. pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a neg. charged surface on the enzyme to interact with the histone tail.
149
Cleland, W. W. Biochim. Biophys. Acta 1963, 67, 104
Google Scholar
There is no corresponding record for this reference.
150
Cleland, W. W. Biochim. Biophys. Acta 1963, 67, 104
Google Scholar
There is no corresponding record for this reference.
151
Segel, I. Enzyme Kinetics; Wiley Interscience: New York, 1975.
Google Scholar
There is no corresponding record for this reference.
152
Zheng, Y.; Thompson, P. R.; Cebrat, M.; Wang, L.; Devlin, M. K.; Alani, R. M.; Cole, P. A. Methods Enzymol. 2004, 376, 188
Google Scholar
There is no corresponding record for this reference.
153
Bowers, E. M.; Yan, G.; Mukherjee, C.; Orry, A.; Wang, L.; Holbert, M. A.; Crump, N. T.; Hazzalin, C. A.; Liszczak, G.; Yuan, H.; Larocca, C.; Saldanha, S. A.; Abagyan, R.; Sun, Y.; Meyers, D. J.; Marmorstein, R.; Mahadevan, L. C.; Alani, R. M.; Cole, P. A. Chem. Biol. 2010, 17, 471
Google Scholar
153
Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor
Bowers, Erin M.; Yan, Gai; Mukherjee, Chandrani; Orry, Andrew; Wang, Ling; Holbert, Marc A.; Crump, Nicholas T.; Hazzalin, Catherine A.; Liszczak, Glen; Yuan, Hua; Larocca, Cecilia; Saldanha, S. Adrian; Abagyan, Ruben; Sun, Yan; Meyers, David J.; Marmorstein, Ronen; Mahadevan, Louis C.; Alani, Rhoda M.; Cole, Philip A.
Chemistry & Biology (Cambridge, MA, United States) (2010), 17 (5), 471-482CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
Summary: The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-site-directed small mol. inhibitor is not yet known. Here the authors use a structure-based, in silico screening approach to identify a com. available pyrazolone-contg. small mol. p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective vs. other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacol. probe and suggest that p300/CBP HAT is a worthy anticancer target.
154
Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
Google Scholar
There is no corresponding record for this reference.
155
Sagar, V.; Zheng, W.; Thompson, P. R.; Cole, P. A. Bioorg. Med. Chem. 2004, 12, 3383
Google Scholar
There is no corresponding record for this reference.
156
Karukurichi, K. R.; Cole, P. A. Bioorg. Chem. 2011, 39, 42
Google Scholar
156
Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs
Karukurichi, Kannan R.; Cole, Philip A.
Bioorganic Chemistry (2011), 39 (1), 42-47CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biol. pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a neg. charged surface on the enzyme to interact with the histone tail.
157
Cebrat, M.; Kim, C. M.; Thompson, P. R.; Daugherty, M.; Cole, P. A. Bioorg. Med. Chem. 2003, 11, 3307
Google Scholar
There is no corresponding record for this reference.
158
Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
Google Scholar
There is no corresponding record for this reference.
159
Chase, J. F.; Tubbs, P. K. Biochem. J. 1969, 111, 225
Google Scholar
There is no corresponding record for this reference.
160
Williams, J. W.; Northrop, D. B. J. Antibiot. 1979, 32, 1147
Google Scholar
There is no corresponding record for this reference.
161
Cullis, P. M.; Wolfenden, R.; Cousens, L. S.; Alberts, B. M. J. Biol. Chem. 1982, 257, 12165
Google Scholar
There is no corresponding record for this reference.
162
Erwin, B. G.; Persson, L.; Pegg, A. E. Biochemistry 1984, 23, 4250
Google Scholar
There is no corresponding record for this reference.
163
Khalil, E. M.; Cole, P. A. J. Am. Chem. Soc. 1998, 120, 6195
Google Scholar
There is no corresponding record for this reference.
164
Khalil, E. M.; De Angelis, J.; Ishii, M.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 12418
Google Scholar
There is no corresponding record for this reference.
165
Kim, C. M.; Cole, P. A. J. Med. Chem. 2001, 44, 2479
Google Scholar
There is no corresponding record for this reference.
166
Yu, M.; Magalhães, M. L.; Cook, P. F.; Blanchard, J. S. Biochemistry 2006, 45, 14788
Google Scholar
There is no corresponding record for this reference.
167
Gao, F.; Yan, X.; Baettig, O. M.; Berghuis, A. M.; Auclair, K. Angew. Chem., Int. Ed. 2005, 44, 6859
Google Scholar
There is no corresponding record for this reference.
168
Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A. M.; Wright, G. D.; Auclair, K. J. Med. Chem. 2006, 49, 5273
Google Scholar
There is no corresponding record for this reference.
169
Gao, F.; Yan, X.; Zahr, O.; Larsen, A.; Vong, K.; Auclair, K. Bioorg. Med. Chem. Lett. 2008, 18, 5518
Google Scholar
There is no corresponding record for this reference.
170
Magalhães, M. L.; Vetting, M. W.; Gao, F.; Freiburger, L.; Auclair, K.; Blanchard, J. S. Biochemistry 2008, 47, 579
Google Scholar
There is no corresponding record for this reference.
171
Barnett, B. P.; Hwang, Y.; Taylor, M. S.; Kirchner, H.; Pfluger, P. T.; Bernard, V.; Lin, Y. Y.; Bowers, E. M.; Mukherjee, C.; Song, W. J.; Longo, P. A.; Leahy, D. J.; Hussain, M. A.; Tschöp, M. H.; Boeke, J. D.; Cole, P. A. Science 2010, 330, 1689
Google Scholar
There is no corresponding record for this reference.
172
Taylor, M. S.; Hwang, Y.; Hsiao, P. Y.; Boeke, J. D.; Cole, P. A. Methods Enzymol. 2012, 514, 205
Google Scholar
There is no corresponding record for this reference.
173
Parang, K.; Till, J. H.; Ablooglu, A. J.; Kohanski, R. A.; Hubbard, S. R.; Cole, P. A. Nat. Struct. Biol. 2001, 8, 37
Google Scholar
There is no corresponding record for this reference.
174
Shen, K.; Hines, A. C.; Schwarzer, D.; Pickin, K. A.; Cole, P. A. Biochim. Biophys. Acta 2005, 1754, 65
Google Scholar
There is no corresponding record for this reference.
175
Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
Google Scholar
There is no corresponding record for this reference.
176
Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
Google Scholar
There is no corresponding record for this reference.
177
Zheng, Y.; Thompson, P. R.; Cebrat, M.; Wang, L.; Devlin, M. K.; Alani, R. M.; Cole, P. A. Methods Enzymol. 2004, 376, 188
Google Scholar
There is no corresponding record for this reference.
178
De Angelis, J.; Gastel, J.; Klein, D. C.; Cole, P. A. J. Biol. Chem. 1998, 273, 3045
Google Scholar
There is no corresponding record for this reference.
179
Lau, O. D.; Courtney, A. D.; Vassilev, A.; Marzilli, L. A.; Cotter, R. J.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2000, 275, 21953
Google Scholar
There is no corresponding record for this reference.
180
Tanner, K. G.; Langer, M. R.; Denu, J. M. Biochemistry 2000, 39, 15652
Google Scholar
There is no corresponding record for this reference.
181
Tanner, K. G.; Langer, M. R.; Kim, Y.; Denu, J. M. J. Biol. Chem. 2000, 275, 22048
Google Scholar
There is no corresponding record for this reference.
182
Yan, Y.; Barlev, N. A.; Haley, R. H.; Berger, S. L.; Marmorstein, R. Mol. Cell 2000, 6, 1195
Google Scholar
There is no corresponding record for this reference.
183
Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
Google Scholar
There is no corresponding record for this reference.
184
Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
Google Scholar
There is no corresponding record for this reference.
185
Lau, O. D.; Courtney, A. D.; Vassilev, A.; Marzilli, L. A.; Cotter, R. J.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2000, 275, 21953
Google Scholar
There is no corresponding record for this reference.
186
Poux, A. N.; Cebrat, M.; Kim, C. M.; Cole, P. A.; Marmorstein, R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14065
Google Scholar
There is no corresponding record for this reference.
187
Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
Google Scholar
There is no corresponding record for this reference.
188
Victor, M.; Bei, Y.; Gay, F.; Calvo, D.; Mello, C.; Shi, Y. EMBO Rep. 2002, 3, 50
Google Scholar
There is no corresponding record for this reference.
189
Huang, Z. Q.; Li, J.; Sachs, L. M.; Cole, P. A.; Wong, J. EMBO J. 2003, 22, 2146
Google Scholar
There is no corresponding record for this reference.
190
Costanzo, A.; Merlo, P.; Pediconi, N.; Fulco, M.; Sartorelli, V.; Cole, P. A.; Fontemaggi, G.; Fanciulli, M.; Schiltz, L.; Blandino, G.; Balsano, C.; Levrero, M. Mol. Cell 2002, 9, 175
Google Scholar
There is no corresponding record for this reference.
191
Kaehlcke, K.; Dorr, A.; Hetzer-Egger, C.; Kiermer, V.; Henklein, P.; Schnoelzer, M.; Loret, E.; Cole, P. A.; Verdin, E.; Ott, M. Mol. Cell 2003, 12, 167
Google Scholar
There is no corresponding record for this reference.
192
Polesskaya, A.; Naguibneva, I.; Fritsch, L.; Duquet, A.; Ait-Si-Ali, S.; Robin, P.; Vervisch, A.; Pritchard, L. L.; Cole, P.; Harel-Bellan, A. EMBO J. 2001, 20, 6816
Google Scholar
There is no corresponding record for this reference.
193
Bandyopadhyay, D.; Okan, N. A.; Bales, E.; Nascimento, L.; Cole, P. A.; Medrano, E. E. Cancer Res. 2002, 62, 6231
Google Scholar
There is no corresponding record for this reference.
194
Cebrat, M.; Kim, C. M.; Thompson, P. R.; Daugherty, M.; Cole, P. A. Bioorg. Med. Chem. 2003, 11, 3307
Google Scholar
There is no corresponding record for this reference.
195
Zheng, Y.; Balasubramanyam, K.; Cebrat, M.; Buck, D.; Guidez, F.; Zelent, A.; Alani, R. M.; Cole, P. A. J. Am. Chem. Soc. 2005, 127, 17182
Google Scholar
There is no corresponding record for this reference.
196
Guidez, F.; Howell, L.; Isalan, M.; Cebrat, M.; Alani, R. M.; Ivins, S.; Hormaeche, I.; McConnell, M. J.; Pierce, S.; Cole, P. A.; Licht, J.; Zelent, A. Mol. Cell. Biol. 2005, 25, 5552
Google Scholar
196
Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein
Guidez, Fabien; Howell, Louise; Isalan, Mark; Cebrat, Marek; Alani, Rhoda M.; Ivins, Sarah; Hormaeche, Itsaso; McConnell, Melanie J.; Pierce, Sarah; Cole, Philip A.; Licht, Jonathan; Zelent, Arthur
Molecular and Cellular Biology (2005), 25 (13), 5552-5566CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-contg. corepressor complexes to specific DNA binding sites. PLZF assocs. with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be pos. regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.
197
Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
Google Scholar
There is no corresponding record for this reference.
198
Rosen, T.; Fordice, D. B. South Med. J. 1994, 87, 543
Google Scholar
198
Cashew nut dermatitis
Rosen T; Fordice D B
Southern medical journal (1994), 87 (4), 543-6 ISSN:0038-4348.
The urushiol dermatitis caused by plants of the Anacardiaceae family is the most common cause of acute allergic contact dermatitis. We have reported a case of cashew nut urushiol dermatitis due to ingestion of homemade cashew nut butter contaminated by cashew nut shell oil. With the precautions taken today to avoid contamination of food products with cashew urushiols, it is rare to find a case of cashew nut dermatitis in the United States. We have found no other report of contact dermatitis due to cashew nut butter. Moreover, though hinted at in the literature, there has been no previous detailed report of perianal contact dermatitis due to cashew ingestion. The fact that our patient was ill enough to require treatment with 3 weeks of systemic steroid therapy highlights the potential public health hazard of consumption of improperly prepared cashew products. However, the risk of cashew nut dermatitis today remains small, and this should not discourage cashew lovers from enjoying their treats. A final lesson to be learned from this case is that perianal eruptions may be due to materials deliberately applied to the anogenital region or to ingested antigens that remain sufficiently intact within the feces to affect perianal skin.
199
Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
Google Scholar
There is no corresponding record for this reference.
200
Ghizzoni, M.; Wu, J.; Gao, T.; Haisma, H. J.; Dekker, F. J.; George Zheng, Y. Eur. J. Med. Chem. 2012, 47, 337
Google Scholar
There is no corresponding record for this reference.
201
Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
Google Scholar
There is no corresponding record for this reference.
202
Chandregowda, V.; Kush, A.; Reddy, G. C. Eur. J. Med. Chem. 2009, 44, 2711
Google Scholar
There is no corresponding record for this reference.
203
Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
Google Scholar
There is no corresponding record for this reference.
204
Devipriya, B.; Parameswari, A. R.; Rajalakshmi, G.; Palvannan, T.; Kumaradhas, P. Indian J. Biochem. Biophys. 2010, 47, 364
Google Scholar
204
Exploring the binding affinities of p300 enzyme activators CTPB and CTB using docking method
Devipriya, B.; Parameswari, A. Renuga; Rajalakshmi, G.; Palvannan, T.; Kumaradhas, P.
Indian Journal of Biochemistry & Biophysics (2010), 47 (6), 364-369CODEN: IJBBBQ; ISSN:0301-1208. (National Institute of Science Communication and Information Resources)
CREB binding protein (CBP) and E1A binding protein p300, also known as p300 are functionally related transcriptional co-activators (CoAs) and histone acetyltransferases (HATs). Some small mols., which target HATs can activate or inhibit the p300 enzyme potently. Here, the binding affinities are reported for two small mols. CTPB [N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide] and CTB [N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxybenzamide] with p300 using docking method to obtain the insight of their interaction with p300. These small mols. bind to the enzyme, subsequently causing a structural change in the enzyme, which is responsible for the HAT activation. CTB exhibits higher binding affinity than CTPB, and their lowest docked energies are -7.72, -1.18 kcal/mol, resp. In CTPB mol., phenolic hydroxyl of Tyr1397 interacts with the non-polar atoms C(5E) and C(5F), and forms polar-non polar interactions. Similar interactions have also been obsd. in CTB. The residues Tyr1446 and Cys1438 interact with the non-pentadecyl atoms. Further, the docking study predicts a N-H···O hydrogen bonding interaction between CTB and Leu1398, in which the H···O contact distance is 2.06 Å. The long pentadecyl chain of CTPB reduces the formation of hydrogen bond with the p300. The H-bond interaction could be the key factor for the better activation of CTB.
205
Mantelingu, K.; Kishore, A. H.; Balasubramanyam, K.; Kumar, G. V.; Altaf, M.; Swamy, S. N.; Selvi, R.; Das, C.; Narayana, C.; Rangappa, K. S.; Kundu, T. K. J. Phys. Chem. B 2007, 111, 4527
Google Scholar
There is no corresponding record for this reference.
206
Varier, R. A.; Swaminathan, V.; Balasubramanyam, K.; Kundu, T. K. Biochem. Pharmacol. 2004, 68, 1215
Google Scholar
There is no corresponding record for this reference.
207
Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163
Google Scholar
There is no corresponding record for this reference.
208
Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B. Biochem. Pharmacol. 2008, 75, 787
Google Scholar
There is no corresponding record for this reference.
209
Maheshwari, R. K.; Singh, A. K.; Gaddipati, J.; Srimal, R. C. Life Sci. 2006, 78, 2081
Google Scholar
There is no corresponding record for this reference.
210
Aggarwal, B. B.; Shishodia, S. Biochem. Pharmacol. 2006, 71, 1397
Google Scholar
210
Molecular targets of dietary agents for prevention and therapy of cancer
Aggarwal, Bharat B.; Shishodia, Shishir
Biochemical Pharmacology (2006), 71 (10), 1397-1421CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
A review. While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the mol. level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various mol. targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts, and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apples, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), β-carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-κB, AP-1, STAT3, Akt, Bcl-2, Bcl-XL, caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the mol. targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.
211
Zhou, H.; Beevers, C. S.; Huang, S. Curr. Drug Targets 2011, 12, 332
Google Scholar
211
The targets of curcumin
Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile
Current Drug Targets (2011), 12 (3), 332-347CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)
A review. Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal prepn. or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various mol. targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacol. aspects of curcumin as well as the underlying action mechanisms. The recently identified mol. targets and signaling pathways modulated by curcumin are also discussed here.
212
Han, X.; Xu, B.; Beevers, C. S.; Odaka, Y.; Chen, L.; Liu, L.; Luo, Y.; Zhou, H.; Chen, W.; Shen, T.; Huang, S. Carcinogenesis 2012, 33, 868
Google Scholar
There is no corresponding record for this reference.
213
Gupta, S. C.; Prasad, S.; Kim, J. H.; Patchva, S.; Webb, L. J.; Priyadarsini, I. K.; Aggarwal, B. B. Nat. Prod. Rep. 2011, 28, 1937
Google Scholar
213
Multitargeting by curcumin as revealed by molecular interaction studies
Gupta, Subash C.; Prasad, Sahdeo; Kim, Ji Hye; Patchva, Sridevi; Webb, Lauren J.; Priyadarsini, Indira K.; Aggarwal, Bharat B.
Natural Product Reports (2011), 28 (12), 1937-1955CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic mol. with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex mol. structure and chem., as well as its ability to influence multiple signaling mols. Curcumin has been shown to bind by multiple forces directly to numerous signaling mols., such as inflammatory mols., cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto-enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromols. include the α, β-unsatd. β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the Ph rings. Various biophys. tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform IR (FTIR) and CD (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunopptn., phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Mol. docking, the most commonly employed computational tool for calcg. binding affinities and predicting binding sites, has also been used to further characterize curcumin's binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its soly. and bioavailability. In this review, we focus on how curcumin directly targets signaling mols., as well as the different forces that bind the curcumin-protein complex and how this interaction affects the biol. properties of proteins. We will also discuss various analogs of curcumin designed to bind selective targets with increased affinity.
214
Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
Google Scholar
There is no corresponding record for this reference.
215
Marcu, M. G.; Jung, Y. J.; Lee, S.; Chung, E. J.; Lee, M. J.; Trepel, J.; Neckers, L. Med. Chem. 2006, 2, 169
Google Scholar
215
Curcumin is an inhibitor of p300 histone acetyltransferase
Marcu, Monica G.; Jung, Yun-Jin; Lee, Sunmin; Chung, Eun-Joo; Lee, Min-Jung; Trepel, Jane; Neckers, Len
Medicinal Chemistry (2006), 2 (2), 169-174CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant mol. targets for drug development. In this study, we demonstrate that the small mol. natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α, β unsatd. carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degrdn. of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addn. to inducing p300 degrdn. curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent assocn. with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compd. for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
216
Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163
Google Scholar
There is no corresponding record for this reference.
217
Anand, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharmaceutics 2007, 4, 807
Google Scholar
217
Bioavailability of Curcumin: Problems and Promises
Anand, Preetha; Kunnumakkara, Ajaikumar B.; Newman, Robert A.; Aggarwal, Bharat B.
Molecular Pharmaceutics (2007), 4 (6), 807-818CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
A review. Curcumin, a polyphenolic compd. derived from dietary spice turmeric, possesses diverse pharmacol. effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clin. trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metab., and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogs of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurol. diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
218
Sharma, R. A.; Euden, S. A.; Platton, S. L.; Cooke, D. N.; Shafayat, A.; Hewitt, H. R.; Marczylo, T. H.; Morgan, B.; Hemingway, D.; Plummer, S. M.; Pirmohamed, M.; Gescher, A. J.; Steward, W. P. Clin. Cancer Res. 2004, 10, 6847
Google Scholar
218
Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance
Sharma, Ricky A.; Euden, Stephanie A.; Platton, Sharon L.; Cooke, Darren N.; Shafayat, Aisha; Hewitt, Heather R.; Marczylo, Timothy H.; Morgan, Bruno; Hemingway, David; Plummer, Simon M.; Pirmohamed, Munir; Gescher, Andreas J.; Steward, William P.
Clinical Cancer Research (2004), 10 (20), 6847-6854CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) prodn., or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacol. of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 mo. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liq. chromatog. and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclin. models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 prodn. induced ex vivo. Dose-limiting toxicity was not obsd. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 prodn. in blood samples taken 1 h after dose on days 1 and 29, resp., of treatment compared with levels obsd. immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 prodn. in blood and target tissue may indicate biol. activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
219
Mishra, S.; Kapoor, N.; Mubarak Ali, A.; Pardhasaradhi, B. V.; Kumari, A. L.; Khar, A.; Misra, K. Free Radical Biol. Med. 2005, 38, 1353
Google Scholar
219
Differential apoptotic and redox regulatory activities of curcumin and its derivatives
Mishra, Satyendra; Kapoor, Neha; Mubarak Ali, A.; Pardhasaradhi, B. V. V.; Kumari, A. Leela; Khar, Ashok; Misra, Krishna
Free Radical Biology & Medicine (2005), 38 (10), 1353-1360CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)
We have synthesized different bioconjugates of curcumin, which were tested for their pro- and antioxidant properties. In the present study five representative derivs. of curcumin, i.e., 4,4'-di-(O-acetyl) curcumin, 4,4'-di-(O-glycinoyl) curcumin, 4,4'-di-(O-glycinoyl-di-N-piperoyl) curcumin, 4,4'-di-(O-piperoyl) curcumin, and 4,4'-(O,O-cystinoyl)-3,3'-dimethoxydiphenyl-1,6-heptadiene-3,5-dione, were used for testing their apoptotic potential on tumor cells. Dipiperoyl and diglycinoyl derivs. showed higher apoptotic activity at lower concns., whereas diacetyl curcumin had slightly lower apoptotic activity on tumor cells. On the other hand, diglycinoyl-dipiperoyl and cystinoyl heptadiene derivs. had lost their apoptotic potential significantly. The apoptotic activity of these derivs. correlated very well with the generation of ROS by the tumor cells, whereas GSH levels remained unaltered. Our studies also indicate down-regulation of Bcl-2 and participation of caspase-3 in the apoptotic death of tumor cells.
220
Weber, W. M.; Hunsaker, L. A.; Abcouwer, S. F.; Deck, L. M.; Vander Jagt, D. L. Bioorg. Med. Chem. 2005, 13, 3811
Google Scholar
There is no corresponding record for this reference.
221
Varier, R. A.; Swaminathan, V.; Balasubramanyam, K.; Kundu, T. K. Biochem. Pharmacol. 2004, 68, 1215
Google Scholar
There is no corresponding record for this reference.
222
Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.; Sadhale, P. P.; Kundu, T. K. J. Biol. Chem. 2004, 279, 33716
Google Scholar
There is no corresponding record for this reference.
223
Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.; Sadhale, P. P.; Kundu, T. K. J. Biol. Chem. 2004, 279, 33716
Google Scholar
There is no corresponding record for this reference.
224
Mantelingu, K.; Reddy, B. A.; Swaminathan, V.; Kishore, A. H.; Siddappa, N. B.; Kumar, G. V.; Nagashankar, G.; Natesh, N.; Roy, S.; Sadhale, P. P.; Ranga, U.; Narayana, C.; Kundu, T. K. Chem. Biol. 2007, 14, 645
Google Scholar
224
Specific Inhibition of p300-HAT Alters Global Gene Expression and Represses HIV Replication
Mantelingu, K.; Reddy, B. A. Ashok; Swaminathan, V.; Kishore, A. Hari; Siddappa, Nagadenahalli B.; Kumar, G. V. Pavan; Nagashankar, G.; Natesh, Nagashayana; Roy, Siddhartha; Sadhale, Parag P.; Ranga, Udaykumar; Narayana, Chandrabhas; Kundu, Tapas K.
Chemistry & Biology (Cambridge, MA, United States) (2007), 14 (6), 645-657CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
Summary: Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-mol. inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
225
Arif, M.; Pradhan, S. K.; Thanuja, G. R.; Vedamurthy, B. M.; Agrawal, S.; Dasgupta, D.; Kundu, T. K. J. Med. Chem. 2009, 52, 267
Google Scholar
There is no corresponding record for this reference.
226
Baggett, S.; Protiva, P.; Mazzola, E. P.; Yang, H.; Ressler, E. T.; Basile, M. J.; Weinstein, I. B.; Kennelly, E. J. J. Nat. Prod. 2005, 68, 354
Google Scholar
There is no corresponding record for this reference.
227
Gartner, M.; Müller, T.; Simon, J. C.; Giannis, A.; Sleeman, J. P. ChemBioChem 2005, 6, 171
Google Scholar
There is no corresponding record for this reference.
228
Dal Piaz, F.; Tosco, A.; Eletto, D.; Piccinelli, A. L.; Moltedo, O.; Franceschelli, S.; Sbardella, G.; Remondelli, P.; Rastrelli, L.; Vesci, L.; Pisano, C.; De Tommasi, N. ChemBioChem 2010, 11, 818
Google Scholar
There is no corresponding record for this reference.
229
Biel, M.; Kretsovali, A.; Karatzali, E.; Papamatheakis, J.; Giannis, A. Angew. Chem., Int. Ed. 2004, 43, 3974
Google Scholar
There is no corresponding record for this reference.
230
Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
Google Scholar
There is no corresponding record for this reference.
231
Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. J. Biol. Chem. 2009, 284, 24453
Google Scholar
There is no corresponding record for this reference.
232
Sandur, S. K.; Ichikawa, H.; Sethi, G.; Ahn, K. S.; Aggarwal, B. B. J. Biol. Chem. 2006, 281, 17023
Google Scholar
There is no corresponding record for this reference.
233
Padhye, S.; Dandawate, P.; Yusufi, M.; Ahmad, A.; Sarkar, F. H. Med. Res. Rev. 2012, 32, 1131
Google Scholar
233
Perspectives on medicinal properties of plumbagin and its analogs
Padhye, Subhash; Dandawate, Prasad; Yusufi, Mujahid; Ahmad, Aamir; Sarkar, Fazlul H.
Medicinal Research Reviews (2012), 32 (6), 1131-1158CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
A review. Plumbagin is one of the simplest plant secondary metabolite of three major phylogenic families viz. Plumbaginaceae, Droseraceae, and Ebenceae, and exhibits highly potent biol. activities, including antioxidant, antiinflammatory, anticancer, antibacterial, and antifungal activities. Recent investigations indicate that these activities arise mainly out of its ability to undergo redox cycling, generating reactive oxygen species and chelating trace metals in biol. system. The compd. is endowed with a property to inhibit the drug efflux mechanism in drug-resistant bacteria, thereby allowing intracellular accumulation of the potent drug mols. An interesting bioactivity exhibited by this compd. is the elimination of stringent, conjugative, multidrug-resistant plasmids from several bacterial strains including opportunistic bacteria, such as Acinetobacter baumannii. Moreover, plumbagin effectively induces apoptosis and causes cell cycle arrest, which is, in part, due to the inactivation of NF-κB in cancer cells. Therefore, it has been suggested that designing "hybrid drug mols." of plumbagin by combining it with other appropriate anticancer agents may lead to the generation of novel and potent anticancer drugs with pleiotropic action against human cancers. This comprehensive review is an attempt to understand the chem. of plumbagin and catalog its biol. activities reported to date.
234
Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. J. Biol. Chem. 2009, 284, 24453
Google Scholar
There is no corresponding record for this reference.
235
Choi, K. C.; Jung, M. G.; Lee, Y. H.; Yoon, J. C.; Kwon, S. H.; Kang, H. B.; Kim, M. J.; Cha, J. H.; Kim, Y. J.; Jun, W. J.; Lee, J. M.; Yoon, H. G. Cancer Res. 2009, 69, 583
Google Scholar
There is no corresponding record for this reference.
236
Neukam, K.; Pastor, N.; Cortés, F. Mutat. Res. 2008, 654, 8
Google Scholar
236
Tea flavanols inhibit cell growth and DNA topoisomerase II activity and induce endoreduplication in cultured Chinese hamster cells
Neukam, Karin; Pastor, Nuria; Cortes, Felipe
Mutation Research, Genetic Toxicology and Environmental Mutagenesis (2008), 654 (1), 8-12CODEN: MRGMFI; ISSN:1383-5718. (Elsevier B.V.)
Tea polyphenols are promising chemopreventive anticancer agents, the properties of which have been studied both in vitro and in vivo, providing evidence that - within this group of compds. - the tea flavanols are able to inhibit carcinogenesis, an effect that in some cases could be correlated with increased cell apoptosis and decreased cell proliferation. Of four main tea flavanols, namely (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (+)-catechin (CA) and (-)-epicatechin (EC), it was found that EGCG was the most potent to inhibit dose dependently the topoisomerase II (TOPO II) catalytic activity isolated from hamster ovary AA8 cells. In the range of concns. that caused TOPO II inhibition, a high level of endoreduplication, a rare phenomenon that consists in two successive rounds of DNA replication without intervening mitosis, was obsd., while neither micronuclei nor DNA strand breaks (Comet assay) were detected at the same doses. We propose that the anticarcinogenic effect of tea flavanols can be partly explained by their potency and effectiveness to induce endoreduplication. Concerning such an induction, max. effect seems to require a pyrogallol structure at the B-ring. Addnl. substitution with a galloylic residue at the C3 hydroxyl group leads to further augmentation of the effect. Thus, we suggest that the chemopreventive properties of tea flavanols can be at least partly due to their ability to interfere with the cell cycle and block cell proliferation at early stages of mitosis.
237
Berger, S. J.; Gupta, S.; Belfi, C. A.; Gosky, D. M.; Mukhtar, H. Biochem. Biophys. Res. Commun. 2001, 288, 101
Google Scholar
There is no corresponding record for this reference.
238
Suzuki, K.; Yahara, S.; Hashimoto, F.; Uyeda, M. Biol. Pharm. Bull. 2001, 24, 1088
Google Scholar
238
Inhibitory activities of (-)-epigallocatechin-3-O-gallate against topoisomerases I and II
Suzuki, Keitarou; Yahara, Shoji; Hashimoto, Furnio; Uyeda, Masaru
Biological & Pharmaceutical Bulletin (2001), 24 (9), 1088-1090CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
The substitution of gallic acid at the 3 position of (-)-epigallocatechin-3-O-gallate (EGCG) increased the inhibition against topoisomerase I from calf thymus gland and topoisomerase II from human placenta, and the substitution of a hydroxyl group at the 3' position increased the inhibition against the topoisomerase I. These results suggested that the 3 and 3' positions of the EGCG mol. play important roles in the process of inhibition of topoisomerases I and II. EGCG showed strong inhibition against topoisomerases I from wheat germ, calf thymus gland, and Vero cells, and showed weak or no inhibition against topoisomerases I from carcinoma cells such as A549, HeLaand COLO 201 cells. EGCG differentially inhibited the topoisomerases I from different sources.
239
Bandele, O. J.; Osheroff, N. Chem. Res. Toxicol. 2008, 21, 936
Google Scholar
There is no corresponding record for this reference.
240
Golden, E. B.; Lam, P. Y.; Kardosh, A.; Gaffney, K. J.; Cadenas, E.; Louie, S. G.; Petasis, N. A.; Chen, T. C.; Schönthal, A. H. Blood 2009, 113, 5927
Google Scholar
There is no corresponding record for this reference.
241
Ge, J.; Tan, B. X.; Chen, Y.; Yang, L.; Peng, X. C.; Li, H. Z.; Lin, H. J.; Zhao, Y.; Wei, M.; Cheng, K.; Li, L. H.; Dong, H.; Gao, F.; He, J. P.; Wu, Y.; Qiu, M.; Zhao, Y. L.; Su, J. M.; Hou, J. M.; Liu, J. Y. J. Mol. Med. 2011, 89, 595
Google Scholar
241
Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability
Ge, Jun; Tan, Ben-Xu; Chen, Ye; Yang, Li; Peng, Xing-Chen; Li, Hong-Ze; Lin, Hong-Jun; Zhao, Yu; Wei, Meng; Cheng, Ke; Li, Long-Hao; Dong, Hang; Gao, Feng; He, Jian-Ping; Wu, Yang; Qiu, Meng; Zhao, Ying-Lan; Su, Jing-Mei; Hou, Jian-Mei; Liu, Ji-Yan
Journal of Molecular Medicine (Heidelberg, Germany) (2011), 89 (6), 595-602CODEN: JMLME8; ISSN:0946-2716. (Springer)
Sunitinib, a novel oral multi-targeted tyrosine kinase inhibitor for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumor, has a good prospect for clin. application and is being investigated for the potential therapy of other tumors. We obsd. the phenomenon that drinking tea interfered with symptom control in an mRCC patient treated with sunitinib and speculated that green tea or its components might interact with sunitinib. This study was performed to investigate whether epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib. The interaction between EGCG and sunitinib was examd. in vitro and in vivo. 1H NMR (1H-NMR) spectroscopy and mass spectrometry (MS) were used to analyze the interaction between these two mols. and whether a new compd. was formed. Solns. of sunitinib and EGCG were intragastrically administered to rats to investigate whether the plasma concns. of sunitinib were affected by EGCG. In this study, we noticed that a ppt. was formed when the solns. of sunitinib and EGCG were mixed under both neutral and acidic conditions. 1H-NMR spectra indicated an interaction between EGCG and sunitinib, but no new compd. was obsd. by MS. Sticky semisolid contents were found in the stomachs of sunitinib and EGCG co-administrated mice. The and C max of plasma sunitinib were markedly reduced by co-administration of EGCG to rats. Our study firstly showed that EGCG interacted with sunitinib and reduced the bioavailability of sunitinib. This finding has significant practical implications for tea-drinking habit during sunitinib administration.
242
Strick, R.; Strissel, P. L.; Borgers, S.; Smith, S. L.; Rowley, J. D. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 4790
Google Scholar
There is no corresponding record for this reference.
243
Ruiz, P. A.; Braune, A.; Hölzlwimmer, G.; Quintanilla-Fend, L.; Haller, D. J. Nutr. 2007, 137, 1208
Google Scholar
243
Quercetin inhibits TNF-induced NF-κB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells
Ruiz, Pedro A.; Braune, Annett; Hoelzlwimmer, Gabriele; Quintanilla-Fend, Leticia; Haller, Dirk
Journal of Nutrition (2007), 137 (5), 1208-1215CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)
Flavonoids may play an important role for adjunct nutritional therapy of chronic intestinal inflammation. In this study, we characterized the mol. mechanisms by which quercetin and its enteric bacterial metabolites, taxifolin, alphitonin, and 3, 4-dihydroxy-phenylacetic acid, inhibit tumor necrosis factor α (TNF)-induced proinflammatory gene expression in the murine small intestinal epithelial cell (IEC) line Mode-K as well as in heterozygous TNFΔARE/WT mice, a murine model of exptl. ileitis. Quercetin inhibited TNF-induced interferon-γ-inducible protein 10 (IP-10) and macrophage inflammatory protein 2 (MIP-2) gene expression in Mode-K cells with effective inhibitory concn. of 40 and 44 μmol/L, resp. Interestingly, taxifolin, alphitonin, and 3,4-dihydroxy-phenylacetic acid did not inhibit TNF responses in IEC, suggesting that microbial transformation of quercetin completely abolished its anti-inflammatory effect. At the mol. level, quercetin inhibited Akt phosphorylation but did not inhibit TNF-induced RelA/I-κB phosphorylation and IκB degrdn. or TNF-α-induced nuclear factor-κB transcriptional activity. Most important for understanding the mechanism involved, chromatin immunopptn. anal. revealed inhibitory effects of quercetin on phospho-RelA recruitment to the IP-10 and MIP-2 gene promoters. In addn., and consistent with the lack of cAMP response element binding protein (CBP)/p300 recruitment and phosphorylation/acetylation of histone 3 at the promoter binding site, quercetin inhibited histone acetyl transferase activity. The oral application of quercetin to heterozygous TNFΔARE/WT mice [10 mg/(d × kg body wt)] significantly inhibited IP-10 and MIP-2 gene expression in primary ileal epithelial cells but did not affect tissue pathol. These studies support an anti-inflammatory effect of quercetin in epithelial cells through mechanisms that inhibit cofactor recruitment at the chromatin of proinflammatory genes.
244
Chen, J.; Han, J.; Wang, J. Toxicol. Ind. Health 2013, 29, 360
Google Scholar
244
Prevention of cytotoxicity of nickel by quercetin: the role of reactive oxygen species and histone acetylation
Chen, Jie; Han, Jia; Wang, Jianmin
Toxicology and Industrial Health (2013), 29 (4), 360-366CODEN: TIHEEC; ISSN:0748-2337. (Sage Publications)
Excessive exposure to nickel may cause health effects on the blood, lung, nose, kidney, reproductive system, skin and the unborn child. In the present study, we found that Ni2+ exposure led to a time- and dosedependent proliferation arrest and death in human leukemia HL-60 cells. In the presence of 1 μM Ni2+, reactive oxygen species (ROS) generation (indicated by the level of malondialdehyde) increased to 323% and histone acetylation decreased to 32%. Interestingly, quercetin (QU) dose dependently prevented Ni2+-induced cell proliferation arrest and death from 0 to 80 μM but showed similar activity of scavenging ROS at the concns. of 20, 40 and 80 μM. When the effect of QU on histone acetylation was studied, QU significantly prevented Ni2+-induced histone hypoacetylation at 40 or 80 μM. Moreover, increase in histone acetylation by trichostatin A could also significantly enhance the protection effect of QU at 10 or 20 μM but not at higher concns. Thus, our results further confirmed the crit. role of ROS and histone hypoacetylation in the cytotoxicity of Ni2+ exposure and proved that QU is a potentially useful native dietary compd. to efficiently prevent Ni2+-caused cytotoxicity through both diminishing ROS generation and increasing histone acetylation.
245
Si, D.; Wang, Y.; Zhou, Y. H.; Guo, Y.; Wang, J.; Zhou, H.; Li, Z. S.; Fawcett, J. P. Drug Metab. Dispos. 2009, 37, 629
Google Scholar
There is no corresponding record for this reference.
246
Saaby, L.; Rasmussen, H. B.; Jäger, A. K. J. Ethnopharmacol. 2009, 121, 178
Google Scholar
There is no corresponding record for this reference.
247
Hilliard, J. J.; Krause, H. M.; Bernstein, J. I.; Fernandez, J. A.; Nguyen, V.; Ohemeng, K. A.; Barrett, J. F. Adv. Exp. Med. Biol. 1995, 390, 59
Google Scholar
There is no corresponding record for this reference.
248
Xiao, X.; Shi, D.; Liu, L.; Wang, J.; Xie, X.; Kang, T.; Deng, W. PLoS One 2011, 6, e22934
Google Scholar
There is no corresponding record for this reference.
249
O’Brien, E.; Dietrich, D. R. Crit. Rev. Toxicol. 2005, 35, 33
Google Scholar
249
Ochratoxin A: The Continuing Enigma
O'Brien, Evelyn; Dietrich, Daniel
Critical Reviews in Toxicology (2005), 35 (1), 33-60CODEN: CRTXB2; ISSN:1040-8444. (Taylor & Francis, Inc.)
A review. The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in lab. and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concn. in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiol. studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species- and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant exptl. data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.
250
Czakai, K.; Müller, K.; Mosesso, P.; Pepe, G.; Schulze, M.; Gohla, A.; Patnaik, D.; Dekant, W.; Higgins, J. M.; Mally, A. Toxicol. Sci. 2011, 122, 317
Google Scholar
250
Perturbation of Mitosis through Inhibition of Histone Acetyltransferases: The Key to Ochratoxin A Toxicity and Carcinogenicity?
Czakai, Kristin; Mueller, Katja; Mosesso, Pasquale; Pepe, Gaetano; Schulze, Markus; Gohla, Antje; Patnaik, Debasis; Dekant, Wolfgang; Higgins, Jonathan M. G.; Mally, Angela
Toxicological Sciences (2011), 122 (2), 317-329CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
Ochratoxin A (OTA) is one of the most potent rodent renal carcinogens studied to date. Although controversial results regarding OTA genotoxicity have been published, it is now widely accepted that OTA is not a mutagenic, DNA-reactive carcinogen. Instead, increasing evidence from both in vivo and in vitro studies suggests that OTA may promote genomic instability and tumorigenesis through interference with cell division. The aim of the present study was to provide further support for disruption of mitosis as a key event in OTA toxicity and to understand how OTA mediates these effects. Immortalized human kidney epithelial cells (IHKE) were treated with OTA and monitored by differential interference contrast microscopy for 15 h. Image anal. confirmed that OTA at concns. ≥ 5 μM, which correlate with plasma concns. in rats under conditions of carcinogenesis, causes sustained mitotic arrest and exit from mitosis without nuclear or cellular division. Mitotic chromosomes were characterized by aberrant condensation and premature sister chromatid sepn. assocd. with altered phosphorylation and acetylation of core histones. To test if OTA directly interferes with histone acetyltransferases (HATs) which regulate lysine acetylation of histones and nonhistone proteins, a cell-free HAT activity assay was conducted using total nuclear exts. of IHKE cells. In this assay, OTA significantly blocked HAT activity in a concn.-dependent manner Overall, results from this study provide further support for a mechanism of OTA carcinogenicity involving interference with the mitotic machinery and suggest HATs as a primary cellular target of OTA.
251
Ravindra, K. C.; Narayan, V.; Lushington, G. H.; Peterson, B. R.; Prabhu, K. S. Chem. Res. Toxicol. 2012, 25, 337
Google Scholar
There is no corresponding record for this reference.
252
Reginato, M. J.; Krakow, S. L.; Bailey, S. T.; Lazar, M. A. J. Biol. Chem. 1998, 273, 1855
Google Scholar
There is no corresponding record for this reference.
253
Ravindra, K. C.; Narayan, V.; Lushington, G. H.; Peterson, B. R.; Prabhu, K. S. Chem. Res. Toxicol. 2012, 25, 337
Google Scholar
There is no corresponding record for this reference.
254
Stimson, L.; Rowlands, M. G.; Newbatt, Y. M.; Smith, N. F.; Raynaud, F. I.; Rogers, P.; Bavetsias, V.; Gorsuch, S.; Jarman, M.; Bannister, A.; Kouzarides, T.; McDonald, E.; Workman, P.; Aherne, G. W. Mol. Cancer Ther. 2005, 4, 1521
Google Scholar
254
Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity
Stimson, Lindsay; Rowlands, Martin G.; Newbatt, Yvette M.; Smith, Nicola F.; Raynaud, Florence I.; Rogers, Paul; Bavetsias, Vassilios; Gorsuch, Stephen; Jarman, Michael; Bannister, Andrew; Kouzarides, Tony; McDonald, Edward; Workman, Paul; Aherne, G. Wynne
Molecular Cancer Therapeutics (2005), 4 (10), 1521-1532CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate high-throughput screen, we identified a series of isothiazolone-based HAT inhibitors. Thirty-five N-substituted analogs inhibited both p300/cAMP-responsive element binding protein-binding protein-assocd. factor (PCAF) and p300 (1 to > 50 μmol/L, resp.) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to > 50 μmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2-48 h of exposure) and a concn.-dependent manner (one to five times, 72 h, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of α-tubulin. Four and 24 h of exposure to the compds. produced the same extent of growth inhibition as 72 h of continuous exposure, suggesting that growth arrest was an early event. Chem. reactivity of these compds., as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-mol. inhibitors of HAT activity, further analog synthesis is being pursued to examine the potential scope for reducing chem. reactivity while maintaining HAT inhibition.
255
Dekker, F. J.; Ghizzoni, M.; van der Meer, N.; Wisastra, R.; Haisma, H. J. Bioorg. Med. Chem. 2009, 17, 460
Google Scholar
There is no corresponding record for this reference.
256
Gorsuch, S.; Bavetsias, V.; Rowlands, M. G.; Aherne, G. W.; Workman, P.; Jarman, M.; McDonald, E. Bioorg. Med. Chem. 2009, 17, 467
Google Scholar
There is no corresponding record for this reference.
257
Gorsuch, S.; Bavetsias, V.; Rowlands, M. G.; Aherne, G. W.; Workman, P.; Jarman, M.; McDonald, E. Bioorg. Med. Chem. 2009, 17, 467
Google Scholar
There is no corresponding record for this reference.
258
Wisastra, R.; Ghizzoni, M.; Maarsingh, H.; Minnaard, A. J.; Haisma, H. J.; Dekker, F. J. Org. Biomol. Chem. 2011, 9, 1817
Google Scholar
There is no corresponding record for this reference.
259
Dekker, F. J.; Ghizzoni, M.; van der Meer, N.; Wisastra, R.; Haisma, H. J. Bioorg. Med. Chem. 2009, 17, 460
Google Scholar
There is no corresponding record for this reference.
260
Ornaghi, P.; Rotili, D.; Sbardella, G.; Mai, A.; Filetici, P. Biochem. Pharmacol. 2005, 70, 911
Google Scholar
There is no corresponding record for this reference.
261
Smith, A. T.; Livingston, M. R.; Mai, A.; Filetici, P.; Queener, S. F.; Sullivan, W. J., Jr. Antimicrob. Agents Chemother. 2007, 51, 1109
Google Scholar
There is no corresponding record for this reference.
262
Mai, A.; Rotili, D.; Tarantino, D.; Ornaghi, P.; Tosi, F.; Vicidomini, C.; Sbardella, G.; Nebbioso, A.; Miceli, M.; Altucci, L.; Filetici, P. J. Med. Chem. 2006, 49, 6897
Google Scholar
There is no corresponding record for this reference.
263
Mai, A.; Rotili, D.; Tarantino, D.; Nebbioso, A.; Castellano, S.; Sbardella, G.; Tini, M.; Altucci, L. Bioorg. Med. Chem. Lett. 2009, 19, 1132
Google Scholar
There is no corresponding record for this reference.
264
Rahim, R.; Strobl, J. S. Anticancer Drugs 2009, 20, 736
Google Scholar
There is no corresponding record for this reference.
265
Tahan, F.; Jazrawi, E.; Moodley, T.; Rovati, G. E.; Adcock, I. M. Clin. Exp. Allergy 2008, 38, 805
Google Scholar
265
Montelukast inhibits tumour necrosis factor-α-mediated interleukin-8 expression through inhibition of nuclear factor-κB p65-associated histone acetyltransferase activity
Tahan, F.; Jazrawi, E.; Moodley, T.; Rovati, G. E.; Adcock, I. M.
Clinical and Experimental Allergy (2008), 38 (5), 805-811CODEN: CLEAEN; ISSN:0954-7894. (Blackwell Publishing Ltd.)
Background: Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the mol. mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-κB-assocd. histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. Methods: We examd. the inhibitory effects of montelukast on TNF-α-induced IL-8 prodn. in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-α (10 ng/mL) in the presence or absence of montelukast (0.01-10 μM) for 24 h. After this time, the concn. of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-α-induced IL-8 release was examd. pharmacol. using selective NF-κB/IKK2 (AS602868, 3 μM), (PD98059, 10 μM) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 μM) inhibitors. NF-κB DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-κB-p65-assocd. histone acetyltransferase (HAT) activity was measured by immunopptn. linked to com. fluorescent HAT. Results: TNF-α-induced IL-8 release was suppressed by an NF-κB inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concn.-dependent inhibition of TNF-α-induced IL-8 release and mRNA expression that reached a plateau at 0.1 μM without affecting cell viability. Montelukast did not affect NF-κB p65 activation as measured by DNA binding but suppressed NF-κB p65-assocd. HAT activity. Conclusion: Montelukast inhibits TNF-α-stimulated IL-8 expression through changes in NF-κB p65-assocd. HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast.
266
Chimenti, F.; Bizzarri, B.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Fioravanti, R.; Granese, A.; Carradori, S.; Tosi, F.; Ballario, P.; Vernarecci, S.; Filetici, P. J. Med. Chem. 2009, 52, 530
Google Scholar
There is no corresponding record for this reference.
267
Wu, J.; Wang, J.; Li, M.; Yang, Y.; Wang, B.; Zheng, Y. G. Bioorg. Chem. 2011, 39, 53
Google Scholar
267
Small molecule inhibitors of histone acetyltransferase Tip60
Wu, Jiang; Wang, Ju-Xian; Li, Min-Yong; Yang, Yu-Tao; Wang, Bing-He; Zheng, Y. George
Bioorganic Chemistry (2011), 39 (1), 53-58CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small mol. inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small mol. inhibitors of Tip60 as mechanistic tools for functional study and as chem. leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small mol. library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compds. with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochem. studies. Further, computer modeling and kinetic assays suggest that these mols. target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chem. hits to develop further potent inhibitors for the MYST HATs.
268
Whitty, A. Future Med. Chem. 2011, 3, 797
Google Scholar
268
Growing PAINS in academic drug discovery
Whitty, Adrian
Future Medicinal Chemistry (2011), 3 (7), 797-801CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
In a recent article it was argued that compds. published as drug leads by academic labs. commonly contain functionality that identifies them as nonspecific pan-assay interference compds.'' (PAINS). The article raises broad questions about why best practices for hit and lead qualification that are well known in industry are not more widely employed in academia, as well as about the role of journals in publishing manuscripts that report drug leads of little potential value. Barriers to adoption of best practices for some academic drug-discovery researchers include knowledge gaps and infrastructure deficiencies, but they also arise from fundamental differences in how academic research is structured and how success is measured. Academic drug discovery should not seek to become identical to com. pharmaceutical research, but we can do a better job of assessing and communicating the true potential of the drug leads we publish, thereby reducing the wastage of resources on nonviable compds.
269
Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53, 2719
Google Scholar
269
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
Baell, Jonathan B.; Holloway, Georgina A.
Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
270
Mujtaba, S.; Zeng, L.; Zhou, M. M. Oncogene 2007, 26, 5521
Google Scholar
There is no corresponding record for this reference.
271
Manning, E. T.; Ikehara, T.; Ito, T.; Kadonaga, J. T.; Kraus, W. L. Mol. Cell. Biol. 2001, 21, 3876
Google Scholar
271
p300 forms a stable, template-committed complex with chromatin: role for the bromodomain
Manning, E. Tory; Ikehara, Tsuyoshi; Ito, Takashi; Kadonaga, James T.; Kraus, W. Lee
Molecular and Cellular Biology (2001), 21 (12), 3876-3887CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
The nature of the interaction of coactivator proteins with transcriptionally active promoters in chromatin is a fundamental question in transcriptional regulation by RNA polymerase II. In this study, we used a biochem. approach to examine the functional assocn. of the coactivator p300 with chromatin templates. Using in vitro transcription template competition assays, we obsd. that p300 forms a stable, template-committed complex with chromatin during the transcription process. The template commitment is dependent on the time of incubation of p300 with the chromatin template and occurs independently of the presence of a transcriptional activator protein. In studies examg. interactions between p300 and chromatin, we found that p300 binds directly to chromatin and that the binding requires the p300 bromodomain, a conserved 110-amino-acid sequence found in many chromatin-assocd. proteins. Furthermore, we obsd. that the isolated p300 bromodomain binds directly to histones, preferentially to histone H3. However, the isolated p300 bromodomain does not bind to nucleosomal histones under the same assay conditions, suggesting that free histones and nucleosomal histones are not equiv. as binding substrates. Collectively, our results suggest that the stable assocn. of p300 with chromatin is mediated, at least in part, by the bromodomain and is critically important for p300 function. Furthermore, our results suggest a model for p300 function that involves distinct activator-dependent targeting and activator-independent chromatin binding activities.
272
Wei, L.; Jamonnak, N.; Choy, J.; Wang, Z.; Zheng, W. Biochem. Biophys. Res. Commun. 2008, 368, 279
Google Scholar
There is no corresponding record for this reference.
273
Polesskaya, A.; Naguibneva, I.; Duquet, A.; Bengal, E.; Robin, P.; Harel-Bellan, A. Mol. Cell. Biol. 2001, 21, 5312
Google Scholar
273
Interaction between acetylated MyoD and the bromodomain of CBP and/or p300
Polesskaya, Anna; Naguibneva, Irina; Duquet, Arnaud; Bengal, Eyal; Robin, Philippe; Harel-Bellan, Annick
Molecular and Cellular Biology (2001), 21 (16), 5312-5320CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
Acetylation is emerging as a posttranslational modification of nuclear proteins that is essential to the regulation of transcription and that modifies transcription factor affinity for binding sites on DNA, stability, and/or nuclear localization. Here, we present both in vitro and in vivo evidence that acetylation increases the affinity of myogenic factor MyoD for acetyltransferases CBP and p300. In myogenic cells, the fraction of endogenous MyoD that is acetylated was found assocd. with CBP or p300. In vitro, the interaction between MyoD and CBP was more resistant to high salt concns. and was detected with lower doses of MyoD when MyoD was acetylated. Interestingly, an anal. of CBP mutants revealed that the interaction with acetylated MyoD involves the bromodomain of CBP. In live cells, MyoD mutants that cannot be acetylated did not assoc. with CBP or p300 and were strongly impaired in their ability to cooperate with CBP for transcriptional activation of a muscle creatine kinase-luciferase construct. Taken together, our data suggest a new mechanism for activation of protein function by acetylation and demonstrate for the first time an acetylation-dependent interaction between the bromodomain of CBP and a nonhistone protein.
274
Hou, T.; Ray, S.; Lee, C.; Brasier, A. R. J. Biol. Chem. 2008, 283, 30725
Google Scholar
There is no corresponding record for this reference.
275
Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O.; Sachchidanand; Sanchez, R.; Zeleznik-Le, N. J.; Ronai, Z.; Zhou, M. M. Mol. Cell 2004, 13, 251
Google Scholar
There is no corresponding record for this reference.
276
Kim, J. H.; Cho, E. J.; Kim, S. T.; Youn, H. D. Nat. Struct. Mol. Biol. 2005, 12, 423
Google Scholar
276
CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain
Kim, Jae-Hwan; Cho, Eun-Jung; Kim, Seong-Tae; Youn, Hong-Duk
Nature Structural & Molecular Biology (2005), 12 (5), 423-428CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been detd. In this study authors found that CtBP1 directly assocs. with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addn., an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissocn. of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.
277
Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
Google Scholar
There is no corresponding record for this reference.
278
Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
Google Scholar
278
p300/CBP proteins: HATs for transcriptional bridges and scaffolds
Chan, Ho Man; La Thangue, Nicholas B.
Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
279
Wang, F.; Marshall, C. B.; Ikura, M. Cell. Mol. Life Sci. 2013, 70, 3989
Google Scholar
279
Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition
Wang, Feng; Marshall, Christopher B.; Ikura, Mitsuhiko
Cellular and Molecular Life Sciences (2013), 70 (21), 3989-4008CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
A review. In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four sep. transactivation domains (TADs) that interact with the TADs of a no. of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiol. and pathol. processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is assocd. with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.
280
Ragvin, A.; Valvatne, H.; Erdal, S.; Arskog, V.; Tufteland, K. R.; Breen, K.; ØYan, A. M.; Eberharter, A.; Gibson, T. J.; Becker, P. B.; Aasland, R. J. Mol. Biol. 2004, 337, 773
Google Scholar
There is no corresponding record for this reference.
281
He, J.; Ye, J.; Cai, Y.; Riquelme, C.; Liu, J. O.; Liu, X.; Han, A.; Chen, L. Nucleic Acids Res. 2011, 39, 4464
Google Scholar
There is no corresponding record for this reference.
282
Zeng, L.; Zhang, Q.; Gerona-Navarro, G.; Moshkina, N.; Zhou, M. M. Structure 2008, 16, 643
Google Scholar
There is no corresponding record for this reference.
283
Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O.; Sachchidanand; Sanchez, R.; Zeleznik-Le, N. J.; Ronai, Z.; Zhou, M. M. Mol. Cell 2004, 13, 251
Google Scholar
There is no corresponding record for this reference.
284
Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
Google Scholar
There is no corresponding record for this reference.
285
Feng, H.; Jenkins, L. M.; Durell, S. R.; Hayashi, R.; Mazur, S. J.; Cherry, S.; Tropea, J. E.; Miller, M.; Wlodawer, A.; Appella, E.; Bai, Y. Structure 2009, 17, 202
Google Scholar
There is no corresponding record for this reference.
286
Wojciak, J. M.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. EMBO J. 2009, 28, 948
Google Scholar
There is no corresponding record for this reference.
287
Das, C.; Roy, S.; Namjoshi, S.; Malarkey, C. S.; Jones, D. N.; Kutateladze, T. G.; Churchill, M. E.; Tyler, J. K. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, E1072
Google Scholar
There is no corresponding record for this reference.
288
Delvecchio, M.; Gaucher, J.; Aguilar-Gurrieri, C.; Ortega, E.; Panne, D. Nat. Struct. Mol. Biol. 2013, 20, 1040
Google Scholar
288
Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation
Delvecchio, Manuela; Gaucher, Jonathan; Aguilar-Gurrieri, Carmen; Ortega, Esther; Panne, Daniel
Nature Structural & Molecular Biology (2013), 20 (9), 1040-1046CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
CBP and p300 are histone acetyltransferases (HATs) that assoc. with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 contg. its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.
289
He, J.; Ye, J.; Cai, Y.; Riquelme, C.; Liu, J. O.; Liu, X.; Han, A.; Chen, L. Nucleic Acids Res. 2011, 39, 4464
Google Scholar
There is no corresponding record for this reference.
290
Feng, H.; Jenkins, L. M.; Durell, S. R.; Hayashi, R.; Mazur, S. J.; Cherry, S.; Tropea, J. E.; Miller, M.; Wlodawer, A.; Appella, E.; Bai, Y. Structure 2009, 17, 202
Google Scholar
There is no corresponding record for this reference.
291
Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
Google Scholar
There is no corresponding record for this reference.
292
Wojciak, J. M.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. EMBO J. 2009, 28, 948
Google Scholar
There is no corresponding record for this reference.
293
Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
Google Scholar
293
p300/CBP proteins: HATs for transcriptional bridges and scaffolds
Chan, Ho Man; La Thangue, Nicholas B.
Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
294
Simone, C.; Stiegler, P.; Forcales, S. V.; Bagella, L.; De Luca, A.; Sartorelli, V.; Giordano, A.; Puri, P. L. Oncogene 2004, 23, 2177
Google Scholar
There is no corresponding record for this reference.
295
Saint Just Ribeiro, M.; Hansson, M. L.; Wallberg, A. E. Biochem. J. 2007, 404, 289
Google Scholar
There is no corresponding record for this reference.
296
Tax, F. E.; Thomas, J. H.; Ferguson, E. L.; Horvitz, H. R. Genetics 1997, 147, 1675
Google Scholar
There is no corresponding record for this reference.
297
Petcherski, A. G.; Kimble, J. Nature 2000, 405, 364
Google Scholar
There is no corresponding record for this reference.
298
Petcherski, A. G.; Kimble, J. Curr. Biol. 2000, 10, R471
Google Scholar
There is no corresponding record for this reference.
299
Kitagawa, M.; Oyama, T.; Kawashima, T.; Yedvobnick, B.; Kumar, A.; Matsuno, K.; Harigaya, K. Mol. Cell. Biol. 2001, 21, 4337
Google Scholar
299
A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of Notch and a CSL protein to build a transcriptional activator complex on target promoters
Kitagawa, Motoo; Oyama, Toshinao; Kawashima, Taichi; Yedvobnick, Barry; Kumar, Anumeha; Matsuno, Kenji; Harigaya, Kenichi
Molecular and Cellular Biology (2001), 21 (13), 4337-4346CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
Mastermind (Mam) has been implicated as an important pos. regulator of the Notch signaling pathway by genetic studies using Drosophila melanogaster. Here we describe a biochem. mechanism of action of Mam within the Notch signaling pathway. Expression of a human sequence related to Drosophila Mam (hMam-1) in mammalian cells augments induction of Hairy Enhancer of split (HES) promoters by Notch signaling. HMam-1 stabilizes and participates in the DNA binding complex of the intracellular domain of human Notch1 and a CSL protein. Truncated versions of hMam-1 that can maintain an assocn. with the complex behave in a dominant neg. fashion and depress transactivation. Furthermore, Drosophila Mam forms a similar complex with the intracellular domain of Drosophila Notch and Drosophila CSL protein during activation of Enhancer of split, the Drosophila counterpart of HES. These results indicate that Mam is an essential component of the transcriptional app. of Notch signaling.
300
Wu, L.; Aster, J. C.; Blacklow, S. C.; Lake, R.; Artavanis-Tsakonas, S.; Griffin, J. D. Nat. Genet. 2000, 26, 484
Google Scholar
300
MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors
Wu, Lizi; Aster, Jon C.; Blacklow, Stephen C.; Lake, Robert; Artavanis-Tsakonas, Spyros; Griffin, James D.
Nature Genetics (2000), 26 (4), 484-489CODEN: NGENEC; ISSN:1061-4036. (Nature America Inc.)
Notch receptors are involved in cell-fate detn. in organisms as diverse as flies, frogs and humans. In Drosophila melanogaster, loss-of-function mutations of Notch produce a "neurogenic" phenotype in which cells destined to become epidermis switch fate and differentiate to neural cells. Upon ligand activation, the intracellular domain of Notch (ICN) translocates to the nucleus, and interacts directly with the DNA-binding protein Suppressor of hairless (Su(H)) in flies, or recombination signal binding protein Jκ (RBP-Jκ) in mammals, to activate gene transcription. But the precise mechanisms of Notch-induced gene expression are not completely understood. The gene mastermind has been identified in multiple genetic screens for modifiers of Notch mutations in Drosophila. Here we clone MAML1, a human homolog of the Drosophila gene Mastermind, and show that it encodes a protein of 130 kD localizing to nuclear bodies. MAML1 binds to the ankyrin repeat domain of all four mammalian NOTCH receptors, forms a DNA-binding complex with ICN and RBP-Jκ, and amplifies NOTCH-induced transcription of HES1. These studies provide a mol. mechanism to explain the genetic links between mastermind and Notch in Drosophila and indicate that MAML1 functions as a transcriptional co-activator for NOTCH signaling.
301
Wilson, J. J.; Kovall, R. A. Cell 2006, 124, 985
Google Scholar
There is no corresponding record for this reference.
302
Arnett, K. L.; Hass, M.; McArthur, D. G.; Ilagan, M. X.; Aster, J. C.; Kopan, R.; Blacklow, S. C. Nat. Struct. Mol. Biol. 2010, 17, 1312
Google Scholar
302
Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes
Arnett, Kelly L.; Hass, Matthew; McArthur, Debbie G.; Ilagan, Ma Xenia G.; Aster, Jon C.; Kopan, Raphael; Blacklow, Stephen C.
Nature Structural & Molecular Biology (2010), 17 (11), 1312-1317CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X-ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling.
303
Nam, Y.; Sliz, P.; Song, L.; Aster, J. C.; Blacklow, S. C. Cell 2006, 124, 973
Google Scholar
There is no corresponding record for this reference.
304
Choi, S. H.; Wales, T. E.; Nam, Y.; O’Donovan, D. J.; Sliz, P.; Engen, J. R.; Blacklow, S. C. Structure 2012, 20, 340
Google Scholar
There is no corresponding record for this reference.
305
Hansson, M. L.; Popko-Scibor, A. E.; Saint Just Ribeiro, M.; Dancy, B. M.; Lindberg, M. J.; Cole, P. A.; Wallberg, A. E. Nucleic Acids Res. 2009, 37, 2996
Google Scholar
There is no corresponding record for this reference.
306
Fryer, C. J.; Lamar, E.; Turbachova, I.; Kintner, C.; Jones, K. A. Genes Dev. 2002, 16, 1397
Google Scholar
There is no corresponding record for this reference.
307
Saint Just Ribeiro, M.; Hansson, M. L.; Wallberg, A. E. Biochem. J. 2007, 404, 289
Google Scholar
There is no corresponding record for this reference.
308
Black, J. C.; Choi, J. E.; Lombardo, S. R.; Carey, M. Mol. Cell 2006, 23, 809
Google Scholar
There is no corresponding record for this reference.
309
Kim, J. H.; Cho, E. J.; Kim, S. T.; Youn, H. D. Nat. Struct. Mol. Biol. 2005, 12, 423
Google Scholar
309
CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain
Kim, Jae-Hwan; Cho, Eun-Jung; Kim, Seong-Tae; Youn, Hong-Duk
Nature Structural & Molecular Biology (2005), 12 (5), 423-428CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been detd. In this study authors found that CtBP1 directly assocs. with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addn., an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissocn. of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.
310
Kraus, W. L.; Manning, E. T.; Kadonaga, J. T. Mol. Cell. Biol. 1999, 19, 8123
Google Scholar
310
Biochemical analysis of distinct activation functions in p300 that enhance transcription initiation with chromatin templates
Kraus, W. Lee; Manning, E. Tory; Kadonaga, James T.
Molecular and Cellular Biology (1999), 19 (12), 8123-8135CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
To investigate the mechanisms of transcriptional enhancement by the p300 coactivator, we analyzed wild-type and mutant versions of p300 with a chromatin transcription system in vitro. Estrogen receptor, NF-κB p65 plus Sp1, and Gal4-VP16 were used as different sequence-specific activators. The CH3 domain (or E1A-binding region) was found to be essential for the function of each of the activators tested. The bromodomain was also obsd. to be generally important for p300 coactivator activity, though to a lesser extent than the CH3 domain/E1A-binding region. The acetyltransferase activity and the C-terminal region (contg. the steroid receptor coactivator/p160-binding region and the glutamine-rich region) were each found to be important for activation by estrogen receptor but not for that by Gal4-VP16. The N-terminal region of p300, which had been previously found to interact with nuclear hormone receptors, was not seen to be required for any of the activators, including estrogen receptor. Single-round transcription expts. revealed that the functionally important subregions of p300 contribute to its ability to promote the assembly of transcription initiation complexes. In addn., the acetyltransferase activity of p300 was obsd. to be distinct from the broadly essential activation function of the CH3 domain/E1A-binding region. These results indicate that specific regions of p300 possess distinct activation functions that are differentially required to enhance the assembly of transcription initiation complexes. Interestingly, with the estrogen receptor, four distinct regions of p300 each have an essential role in the transcription activation process. These data exemplify a situation in which a network of multiple activation functions is required to achieve gene transcription.
311
Delvecchio, M.; Gaucher, J.; Aguilar-Gurrieri, C.; Ortega, E.; Panne, D. Nat. Struct. Mol. Biol. 2013, 20, 1040
Google Scholar
311
Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation
Delvecchio, Manuela; Gaucher, Jonathan; Aguilar-Gurrieri, Carmen; Ortega, Esther; Panne, Daniel
Nature Structural & Molecular Biology (2013), 20 (9), 1040-1046CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
CBP and p300 are histone acetyltransferases (HATs) that assoc. with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 contg. its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.
312
Filippakopoulos, P.; Knapp, S. Nat. Rev. Drug Discovery 2014, 13, 337
Google Scholar
312
Targeting bromodomains: epigenetic readers of lysine acetylation
Filippakopoulos, Panagis; Knapp, Stefan
Nature Reviews Drug Discovery (2014), 13 (5), 337-356CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A review. Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programs that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncol., where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addn., targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.
313
Nicodeme, E.; Jeffrey, K. L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C. W.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; White, J.; Kirilovsky, J.; Rice, C. M.; Lora, J. M.; Prinjha, R. K.; Lee, K.; Tarakhovsky, A. Nature 2010, 468, 1119
Google Scholar
There is no corresponding record for this reference.
314
Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V. L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A. B.; Boursier, E.; Martin, S.; Brusq, J. M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. Bioorg. Med. Chem. Lett. 2012, 22, 2963
Google Scholar
There is no corresponding record for this reference.
315
Dawson, M. A.; Prinjha, R. K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W. I.; Robson, S. C.; Chung, C. W.; Hopf, C.; Savitski, M. M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T. D.; Roberts, E. J.; Soden, P. E.; Auger, K. R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A. K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B. J.; Kouzarides, T. Nature 2011, 478, 529
Google Scholar
There is no corresponding record for this reference.
316
Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T. T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.; West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; La Thangue, N.; French, C. A.; Wiest, O.; Kung, A. L.; Knapp, S.; Bradner, J. E. Nature 2010, 468, 1067
Google Scholar
316
Selective inhibition of BET bromodomains
Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; Shen, Yao; Smith, William B.; Fedorov, Oleg; Morse, Elizabeth M.; Keates, Tracey; Hickman, Tyler T.; Felletar, Ildiko; Philpott, Martin; Munro, Shongah; McKeown, Michael R.; Wang, Yuchuan; Christie, Amanda L.; West, Nathan; Cameron, Michael J.; Schwartz, Brian; Heightman, Tom D.; La Thangue, Nicholas; French, Christopher; Wiest, Olaf; Kung, Andrew L.; Knapp, Stefan; Bradner, James E.
Nature (London, United Kingdom) (2010), 468 (7327), 1067-1073CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here the authors report a cell-permeable small mol. (I,JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is obsd. in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chem. scaffold for the development of chem. probes more broadly throughout the bromodomain family.
317
Fish, P. V.; Filippakopoulos, P.; Bish, G.; Brennan, P. E.; Bunnage, M. E.; Cook, A. S.; Federov, O.; Gerstenberger, B. S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D. R.; Philpott, M.; Picaud, S.; Primiano, M. J.; Ralph, M. J.; Sciammetta, N.; Trzupek, J. D. J. Med. Chem. 2012, 55, 9831
Google Scholar
There is no corresponding record for this reference.
318
Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P. V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P.; O’Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S. Cancer Res. 2013, 73, 3336
Google Scholar
There is no corresponding record for this reference.
319
Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. J. Med. Chem. 2011, 54, 6761
Google Scholar
There is no corresponding record for this reference.
320
Hay, D.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Philpott, M.; Picaud, S.; Hewings, D. S.; Uttakar, S.; Heightman, T. D.; Conway, S. J.; Knapp, S.; Brennan, P. E. Med. Chem. Commun. 2013, 4, 140
Google Scholar
There is no corresponding record for this reference.
321
Bamborough, P.; Diallo, H.; Goodacre, J. D.; Gordon, L.; Lewis, A.; Seal, J. T.; Wilson, D. M.; Woodrow, M. D.; Chung, C. W. J. Med. Chem. 2012, 55, 587
Google Scholar
There is no corresponding record for this reference.
322
Boehm, D.; Calvanese, V.; Dar, R. D.; Xing, S.; Schroeder, S.; Martins, L.; Aull, K.; Li, P. C.; Planelles, V.; Bradner, J. E.; Zhou, M. M.; Siliciano, R. F.; Weinberger, L.; Verdin, E.; Ott, M. Cell Cycle 2013, 12, 452
Google Scholar
There is no corresponding record for this reference.
323
Li, Z.; Guo, J.; Wu, Y.; Zhou, Q. Nucleic Acids Res. 2013, 41, 277
Google Scholar
There is no corresponding record for this reference.
324
Zhu, J.; Gaiha, G. D.; John, S. P.; Pertel, T.; Chin, C. R.; Gao, G.; Qu, H.; Walker, B. D.; Elledge, S. J.; Brass, A. L. Cell Rep. 2012, 2, 807
Google Scholar
324
Reactivation of latent HIV-1 by inhibition of BRD4
Zhu, Jian; Gaiha, Gaurav D.; John, Sinu P.; Pertel, Thomas; Chin, Christopher R.; Gao, Geng; Qu, Hongjing; Walker, Bruce D.; Elledge, Stephen J.; Brass, Abraham L.
Cell Reports (2012), 2 (4), 807-816CODEN: CREED8; ISSN:2211-1247. (Cell Press)
HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the redn. of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain contg. 4 (BRD4) as a neg. regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small mol. inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection.
325
Banerjee, C.; Archin, N.; Michaels, D.; Belkina, A. C.; Denis, G. V.; Bradner, J.; Sebastiani, P.; Margolis, D. M.; Montano, M. J. Leukocyte Biol. 2012, 92, 1147
Google Scholar
325
BET bromodomain inhibition as a novel strategy for reactivation of HIV-1
Banerjee, Camellia; Archin, Nancie; Michaels, Daniel; Belkina, Anna C.; Denis, Gerald V.; Bradner, James; Sebastiani, Paola; Margolis, David M.; Montano, Monty
Journal of Leukocyte Biology (2012), 92 (6), 1147-1154CODEN: JLBIE7; ISSN:0741-5400. (Society for Leukocyte Biology)
The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. We report the capacity for HIV reactivation by a selective small mol. inhibitor of BET family bromodomains, JQ1, a promising therapeutic agent with antioncogenic properties. JQ1 reactivated HIV transcription in models of latent T cell infection and latent monocyte infection. We also tested the effect of exposure to JQ1 to allow recovery of replication-competent HIV from pools of resting CD4+ T cells isolated from HIV-infected, ART-treated patients. In one of three patients, JQ1 allowed recovery of virus at a frequency above unstimulated conditions. JQ1 potently suppressed T cell proliferation with minimal cytotoxic effect. Transcriptional profiling of T cells with JQ1 showed potent down-regulation of T cell activation genes, including CD3, CD28, and CXCR4, similar to HDAC inhibitors, but JQ1 also showed potent up-regulation of chromatin modification genes, including SIRT1, HDAC6, and multiple lysine demethylases (KDMs). Thus, JQ1 reactivates HIV-1 while suppressing T cell activation genes and up-regulating histone modification genes predicted to favor increased Tat activity. Thus, JQ1 may be useful in studies of potentially novel mechanisms for transcriptional control as well as in translational efforts to identify therapeutic mols. to achieve viral eradication.
326
Wang, X.; Li, J.; Schowalter, R. M.; Jiao, J.; Buck, C. B.; You, J. PLoS Pathog. 2012, 8, e1003021
Google Scholar
There is no corresponding record for this reference.
327
Goupille, O.; Penglong, T.; Lefèvre, C.; Granger, M.; Kadri, Z.; Fucharoen, S.; Maouche-Chrétien, L.; Leboulch, P.; Chrétien, S. Biochem. Biophys. Res. Commun. 2012, 429, 1
Google Scholar
There is no corresponding record for this reference.
328
Ott, C. J.; Kopp, N.; Bird, L.; Paranal, R. M.; Qi, J.; Bowman, T.; Rodig, S. J.; Kung, A. L.; Bradner, J. E.; Weinstock, D. M. Blood 2012, 120, 2843
Google Scholar
There is no corresponding record for this reference.
329
Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P. V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P.; O’Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S. Cancer Res. 2013, 73, 3336
Google Scholar
There is no corresponding record for this reference.
330
Dawson, M. A.; Prinjha, R. K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W. I.; Robson, S. C.; Chung, C. W.; Hopf, C.; Savitski, M. M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T. D.; Roberts, E. J.; Soden, P. E.; Auger, K. R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A. K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B. J.; Kouzarides, T. Nature 2011, 478, 529
Google Scholar
There is no corresponding record for this reference.
331
Zuber, J.; Shi, J.; Wang, E.; Rappaport, A. R.; Herrmann, H.; Sison, E. A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; Taylor, M. J.; Johns, C.; Chicas, A.; Mulloy, J. C.; Kogan, S. C.; Brown, P.; Valent, P.; Bradner, J. E.; Lowe, S. W.; Vakoc, C. R. Nature 2011, 478, 524
Google Scholar
There is no corresponding record for this reference.
332
Mertz, J. A.; Conery, A. R.; Bryant, B. M.; Sandy, P.; Balasubramanian, S.; Mele, D. A.; Bergeron, L.; Sims, R. J., III. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 16669
Google Scholar
There is no corresponding record for this reference.
333
Delmore, J. E.; Issa, G. C.; Lemieux, M. E.; Rahl, P. B.; Shi, J.; Jacobs, H. M.; Kastritis, E.; Gilpatrick, T.; Paranal, R. M.; Qi, J.; Chesi, M.; Schinzel, A. C.; McKeown, M. R.; Heffernan, T. P.; Vakoc, C. R.; Bergsagel, P. L.; Ghobrial, I. M.; Richardson, P. G.; Young, R. A.; Hahn, W. C.; Anderson, K. C.; Kung, A. L.; Bradner, J. E.; Mitsiades, C. S. Cell 2011, 146, 904
Google Scholar
There is no corresponding record for this reference.
334
Lockwood, W. W.; Zejnullahu, K.; Bradner, J. E.; Varmus, H. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 19408
Google Scholar
There is no corresponding record for this reference.
335
Bandukwala, H. S.; Gagnon, J.; Togher, S.; Greenbaum, J. A.; Lamperti, E. D.; Parr, N. J.; Molesworth, A. M.; Smithers, N.; Lee, K.; Witherington, J.; Tough, D. F.; Prinjha, R. K.; Peters, B.; Rao, A. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 14532
Google Scholar
There is no corresponding record for this reference.
336
Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V. L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A. B.; Boursier, E.; Martin, S.; Brusq, J. M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. Bioorg. Med. Chem. Lett. 2012, 22, 2963
Google Scholar
There is no corresponding record for this reference.
337
Bamborough, P.; Diallo, H.; Goodacre, J. D.; Gordon, L.; Lewis, A.; Seal, J. T.; Wilson, D. M.; Woodrow, M. D.; Chung, C. W. J. Med. Chem. 2012, 55, 587
Google Scholar
There is no corresponding record for this reference.
338
Zhang, G.; Liu, R.; Zhong, Y.; Plotnikov, A. N.; Zhang, W.; Zeng, L.; Rusinova, E.; Gerona-Nevarro, G.; Moshkina, N.; Joshua, J.; Chuang, P. Y.; Ohlmeyer, M.; He, J. C.; Zhou, M. M. J. Biol. Chem. 2012, 287, 28840– 51
Google Scholar
There is no corresponding record for this reference.
339
Matzuk, M. M.; McKeown, M. R.; Filippakopoulos, P.; Li, Q.; Ma, L.; Agno, J. E.; Lemieux, M. E.; Picaud, S.; Yu, R. N.; Qi, J.; Knapp, S.; Bradner, J. E. Cell 2012, 150, 673
Google Scholar
There is no corresponding record for this reference.
340
Ferguson, F. M.; Fedorov, O.; Chaikuad, A.; Philpott, M.; Muniz, J. R.; Felletar, I.; von Delft, F.; Heightman, T.; Knapp, S.; Abell, C.; Ciulli, A. J. Med. Chem. 2013, 56, 10183
Google Scholar
There is no corresponding record for this reference.
341
Zhang, W.; Prakash, C.; Sum, C.; Gong, Y.; Li, Y.; Kwok, J. J.; Thiessen, N.; Pettersson, S.; Jones, S. J.; Knapp, S.; Yang, H.; Chin, K. C. J. Biol. Chem. 2012, 287, 43137
Google Scholar
There is no corresponding record for this reference.
342
Bartholomeeusen, K.; Xiang, Y.; Fujinaga, K.; Peterlin, B. M. J. Biol. Chem. 2012, 287, 36609
Google Scholar
There is no corresponding record for this reference.
343
Devaiah, B. N.; Lewis, B. A.; Cherman, N.; Hewitt, M. C.; Albrecht, B. K.; Robey, P. G.; Ozato, K.; Sims, R. J., III; Singer, D. S. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 6927
Google Scholar
There is no corresponding record for this reference.
344
Palermo, R. D.; Webb, H. M.; West, M. J. PLoS Pathog. 2011, 7, e1002334
Google Scholar
There is no corresponding record for this reference.
345
Delmore, J. E.; Issa, G. C.; Lemieux, M. E.; Rahl, P. B.; Shi, J.; Jacobs, H. M.; Kastritis, E.; Gilpatrick, T.; Paranal, R. M.; Qi, J.; Chesi, M.; Schinzel, A. C.; McKeown, M. R.; Heffernan, T. P.; Vakoc, C. R.; Bergsagel, P. L.; Ghobrial, I. M.; Richardson, P. G.; Young, R. A.; Hahn, W. C.; Anderson, K. C.; Kung, A. L.; Bradner, J. E.; Mitsiades, C. S. Cell 2011, 146, 904
Google Scholar
There is no corresponding record for this reference.
346
Sachchidanand; Resnick-Silverman, L.; Yan, S.; Mutjaba, S.; Liu, W. J.; Zeng, L.; Manfredi, J. J.; Zhou, M. M. Chem. Biol. 2006, 13, 81
Google Scholar
346
Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein Association
Sachchidanand; Resnick-Silverman, Lois; Yan, Sherry; Mutjaba, Shiraz; Liu, Wen-jun; Zeng, Lei; Manfredi, James J.; Zhou, Ming-Ming
Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (1), 81-90CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small mols. that block lysine 382-acetylated p53 assocn. with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chems. were discovered in target structure-guided NMR spectroscopy screening of a focused chem. library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chems. inhibit CBP/p53 assocn. by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chems. can modulate p53 stability and function in response to doxorubicin-induced DNA damage.
347
Borah, J. C.; Mujtaba, S.; Karakikes, I.; Zeng, L.; Muller, M.; Patel, J.; Moshkina, N.; Morohashi, K.; Zhang, W.; Gerona-Navarro, G.; Hajjar, R. J.; Zhou, M. M. Chem. Biol. 2011, 18, 531
Google Scholar
347
A Small Molecule Binding to the Coactivator CREB-Binding Protein Blocks Apoptosis in Cardiomyocytes
Borah, Jagat C.; Mujtaba, Shiraz; Karakikes, Ioannis; Zeng, Lei; Muller, Michaela; Patel, Jigneshkumar; Moshkina, Natasha; Morohashi, Keita; Zhang, Weijia; Gerona-Navarro, Guillermo; Hajjar, Roger J.; Zhou, Ming-Ming
Chemistry & Biology (Cambridge, MA, United States) (2011), 18 (4), 531-541CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
Summary: As a master transcription factor in cellular responses to external stress, tumor suppressor p53 is tightly regulated. Excessive p53 activity during myocardial ischemia causes irreversible cellular injury and cardiomyocyte death. P53 activation is dependent on lysine acetylation by the lysine acetyltransferase and transcriptional coactivator CREB-binding protein (CBP) and on acetylation-directed CBP recruitment for p53 target gene expression. Here, we report a small mol. ischemin, developed with a structure-guided approach to inhibit the acetyl-lysine binding activity of the bromodomain of CBP. We show that ischemin alters post-translational modifications on p53 and histones, inhibits p53 interaction with CBP and transcriptional activity in cells, and prevents apoptosis in ischemic cardiomyocytes. Our study suggests small mol. modulation of acetylation-mediated interactions in gene transcription as a new approach to therapeutic interventions of human disorders such as myocardial ischemia.
348
Gerona-Navarro, G.; Yoel-Rodríguez; Mujtaba, S.; Frasca, A.; Patel, J.; Zeng, L.; Plotnikov, A. N.; Osman, R.; Zhou, M. M. J. Am. Chem. Soc. 2011, 133, 2040
Google Scholar
There is no corresponding record for this reference.
349
Rooney, T. P.; Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Cortopassi, W. A.; Hay, D. A.; Martin, S.; Tumber, A.; Rogers, C. M.; Philpott, M.; Wang, M.; Thompson, A. L.; Heightman, T. D.; Pryde, D. C.; Cook, A.; Paton, R. S.; Müller, S.; Knapp, S.; Brennan, P. E.; Conway, S. J. Angew. Chem., Int. Ed. 2014, 53, 6126
Google Scholar
There is no corresponding record for this reference.
350
Fedorov, O.; Lingard, H.; Wells, C.; Monteiro, O. P.; Picaud, S.; Keates, T.; Yapp, C.; Philpott, M.; Martin, S. J.; Felletar, I.; Marsden, B. D.; Filippakopoulos, P.; Müller, S.; Knapp, S.; Brennan, P. E. J. Med. Chem. 2014, 57, 462
Google Scholar
There is no corresponding record for this reference.
351
Chung, C. W.; Dean, A. W.; Woolven, J. M.; Bamborough, P. J. Med. Chem. 2012, 55, 576
Google Scholar
There is no corresponding record for this reference.
352
Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. J. Med. Chem. 2011, 54, 6761
Google Scholar
There is no corresponding record for this reference.
353
Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Müller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E. J. Am. Chem. Soc. 2014, 136, 9308
Google Scholar
There is no corresponding record for this reference.
354
Dey, A.; Wong, E. T.; Cheok, C. F.; Tergaonkar, V.; Lane, D. P. Cell Death Differ. 2008, 15, 263
Google Scholar
354
R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy
Dey, A.; Wong, E. T.; Cheok, C. F.; Tergaonkar, V.; Lane, D. P.
Cell Death and Differentiation (2008), 15 (2), 263-273CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that is currently in phase II clin. trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate nuclear factor-kappa B (NF-κB) activation in response to tumor necrosis factor (TNF)α and interleukin 1. Activation of p53-dependent transcription is not compromised when R-Roscovitine is combined with TNFα. We characterize the mol. mechanism governing NF-κB repression and show that R-Roscovitine inhibits the IκB kinase (IKK) kinase activity, which leads to defective IκBα phosphorylation, degrdn. and hence nuclear function of NF-κB. We further show that the downregulation of the NF-κB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-κB target genes monocyte chemoattractant protein, intercellular adhesion mol.-1, cyclooxygenase-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFα and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anticancer drug that functions by simultaneously causing p53 activation and NF-κB suppression. This study also provides mechanistic insight into the mol. mechanism of action of R-Roscovitine, thereby possibly explaining its anti-inflammatory properties. Cell Death and Differentiation (2008) 15, 263-273; doi:10.1038/sj.cdd.4402257; published online 2 Nov. 2007.
355
Li, B. X.; Xiao, X. ChemBioChem 2009, 10, 2721
Google Scholar
There is no corresponding record for this reference.
356
Best, J. L.; Amezcua, C. A.; Mayr, B.; Flechner, L.; Murawsky, C. M.; Emerson, B.; Zor, T.; Gardner, K. H.; Montminy, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 17622
Google Scholar
There is no corresponding record for this reference.
357
Minter, A. R.; Brennan, B. B.; Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 10504
Google Scholar
There is no corresponding record for this reference.
358
Buhrlage, S. J.; Bates, C. A.; Rowe, S. P.; Minter, A. R.; Brennan, B. B.; Majmudar, C. Y.; Wemmer, D. E.; Al-Hashimi, H.; Mapp, A. K. ACS Chem. Biol. 2009, 4, 335
Google Scholar
There is no corresponding record for this reference.
359
Bates, C. A.; Pomerantz, W. C.; Mapp, A. K. Biopolymers 2011, 95, 17
Google Scholar
There is no corresponding record for this reference.
360
Rowe, S. P.; Casey, R. J.; Brennan, B. B.; Buhrlage, S. J.; Mapp, A. K. J. Am. Chem. Soc. 2007, 129, 10654
Google Scholar
There is no corresponding record for this reference.
361
Henderson, W. R., Jr.; Chi, E. Y.; Ye, X.; Nguyen, C.; Tien, Y. T.; Zhou, B.; Borok, Z.; Knight, D. A.; Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 14309
Google Scholar
There is no corresponding record for this reference.
362
Emami, K. H.; Nguyen, C.; Ma, H.; Kim, D. H.; Jeong, K. W.; Eguchi, M.; Moon, R. T.; Teo, J. L.; Kim, H. Y.; Moon, S. H.; Ha, J. R.; Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12682
Google Scholar
There is no corresponding record for this reference.
363
Sasaki, T.; Hwang, H.; Nguyen, C.; Kloner, R. A.; Kahn, M. PLoS One 2013, 8, e75010
Google Scholar
There is no corresponding record for this reference.
364
Hao, S.; He, W.; Li, Y.; Ding, H.; Hou, Y.; Nie, J.; Hou, F. F.; Kahn, M.; Liu, Y. J. Am. Soc. Nephrol. 2011, 22, 1642
Google Scholar
364
Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis
Hao, Sha; He, Weichun; Li, Yingjian; Ding, Hong; Hou, Yayi; Nie, Jing; Hou, Fan Fan; Kahn, Michael; Liu, Youhua
Journal of the American Society of Nephrology (2011), 22 (9), 1642-1653CODEN: JASNEU; ISSN:1046-6673. (American Society of Nephrology)
Because fibrotic kidneys exhibit aberrant activation of β-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examd. the effects of β-catenin activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small mol. ICG-001, which specifically disrupts β-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized β-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed β-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-β1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and α-smooth muscle actin (α-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, α-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting β-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.
365
Majmudar, C. Y.; Højfeldt, J. W.; Arevang, C. J.; Pomerantz, W. C.; Gagnon, J. K.; Schultz, P. J.; Cesa, L. C.; Doss, C. H.; Rowe, S. P.; Vásquez, V.; Tamayo-Castillo, G.; Cierpicki, T.; Brooks, C. L., III; Sherman, D. H.; Mapp, A. K. Angew. Chem., Int. Ed. 2012, 51, 11258
Google Scholar
There is no corresponding record for this reference.
366
Kung, A. L.; Zabludoff, S. D.; France, D. S.; Freedman, S. J.; Tanner, E. A.; Vieira, A.; Cornell-Kennon, S.; Lee, J.; Wang, B.; Wang, J.; Memmert, K.; Naegeli, H. U.; Petersen, F.; Eck, M. J.; Bair, K. W.; Wood, A. W.; Livingston, D. M. Cancer Cell 2004, 6, 33
Google Scholar
366
Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway
Kung, Andrew L.; Zabludoff, Sonya D.; France, Dennis S.; Freedman, Steven J.; Tanner, Elizabeth A.; Vieira, Annelisa; Cornell-Kennon, Susan; Lee, Jennifer; Wang, Beqing; Wang, Jamin; Memmert, Klaus; Naegeli, Hans-Ulrich; Petersen, Frank; Eck, Michael J.; Bair, Kenneth W.; Wood, Alexander W.; Livingston, David M.
Cancer Cell (2004), 6 (1), 33-43CODEN: CCAECI; ISSN:1535-6108. (Cell Press)
Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, the authors identified chetomin as a disrupter of HIF binding to p300. At a mol. level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacol. attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small mol.
367
Block, K. M.; Wang, H.; Szabó, L. Z.; Polaske, N. W.; Henchey, L. K.; Dubey, R.; Kushal, S.; László, C. F.; Makhoul, J.; Song, Z.; Meuillet, E. J.; Olenyuk, B. Z. J. Am. Chem. Soc. 2009, 131, 18078
Google Scholar
There is no corresponding record for this reference.
368
Yin, S.; Kaluz, S.; Devi, N. S.; Jabbar, A. A.; de Noronha, R. G.; Mun, J.; Zhang, Z.; Boreddy, P. R.; Wang, W.; Wang, Z.; Abbruscato, T.; Chen, Z.; Olson, J. J.; Zhang, R.; Goodman, M. M.; Nicolaou, K. C.; Van Meir, E. G. Clin. Cancer Res. 2012, 18, 6623
Google Scholar
368
Arylsulfonamide KCN1 Inhibits In Vivo Glioma Growth and Interferes with HIF Signaling by Disrupting HIF-1α Interaction with Cofactors p300/CBP
Yin, Shaoman; Kaluz, Stefan; Devi, Narra S.; Jabbar, Adnan A.; de Noronha, Rita G.; Mun, Jiyoung; Zhang, Zhaobin; Boreddy, Purushotham R.; Wang, Wei; Wang, Zhibo; Abbruscato, Thomas; Chen, Zhengjia; Olson, Jeffrey J.; Zhang, Ruiwen; Goodman, Mark M.; Nicolaou, K. C.; Van Meir, Erwin G.
Clinical Cancer Research (2012), 18 (24), 6623-6633CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
Purpose: The hypoxia-inducible factor-1 (HIF-1) plays a crit. role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we detd. whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action. Exptl. Design: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examd. its influence on the assembly of a functional HIF-1α/HIF-1β/p300 transcription complex. Results: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of s.c. malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α with transcriptional coactivators p300/CBP. Conclusions: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression.
369
Tanaka, Y.; Naruse, I.; Maekawa, T.; Masuya, H.; Shiroishi, T.; Ishii, S. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10215
Google Scholar
There is no corresponding record for this reference.
370
Yao, T. P.; Oh, S. P.; Fuchs, M.; Zhou, N. D.; Ch’ng, L. E.; Newsome, D.; Bronson, R. T.; Li, E.; Livingston, D. M.; Eckner, R. Cell 1998, 93, 361
Google Scholar
There is no corresponding record for this reference.
371
Roelfsema, J. H.; Peters, D. J. Expert Rev. Mol. Med. 2007, 9, 1
Google Scholar
371
Rubinstein-Taybi syndrome: clinical and molecular overview
Roelfsema Jeroen H; Peters Dorien J M
Expert reviews in molecular medicine (2007), 9 (23), 1-16 ISSN:.
Rubinstein-Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100,000 newborns. Mutations in two genes - CREBBP and EP300 - have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein-Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein-Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.
372
Qaksen, H.; Bartsch, O.; Okur, M.; Temel, H.; Açikgoz, M.; Yilmaz, C. Genet. Couns. 2009, 20, 255
Google Scholar
There is no corresponding record for this reference.
373
Viosca, J.; Lopez-Atalaya, J. P.; Olivares, R.; Eckner, R.; Barco, A. Neurobiol. Dis. 2010, 37, 186
Google Scholar
373
Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology
Viosca Jose; Lopez-Atalaya Jose P; Olivares Roman; Eckner Richard; Barco Angel
Neurobiology of disease (2010), 37 (1), 186-94 ISSN:.
Rubinstein-Taybi syndrome (RSTS) is a complex autosomal-dominant disease characterized by mental and growth retardation and skeletal abnormalities. A majority of the individuals diagnosed with RSTS carry heterozygous mutation in the gene CREBBP, but a small percentage of cases are caused by mutations in EP300. To investigate the contribution of p300 to RSTS pathoetiology, we carried out a comprehensive and multidisciplinary characterization of p300(+/-) mice. These mice exhibited facial abnormalities and impaired growth, two traits associated to RSTS in humans. We also observed abnormal gait, reduced swimming speed, enhanced anxiety in the elevated plus maze, and mild cognitive impairment during the transfer task in the water maze. These analyses demonstrate that p300(+/-) mice exhibit phenotypes that are reminiscent of neurological traits observed in RSTS patients, but their comparison with previous studies on CBP deficient strains also indicates that, in agreement with the most recent findings in human patients, the activity of p300 in cognition is likely less relevant or more susceptible to compensation than the activity of CBP.
374
Roelfsema, J. H.; Peters, D. J. Expert Rev. Mol. Med. 2007, 9, 1
Google Scholar
374
Rubinstein-Taybi syndrome: clinical and molecular overview
Roelfsema Jeroen H; Peters Dorien J M
Expert reviews in molecular medicine (2007), 9 (23), 1-16 ISSN:.
Rubinstein-Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100,000 newborns. Mutations in two genes - CREBBP and EP300 - have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein-Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein-Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.
375
Gervasini, C.; Mottadelli, F.; Ciccone, R.; Castronovo, P.; Milani, D.; Scarano, G.; Bedeschi, M. F.; Belli, S.; Pilotta, A.; Selicorni, A.; Zuffardi, O.; Larizza, L. Eur. J. Hum. Genet. 2010, 18, 768
Google Scholar
375
High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis
Gervasini, Cristina; Mottadelli, Federica; Ciccone, Roberto; Castronovo, Paola; Milani, Donatella; Scarano, Gioacchino; Bedeschi, Maria Francesca; Belli, Serena; Pilotta, Alba; Selicorni, Angelo; Zuffardi, Orsetta; Larizza, Lidia
European Journal of Human Genetics (2010), 18 (7), 768-775CODEN: EJHGEU; ISSN:1018-4813. (Nature Publishing Group)
Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterized by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were neg. at fluorescence in situ hybridization analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): Four de novo and three inherited rearrangements not reported among the copy no. variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clin. RSTS phenotype is difficult to assess.
376
Foley, P.; Bunyan, D.; Stratton, J.; Dillon, M.; Lynch, S. A. Am. J. Med. Genet., Part A 2009, 149A, 997
Google Scholar
376
Further case of Rubinstein-Taybi syndrome due to a deletion in EP300
Foley, Patricia; Bunyan, David; Stratton, John; Dillon, Michelle; Lynch, Sally Ann
American Journal of Medical Genetics, Part A (2009), 149A (5), 997-1000CODEN: AJMGB8; ISSN:1552-4825. (Wiley-Liss, Inc.)
Rubinstein-Taybi syndrome (RSTS) is a heterogeneous disorder with approx. 45-55% of patients showing mutations in the CREB binding protein and a further 3% of patients having mutations in EP300. We report a male child with a deletion of exons 3-8 of the EP300 gene who has RSTS. He has a milder skeletal phenotype, a finding that has been described in other cases with EP300 mutations. The mother suffered from preeclampsia and HELLP syndrome in the pregnancy. She subsequently developed a mullerian tumor of her cervix 6 years after the birth of her son.
377
Bartholdi, D.; Roelfsema, J. H.; Papadia, F.; Breuning, M. H.; Niedrist, D.; Hennekam, R. C.; Schinzel, A.; Peters, D. J. J. Med. Genet. 2007, 44, 327
Google Scholar
377
Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300
Bartholdi, Deborah; Roelfsema, Jeroen H.; Papadia, Francesco; Breuning, Martijn H.; Niedrist, Dunja; Hennekam, Raoul C.; Schinzel, Albert; Peters, Dorien J. M.
Journal of Medical Genetics (2007), 44 (5), 327-333CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is assocd. with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically obsd. in patients with RSTS. Part of the clin. variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.
378
Tsai, A. C.; Dossett, C. J.; Walton, C. S.; Cramer, A. E.; Eng, P. A.; Nowakowska, B. A.; Pursley, A. N.; Stankiewicz, P.; Wiszniewska, J.; Cheung, S. W. Eur. J. Hum. Genet. 2011, 19, 43
Google Scholar
378
Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH
Tsai Anne Chun-Hui; Dossett Cherilyn J; Walton Carol S; Cramer Andrea E; Eng Patti A; Nowakowska Beata A; Pursley Amber N; Stankiewicz Pawel; Wiszniewska Joanna; Cheung Sau Wai
European journal of human genetics : EJHG (2011), 19 (1), 43-9 ISSN:.
We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which approximately 45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest.
379
Zimmermann, N.; Acosta, A. M.; Kohlhase, J.; Bartsch, O. Eur. J. Hum. Genet. 2007, 15, 837
Google Scholar
379
Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome
Zimmermann, Nicole; Acosta, Ana Maria Bravo Ferrer; Kohlhase, Juergen; Bartsch, Oliver
European Journal of Human Genetics (2007), 15 (8), 837-842CODEN: EJHGEU; ISSN:1018-4813. (Nature Publishing Group)
The Rubinstein-Taybi syndrome (RSTS, MIM 180849), a dominant Mendelian disorder with typical face, short stature, skeletal abnormalities, and mental retardation, is usually caused by heterozygous mutations of the CREBBP gene, but recently, EP300 gene mutations were reported in three individuals. Using quant. PCR (for the CREBBP and EP300 genes) and genomic sequencing (for the EP300 gene), we studied here 13 patients who had shown no mutation after genomic sequencing of the CREBBP gene in a previous investigation. Two new disease-causing mutations were identified, including a partial deletion of CREBBP and a 1-bp deletion in EP300, c.7100delC (p.P2366fsX2401). The 1-bp deletion represents the fourth EP300 mutation reported to date and was identified in a patient with non-classical RSTS. Based on the very similar structure of the CREBBP and EP300 genes and the higher rate of single-nucleotide polymorphisms in EP300 (2.23 per individual) as compared to CREBBP (0.71 per individual) (P>0.001, Wilcoxon test), it may be assumed that EP300 gene mutations should be as frequent as CREBBP gene mutations. Based on the location of the EP300 gene mutations identified so far (outside the histone acetyl transferase domain) and the obsd. (although not very striking) phenotypical differences with the EP300 mutations, we propose that most EP300 mutations could be assocd. with other phenotypes, not classical RSTS.
380
Bartholdi, D.; Roelfsema, J. H.; Papadia, F.; Breuning, M. H.; Niedrist, D.; Hennekam, R. C.; Schinzel, A.; Peters, D. J. J. Med. Genet. 2007, 44, 327
Google Scholar
380
Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300
Bartholdi, Deborah; Roelfsema, Jeroen H.; Papadia, Francesco; Breuning, Martijn H.; Niedrist, Dunja; Hennekam, Raoul C.; Schinzel, Albert; Peters, Dorien J. M.
Journal of Medical Genetics (2007), 44 (5), 327-333CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is assocd. with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically obsd. in patients with RSTS. Part of the clin. variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.
381
Lopez-Atalaya, J. P.; Gervasini, C.; Mottadelli, F.; Spena, S.; Piccione, M.; Scarano, G.; Selicorni, A.; Barco, A.; Larizza, L. J. Med. Genet. 2012, 49, 66
Google Scholar
381
Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome
Lopez-Atalaya, J. P.; Gervasini, C.; Mottadelli, F.; Spena, S.; Piccione, M.; Scarano, G.; Selicorni, A.; Barco, A.; Larizza, L.
Journal of Medical Genetics (2012), 49 (1), 66-74CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
Background: Rubinstein-Taybi syndrome (RSTS) is a congenital neurodevelopmental disorder defined by postnatal growth deficiency, characteristic skeletal abnormalities and mental retardation and caused by mutations in the genes encoding for the transcriptional co-activators with intrinsic lysine acetyltransferase (KAT) activity CBP and p300. Previous studies have shown that neuronal histone acetylation is reduced in mouse models of RSTS. Methods: The authors identified different mutations at the CREBBP locus and generated lymphoblastoid cell lines derived from nine patients with RSTS carrying distinct CREBBP mutations that illustrate different grades of the clin. severity in the spectrum of the syndrome. They next assessed whether histone acetylation levels were altered in these cell lines. Results: The comparison of CREBBP-mutated RSTS cell lines with cell lines derived from patients with an unrelated mental retardation syndrome or healthy controls revealed significant deficits in histone acetylation, affecting primarily histone H2B and histone H2A. The most severe defects were obsd. in the lines carrying the whole deletion of the CREBBP gene and the truncating mutation, both leading to a haploinsufficiency state. Interestingly, this deficit was rescued by treatment with an inhibitor of histone deacetylases (HDACi). Conclusions: The authors' results extend to humans the seminal observations in RSTS mouse models and point to histone acetylation defects, mainly involving H2B and H2A, as relevant mol. markers of the disease.
382
Miller, R. W.; Rubinstein, J. H. Am. J. Med. Genet. 1995, 56, 112
Google Scholar
382
Tumors in Rubinstein-Taybi syndrome
Miller R W; Rubinstein J H
American journal of medical genetics (1995), 56 (1), 112-5 ISSN:0148-7299.
The 14 tumors reported in Rubinstein-Taybi syndrome since 1989, when added to the 22 previously reported, are beginning to show a pattern of neural and developmental tumors, especially of the head, which is malformed in the syndrome. Among the neoplasms were 12 of the nervous system: 2 each of oligodendroglioma, medulloblastoma, neuroblastoma, and benign meningioma, a pheochromocytoma, and 3 other benign tumors; 2 of nasopharyngeal rhabdomyosarcoma; and 1 each of leiomyosarcoma, seminoma, and embryonal carcinoma. Among the other benign tumors were an odontoma, a choristoma, a dermoid cyst, and 2 pilomatrixomas.
383
Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
Google Scholar
383
p300/CBP and cancer
Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
384
Tillinghast, G. W.; Partee, J.; Albert, P.; Kelley, J. M.; Burtow, K. H.; Kelly, K. Genes, Chromosomes Cancer 2003, 37, 121
Google Scholar
384
Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines
Tillinghast, Guy W.; Partee, Jason; Albert, Paul; Kelley, Jenny M.; Burtow, Kenneth H.; Kelly, Kathleen
Genes, Chromosomes & Cancer (2003), 37 (2), 121-131CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
EP300 (p300) and CREBBP (CBP) are highly related transcriptional co-activators possessing histone acetyltransferase activity. These proteins have been implicated in coordinating numerous transcriptional responses that are important in the processes of proliferation and differentiation. A role for EP300 and CREBBP as tumor suppressors in cancer has been suggested by the fact that they are targeted by viral oncogenes; there is an increased incidence of hematol. malignancies in mice monoallelic for CREBBP; and loss, albeit at a low frequency, of both EP300 alleles in epithelial cancers has been obsd. Because the level of EP300/CREBBP appears to have a crit. effect on integrating certain transcriptional processes, we sought to det. whether a loss in the combined gene dosage of EP300 and CREBBP might play a role in cancer. Accordingly, we screened a panel of 103 cell lines for loss of heterozygosity and found 35 and 51% LOH for the CREBBP and EP300 loci, resp. Concordant loss of CREBBP and EP300 was not assocd. with mutations in important regions of the remaining EP300 or CREBBP genes. In addn., there did not appear to be a statistically significant selection in cancer cells, stratified by various criteria, for the concordant loss of EP300 and CREBBP. We conclude that EP300 and CREBBP rarely act as classical tumor suppressors in human cancer.
385
Bryan, E. J.; Jokubaitis, V. J.; Chamberlain, N. L.; Baxter, S. W.; Dawson, E.; Choong, D. Y.; Campbell, I. G. Int. J. Cancer 2002, 102, 137
Google Scholar
385
Mutation analysis of EP300 in colon, breast and ovarian carcinomas
Bryan, Emma J.; Jokubaitis, Venta J.; Chamberlain, Narelle L.; Baxter, Simon W.; Dawson, Elisabeth; Choong, David Y. H.; Campbell, Ian G.
International Journal of Cancer (2002), 102 (2), 137-141CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
The putative tumor suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. The authors analyzed 203 human breast, colon and ovarian primary tumors and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumors but no somatic mutations in EP300 were identified in any primary tumor. Anal. of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). The authors confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbors an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot anal. confirmed the presence of an apparently wild-type protein. The authors' study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harboring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumor types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.
386
Muraoka, M.; Konishi, M.; Kikuchi-Yanoshita, R.; Tanaka, K.; Shitara, N.; Chong, J. M.; Iwama, T.; Miyaki, M. Oncogene 1996, 12, 1565
Google Scholar
There is no corresponding record for this reference.
387
Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
Google Scholar
387
p300/CBP and cancer
Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
388
Pasqualucci, L.; Dominguez-Sola, D.; Chiarenza, A.; Fabbri, G.; Grunn, A.; Trifonov, V.; Kasper, L. H.; Lerach, S.; Tang, H.; Ma, J.; Rossi, D.; Chadburn, A.; Murty, V. V.; Mullighan, C. G.; Gaidano, G.; Rabadan, R. Nature 2011, 471, 189
Google Scholar
There is no corresponding record for this reference.
389
Kishimoto, M.; Kohno, T.; Okudela, K.; Otsuka, A.; Sasaki, H.; Tanabe, C.; Sakiyama, T.; Hirama, C.; Kitabayashi, I.; Minna, J. D.; Takenoshita, S.; Yokota, J. Clin. Cancer Res. 2005, 11, 512
Google Scholar
389
Mutations and deletions of the CBP gene in human lung cancer
Kishimoto, Masahiro; Kohno, Takashi; Okudela, Koji; Otsuka, Ayaka; Sasaki, Hiroki; Tanabe, Chikako; Sakiyama, Tokuki; Hirama, Chie; Kitabayashi, Issay; Minna, John D.; Takenoshita, Seiichi; Yokota, Jun
Clinical Cancer Research (2005), 11 (2, Pt. 1), 512-519CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
Microarray-based comparative genomic hybridization anal. led us to detect a homozygous deletion at the cAMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive anal. of genetic CBP alterations in human lung cancer. Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene. Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examd. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant redn. in transcription activation activity of CBP protein in vivo. A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.
390
Suganuma, T.; Kawabata, M.; Ohshima, T.; Ikeda, M. A. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13073
Google Scholar
There is no corresponding record for this reference.
391
Mullighan, C. G.; Zhang, J.; Kasper, L. H.; Lerach, S.; Payne-Turner, D.; Phillips, L. A.; Heatley, S. L.; Holmfeldt, L.; Collins-Underwood, J. R.; Ma, J.; Buetow, K. H.; Pui, C. H.; Baker, S. D. Nature 2011, 471, 235
Google Scholar
There is no corresponding record for this reference.
392
Sánchez-Molina, S.; Oliva, J. L.; García-Vargas, S.; Valls, E.; Rojas, J. M.; Martínez-Balbás, M. A. Biochem. J. 2006, 398, 215
Google Scholar
There is no corresponding record for this reference.
393
Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
Google Scholar
393
p300/CBP and cancer
Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
394
Fan, S.; Ma, Y. X.; Wang, C.; Yuan, R. Q.; Meng, Q.; Wang, J. A.; Erdos, M.; Goldberg, I. D.; Webb, P.; Kushner, P. J.; Pestell, R. G.; Rosen, E. M. Cancer Res. 2002, 62, 141
Google Scholar
There is no corresponding record for this reference.
395
Liang, J.; Prouty, L.; Williams, B. J.; Dayton, M. A.; Blanchard, K. L. Blood 1998, 92, 2118
Google Scholar
There is no corresponding record for this reference.
396
Carapeti, M.; Aguiar, R. C.; Goldman, J. M.; Cross, N. C. Blood 1998, 91, 3127
Google Scholar
There is no corresponding record for this reference.
397
Kindle, K. B.; Troke, P. J.; Collins, H. M.; Matsuda, S.; Bossi, D.; Bellodi, C.; Kalkhoven, E.; Salomoni, P.; Pelicci, P. G.; Minucci, S.; Heery, D. M. Mol. Cell. Biol. 2005, 25, 988
Google Scholar
397
MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function
Kindle, Karin B.; Troke, Philip J. F.; Collins, Hilary M.; Matsuda, Sachiko; Bossi, Daniela; Bellodi, Cristian; Kalkhoven, Eric; Salomoni, Paolo; Pelicci, Pier Giuseppe; Minucci, Saverio; Heery, David M.
Molecular and Cellular Biology (2005), 25 (3), 988-1002CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
Chromosomal rearrangements assocd. with acute myeloid leukemia (AML) include fusions of the genes encoding the acetyltransferase MOZ or MORF with genes encoding the nuclear receptor coactivator TIF2, p300, or CBP. Here we show that MOZ-TIF2 acts as a dominant inhibitor of the transcriptional activities of CBP-dependent activators such as nuclear receptors and p53. The dominant neg. property of MOZ-TIF2 requires the CBP-binding domain (activation domain 1 [AD1]), and coimmunopptn. and fluorescent resonance energy transfer expts. show that MOZ-TIF2 interacts with CBP directly in vivo. The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-neg. cells in vitro. We show that MOZ-TIF2 displays an aberrant nuclear distribution and that cells expressing this protein have reduced levels of cellular CBP, leading to depletion of CBP from PML bodies. In summary, our results indicate that disruption of the normal function of CBP and CBP-dependent activators is an important feature of MOZ-TIF2 action in AML.
398
Ito, Y.; Miyazono, K. Curr. Opin. Genet. Dev. 2003, 13, 43
Google Scholar
There is no corresponding record for this reference.
399
Grossman, S. R. Eur. J. Biochem. 2001, 268, 2773
Google Scholar
399
p300/CBP/p53 interaction and regulation of the p53 response
Grossman, Steven R.
European Journal of Biochemistry (2001), 268 (10), 2773-2778CODEN: EJBCAI; ISSN:0014-2956. (Blackwell Science Ltd.)
A review with 50 refs. Substantial evidence points to a crit. role for the p300/CREB binding protein (CBP) co-activators in p53 responses to DNA damage. The p300/CBP and the assocd. protein P/CAF bind to and acetylate p53 during the DNA damage response, and are needed for full p53 transactivation as well as downstream p53 effects of growth arrest and/or apoptosis. Beyond this simplistic model, p300/CBP appear to be complex integrators of signals that regulate p53, and biochem., the multipartite p53/p300/CBP interaction is equally complex. Through phys. interaction with p53, p300/CBP can both pos. and neg. regulate p53 transactivation, as well as p53 protein turnover depending on cellular context and environmental stimuli, such as DNA damage.
400
Iyer, N. G.; Xian, J.; Chin, S. F.; Bannister, A. J.; Daigo, Y.; Aparicio, S.; Kouzarides, T.; Caldas, C. Oncogene 2007, 26, 21
Google Scholar
There is no corresponding record for this reference.
401
Galbiati, L.; Mendoza-Maldonado, R.; Gutierrez, M. I.; Giacca, M. Cell Cycle 2005, 4, 930
Google Scholar
There is no corresponding record for this reference.
402
Oike, Y.; Hata, A.; Mamiya, T.; Kaname, T.; Noda, Y.; Suzuki, M.; Yasue, H.; Nabeshima, T.; Araki, K.; Yamamura, K. Hum. Mol. Genet. 1999, 8, 387
Google Scholar
402
Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism
Oike, Yuichi; Hata, Akira; Mamiya, Takayoshi; Kaname, Tadashi; Noda, Yukihiro; Suzuki, Misao; Yasue, Hirofumi; Nabeshima, Toshitaka; Araki, Kimi; Yamamura, Ken-Ichi
Human Molecular Genetics (1999), 8 (3), 387-396CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cAMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) contg. the CREB-binding domain (residues 462-661), showed clin. features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-neg. inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP+/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.
403
Viosca, J.; Lopez-Atalaya, J. P.; Olivares, R.; Eckner, R.; Barco, A. Neurobiol. Dis. 2010, 37, 186
Google Scholar
403
Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology
Viosca Jose; Lopez-Atalaya Jose P; Olivares Roman; Eckner Richard; Barco Angel
Neurobiology of disease (2010), 37 (1), 186-94 ISSN:.
Rubinstein-Taybi syndrome (RSTS) is a complex autosomal-dominant disease characterized by mental and growth retardation and skeletal abnormalities. A majority of the individuals diagnosed with RSTS carry heterozygous mutation in the gene CREBBP, but a small percentage of cases are caused by mutations in EP300. To investigate the contribution of p300 to RSTS pathoetiology, we carried out a comprehensive and multidisciplinary characterization of p300(+/-) mice. These mice exhibited facial abnormalities and impaired growth, two traits associated to RSTS in humans. We also observed abnormal gait, reduced swimming speed, enhanced anxiety in the elevated plus maze, and mild cognitive impairment during the transfer task in the water maze. These analyses demonstrate that p300(+/-) mice exhibit phenotypes that are reminiscent of neurological traits observed in RSTS patients, but their comparison with previous studies on CBP deficient strains also indicates that, in agreement with the most recent findings in human patients, the activity of p300 in cognition is likely less relevant or more susceptible to compensation than the activity of CBP.
404
Kung, A. L.; Rebel, V. I.; Bronson, R. T.; Ch’ng, L. E.; Sieff, C. A.; Livingston, D. M.; Yao, T. P. Genes Dev. 2000, 14, 272
Google Scholar
There is no corresponding record for this reference.
405
Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
Google Scholar
405
Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
406
Rebel, V. I.; Kung, A. L.; Tanner, E. A.; Yang, H.; Bronson, R. T.; Livingston, D. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14789
Google Scholar
There is no corresponding record for this reference.
407
Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
Google Scholar
407
Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
408
Qiao, Y.; Molina, H.; Pandey, A.; Zhang, J.; Cole, P. A. Science 2006, 311, 1293
Google Scholar
There is no corresponding record for this reference.
409
Liao, Z. W.; Zhou, T. C.; Tan, X. J.; Song, X. L.; Liu, Y.; Shi, X. Y.; Huang, W. J.; Du, L. L.; Tu, B. J.; Lin, X. D. J. Transl. Med. 2012, 10, 110
Google Scholar
409
High expression of p300 is linked to aggressive features and poor prognosis of nasopharyngeal carcinoma
Liao, Zhi-Wei; Zhou, Tong-Chong; Tan, Xiao-Jun; Song, Xian-Lu; Liu, Yuan; Shi, Xing-Yuan; Huang, Wen-Jin; Du, Li-Li; Tu, Bo-Jun; Lin, Xiao-Dan
Journal of Translational Medicine (2012), 10 (), 110CODEN: JTMOBV; ISSN:1479-5876. (BioMed Central Ltd.)
Background: Increased expression of transcriptional coactivator p300 has been obsd. in a variety of human cancers. However, the expression status of p300 protein/mRNA in nasopharyngeal carcinoma (NPC) tissues and its clinicopathol./prognostic implication are poorly understood. Methods: In our study, mRNA and protein expression levels of p300 was explored by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting (WB) and immunohistochem. (IHC) in nasopharyngeal mucosal and NPC tissues. The data were analyzed by receiver operating characteristic (ROC) curve anal., spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model. Results: Up-regulated expression of p300 mRNA/p300 protein was detected in NPC tissues by RT-PCR and WB, when compared to nasopharyngeal mucosal tissues. Based on ROC curve anal., the cutoff score for p300 high expression was defined when more than 35% of the tumor cells were pos. stained. High expression of p300 was obsd. in 127/209 (60.7%) of NPCs. In NPCs, high expression of p300 was pos. assocd. with later T classification, later N classification, distant metastasis and later clin. stage (P < 0.05). In univariate survival anal., overexpression of p300 was found to be an indicator of progression-free (P = 0.002) and overall survival (P = 0.001) in NPCs. More importantly, p300 expression was evaluated as an independent prognostic factor for NPC in multivariate anal. (P = 0.036). Conclusions: Our findings support that high expression of p300 protein might be important in conferring a more aggressive behavior, and is an independent mol. marker for shortened survival time of patients with NPC.
410
Li, M.; Luo, R. Z.; Chen, J. W.; Cao, Y.; Lu, J. B.; He, J. H.; Wu, Q. L.; Cai, M. Y. J. Transl. Med. 2011, 9, 5
Google Scholar
410
High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma
Li, Mei; Luo, Rong-Zhen; Chen, Jie-Wei; Cao, Yun; Lu, Jia-Bin; He, Jie-Hua; Wu, Qiu-Liang; Cai, Mu-Yan
Journal of Translational Medicine (2011), 9 (), 5CODEN: JTMOBV; ISSN:1479-5876. (BioMed Central Ltd.)
Background: It has been suggested that p300 participates in the regulation of a wide range of cell biol. processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clin./prognostic significance are unclear. Methods: In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochem. (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve anal., spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results: Up-regulated expression of p300 mRNA and protein was obsd. in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were pos. stained. High expression of p300 was examd. in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival anal., a significant assocn. between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate anal. (P = 0.021). Consequently, a new clinicopathol. prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001). Conclusions: Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examd. by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathol. prognostic model may become a useful tool for identifying HCC patients with different clin. outcomes.
411
Vleugel, M. M.; Shvarts, D.; van der Wall, E.; van Diest, P. J. Hum. Pathol. 2006, 37, 1085
Google Scholar
411
p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer
Vleugel, Marije M.; Shvarts, David; van der Wall, Elsken; van Diest, Paul J.
Human Pathology (2006), 37 (8), 1085-1092CODEN: HPCQA4; ISSN:0046-8177. (Elsevier Inc.)
In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)-1α in breast cancer, esp. the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1α and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochem. was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1α, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated pos. with HIF-1α expression (P = .04), p53 accumulation (P = .001), and overexpression of glucose transporter 1 (GLUT-1) (P < .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly assocd. with p300 in HIF-1α pos. patients (P = .02). p53 accumulation significantly pos. correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1α-pos. patients (P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly assocd. with GLUT-1 overexpression (P = .01) and coexpression of CAIX/GLUT-1 (P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly assocd. with p53 accumulation and HIF-1α levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1α-overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1-regulated response toward hypoxia.
412
Hudelist, G.; Czerwenka, K.; Kubista, E.; Marton, E.; Pischinger, K.; Singer, C. F. Breast Cancer Res. Treat. 2003, 78, 193
Google Scholar
412
Expression of Sex Steroid Receptors and their Co-Factors in Normal and Malignant Breast Tissue: AIB1 is a Carcinoma-Specific Co-Activator
Hudelist, Gernot; Czerwenka, Klaus; Kubista, Ernst; Marton, Erika; Pischinger, Kerstin; Singer, Christian F.
Breast Cancer Research and Treatment (2003), 78 (2), 193-204CODEN: BCTRD6; ISSN:0167-6806. (Kluwer Academic Publishers)
The differential expression pattern of estrogen receptor alpha (ER-α), estrogen receptor beta (ER-β) and their co-activator/co-repressor proteins is thought to modulate estrogenic action and to be present already during the early stages of tumorigenesis. It has therefore been postulated that certain co-activator and co-repressor proteins contribute to the development of breast cancer. There are some reports providing information on gene amplification and mRNA over-expression of certain co-factors in breast cancer, but to date there is only limited knowledge about their resp. protein expressions. The aim of this study was to examine the expression of four steroid receptor co-activators (steroid receptor co-activator 1 (SRC-1), transcription intermediary factor 2 (TIF 2), protein 300 kDa/CREB binding protein (p300/CBP), amplified in breast cancer 1 (AIB1)), and of the co-repressor nuclear receptor co-repressor (NCoR), in malignant breast tissues and in matching normal breast biopsies of the same individuals. Protein expression was analyzed by immunohistochem. and was compared to prognostic parameters such as lymph node involvement, tumor grading and receptor status. All members of the co-regulatory protein family were detected in both, benign and matching malignant tissue samples, except for AIB1, which was found to be expressed exclusively in malignant epithelium. AIB1 was preferentially present in carcinomas with high tumor grade (r = 0.48, p = 0.014), and was co-expressed with p300/CBP (r = 0.54, p = 0.006). TIF 2 correlated significantly to nodal status (r = 0.46, p = 0.025). Furthermore, protein levels of ER-β, p300/CBP and AIB1 were higher in invasive ductal carcinomas than in normal mammary tissue. The tumoral ER-α protein expression was significantly correlated with that of PgR (r = 0.61, p = 0.001) and NCoR (r = 0.4, p = 0.043), whereas ER-β expression was assocd. with SRC-1 (r = 0.68, p ≤ 0.001), TIF 2 (r = 0.64, p = 0.001) and NCoR (r = 0.48, p = 0.014) protein levels in malignant specimens. In our hands, 20% of ER-β pos. tumors did not express ER-α protein, thereby suggesting that a substantial fraction of ER-beta pos. tumors is falsely considered to be estrogen receptor neg.' if only ER-α specific antibodies are employed in the histol. assessment of the ER status.
413
Debes, J. D.; Sebo, T. J.; Lohse, C. M.; Murphy, L. M.; Haugen, D. A.; Tindall, D. J. Cancer Res. 2003, 63, 7638
Google Scholar
There is no corresponding record for this reference.
414
Isharwal, S.; Miller, M. C.; Marlow, C.; Makarov, D. V.; Partin, A. W.; Veltri, R. W. Prostate 2008, 68, 1097
Google Scholar
There is no corresponding record for this reference.
415
Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
Google Scholar
There is no corresponding record for this reference.
416
Lin, W. M.; Baker, A. C.; Beroukhim, R.; Winckler, W.; Feng, W.; Marmion, J. M.; Laine, E.; Greulich, H.; Tseng, H.; Gates, C.; Hodi, F. S.; Dranoff, G.; Sellers, W. R.; Thomas, R. K.; Meyerson, M.; Golub, T. R.; Dummer, R.; Herlyn, M.; Getz, G.; Garraway, L. A. Cancer Res. 2008, 68, 664
Google Scholar
There is no corresponding record for this reference.
417
Rotte, A.; Bhandaru, M.; Cheng, Y.; Sjoestroem, C.; Martinka, M.; Li, G. PLoS One 2013, 8, e75405
Google Scholar
There is no corresponding record for this reference.
418
Bhandaru, M.; Ardekani, G. S.; Zhang, G.; Martinka, M.; McElwee, K. J.; Li, G.; Rotte, A. BMC Cancer 2014, 14– 398
Google Scholar
There is no corresponding record for this reference.
419
Bandyopadhyay, D.; Okan, N. A.; Bales, E.; Nascimento, L.; Cole, P. A.; Medrano, E. E. Cancer Res. 2002, 62, 6231
Google Scholar
There is no corresponding record for this reference.
420
Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
Google Scholar
There is no corresponding record for this reference.
421
Iyer, N. G.; Chin, S. F.; Ozdag, H.; Daigo, Y.; Hu, D. E.; Cariati, M.; Brindle, K.; Aparicio, S.; Caldas, C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 7386
Google Scholar
There is no corresponding record for this reference.
422
Giles, R. H.; Petrij, F.; Dauwerse, H. G.; den Hollander, A. I.; Lushnikova, T.; van Ommen, G. J.; Goodman, R. H.; Deaven, L. L.; Doggett, N. A.; Peters, D. J.; Breuning, M. H. Genomics 1997, 42, 96
Google Scholar
There is no corresponding record for this reference.
423
Rozman, M.; Camós, M.; Colomer, D.; Villamor, N.; Esteve, J.; Costa, D.; Carrió, A.; Aymerich, M.; Aguilar, J. L.; Domingo, A.; Solé, F.; Gomis, F.; Florensa, L.; Montserrat, E.; Campo, E. Genes, Chromosomes Cancer 2004, 40, 140
Google Scholar
423
Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation
Rozman, Maria; Camos, Mireia; Colomer, Dolors; Villamor, Neus; Esteve, Jordi; Costa, Dolors; Carrio, Ana; Aymerich, Marta; Aguilar, Josep Lluis; Domingo, Alicia; Sole, Francesc; Gomis, Federico; Florensa, Lourdes; Montserrat, Emili; Campo, Elias
Genes, Chromosomes & Cancer (2004), 40 (2), 140-145CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
The t(8;16)(p11;p13) fuses the MOZ (MYST3) gene at 8p11 with CBP (CREBBP) at 16p13 and is assocd. with an infrequent but well-defined type of acute myeloid leukemia (AML) that has unique morphocytochem. findings (monocytoid blast morphol. with erythrophagocytosis and simultaneously pos. for myeloperoxidase and nonspecific esterases). RT-PCR amplification of MOZ/CBP (MYST3/CREBBP) chimera has proved difficult, with four different transcripts found in four reported cases. The authors studied 7 AML-t(8;16) patients, 5 with cytogenetically demonstrated t(8;16) and 2 with similar morphocytochem. and immunophenotypical characteristics. Clin., 3 cases presented as therapy-related leukemia. Extramedullar involvement was obsd. at presentation in 2 patients and coagulopathy in 4. The clinicobiol. findings confirmed the distinctiveness of this entity. Of note is the erythrophagocytosis in 5 of 7 cases and the immunol. negativity for CD34 and CD117 and positivity for CD56. Using a new RT-PCR strategy, the authors were able to amplify a specific band of 212 bp in six cases in which sequence anal. confirmed the presence of the previously described MOZ/CBP fusion transcript type 1. This is the largest molecularly studied AML-t(8;16) series, which demonstrates that MOZ/CBP breakpoints are usually clustered in intron 16 of MOZ and intron 2 of CBP. The newly designed single-round PCR provides a simple tool for the mol. confirmation of MOZ/CBP rearrangement.
424
Borrow, J.; Stanton, V. P., Jr.; Andresen, J. M.; Becher, R.; Behm, F. G.; Chaganti, R. S.; Civin, C. I.; Disteche, C.; Dubé, I.; Frischauf, A. M.; Horsman, D.; Mitelman, F.; Volinia, S.; Watmore, A. E.; Housman, D. E. Nat. Genet. 1996, 14, 33
Google Scholar
424
The translocation t(8;16)(p11;p13) of acute myeloid leukemia fuses a putative acetyltransferase to the CREB-binding protein
Borrow, Julian; Stanton, Vincent P., Jr.; Andresen, J. Michael; Becher, Reinhard; Behm, Frederick G.; Chagaanti, Raju S. K.; Civin, Curt I.; Disteche, Christine; Dube, Ian; et al.
Nature Genetics (1996), 14 (1), 33-41CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Co.)
The recurrent translocation t(8;16)(p11;p13) is a cytogenetic hallmark for the M4/M5 subtype of acute myeloid leukemia. Here the authors identify the breakpoint-assocd. genes. Positional cloning on chromosome 16 implicates the CREB-binding protein (CBP), a transcriptional adaptor/co-activator protein. At the chromosome 8 breakpoint the authors identify a novel gene, MOZ, which encodes a 2,004-amino-acid protein characterized by two C4HC3 zinc fingers and a single C2HC zinc finger in conjunction with a putative acetyltransferase signature. In-frame MOZ-CBP fusion transcripts combine the MOZ finger motifs and putative acetyltransferase domain with a largely intact CBP. The authors suggest that MOZ may represent a chromatin-assocd. acetyltransferase, and raise the possibility that a dominant MOZ-CBP fusion protein could mediate leukemogenesis via aberrant chromatin acetylation.
425
Chaffanet, M.; Gressin, L.; Preudhomme, C.; Soenen-Cornu, V.; Birnbaum, D.; Pébusque, M. J. Genes, Chromosomes Cancer 2000, 28, 138
Google Scholar
425
MOZ is fused to p300 in an acute monocytic leukemia with t(8;22)
Chaffanet, Max; Gressin, Laetitia; Preudhomme, Claude; Soenen-Cornu, Valerie; Birnbaum, Daniel; Pebusque, Marie-Josephe
Genes, Chromosomes & Cancer (2000), 28 (2), 138-144CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
The authors report on the fusion of the monocytic leukemia zinc finger protein (MOZ) gene to the adenoviral EIA-assocd. protein p300 gene in acute monocytic leukemia MS assocd. with a t(8;22)(p11;q13) translocation. The authors studied two patients with double-color fluorescence in situ hybridization (FISH) using the yeast artificial chromosome 176C9 and the bacterial artificial chromosome clone H59D10 specific to the MOZ and p300 genes, resp. Both probes were split in the patients' chromosome metaphase cells, and the two deriv. chromosomes were each labeled with both probes. The authors showed by Southern blot the rearrangement of the MOZ gene, and cloned the fusion transcripts in one patient carrying the t(8;22) by reverse transcription-polymerase chain reaction using MOZ- and p300-specific primers. Both fusion transcripts were expressed. This result defines a novel reciprocal translocation involving two acetyltransferases, MOZ and p300, resulting in an abnormal transcriptional co-activator that could play a crit. role in leukemogenesis.
426
Kitabayashi, I.; Aikawa, Y.; Yokoyama, A.; Hosoda, F.; Nagai, M.; Kakazu, N.; Abe, T.; Ohki, M. Leukemia 2001, 15, 89
Google Scholar
There is no corresponding record for this reference.
427
Panagopoulos, I.; Fioretos, T.; Isaksson, M.; Samuelsson, U.; Billström, R.; Strömbeck, B.; Mitelman, F.; Johansson, B. Hum. Mol. Genet. 2001, 10, 395
Google Scholar
427
Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13)
Panagopoulos, Ioannis; Fioretos, Thoas; Isaksson, Margareth; Samuelsson, Ulf; Billstrom, Rolf; Strombeck, Bodil; Mitelman, Felix; Johansson, Bertil
Human Molecular Genetics (2001), 10 (4), 395-404CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
The CBP gene at 16p13 fuses to MOZ and MLL as a result of the t(8;16)(p11;p13) in acute (myelo)monocytic leukemias (AML M4/M5) and the t(11;16)(q23;p13) in treatment-related AML, resp. Here the authors show that a novel t(10;16)(q22;p13) in a childhood AML M5a leads to a MORF-CBP chimera. RT-PCR using MORF forward and CBP reverse primers amplified a MORF-CBP fusion in which nucleotide 3103 of MORF was fused in-frame with nucleotide 284 of CBP. Nested RT-PCR with CBP forward and MORF reverse primers generated a CBP-MORF transcript in which nucleotide 283 of CBP was fused in-frame with nucleotide 3104 of MORF. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. A database search using MORF cDNA enabled us to construct an exon-intron map of the MORF gene. The MORF-CBP protein retains the zinc fingers, two nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF and the CBP protein downstream of codon 29. Thus, the part of CBP encoding the RARA-binding domain, the CREB-binding domain, the three Cys/His-rich regions, the bromodomain, the HAT domain and the Glu-rich domains is present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal Ser- and Met-rich regions of MORF are likely to be driven by the CBP promoter. Since both fusion transcripts were present, their exact role in the leukemogenic process remains to be elucidated.
428
Vizmanos, J. L.; Larráyoz, M. J.; Lahortiga, I.; Floristán, F.; Alvarez, C.; Odero, M. D.; Novo, F. J.; Calasanz, M. J. Genes, Chromosomes Cancer 2003, 36, 402
Google Scholar
428
t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia
Vizmanos, Jose L.; Larrayoz, Maria J.; Lahortiga, Idoya; Floristan, Filomena; Alvarez, Carmen; Odero, Maria D.; Novo, Francisco J.; Calasanz, Maria J.
Genes, Chromosomes & Cancer (2003), 36 (4), 402-405CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
Recently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in a case of childhood acute myeloid leukemia (AML) M5a, with a complex karyotype contg. other rearrangements. Here, we report a new case with the MORF-CREBBP fusion in an 84-yr-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration. This supports that this is a recurrent pathogenic translocation in AML.
429
Uppal, G. K.; Leighton, J.; Da Costa, D.; Czulewicz, A.; Palazzo, I. E. Hematol. Rep. 2011, 3, e23
Google Scholar
There is no corresponding record for this reference.
430
Kojima, K.; Kaneda, K.; Yoshida, C.; Dansako, H.; Fujii, N.; Yano, T.; Shinagawa, K.; Yasukawa, M.; Fujita, S.; Tanimoto, M. Br. J. Haematol. 2003, 120, 271
Google Scholar
430
A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13)
Kojima, Kensuke; Kaneda, Kinuyo; Yoshida, Chikamasa; Dansako, Hirokata; Fujii, Nobuharu; Yano, Tomofumi; Shinagawa, Katsuji; Yasukawa, Masaki; Fujita, Shigeru; Tanimoto, Mitsune
British Journal of Haematology (2003), 120 (2), 271-273CODEN: BJHEAL; ISSN:0007-1048. (Blackwell Publishing Ltd.)
We report a case of therapy-related myelodysplastic syndrome (t-MDS) with t(10;16)(q22;p13), in which novel fusion transcripts of the MORF and CBP genes were detected. In one MORF-CBP fusion transcript, exon 15 of the MORF gene was fused in frame with exon 5 of the CBP gene. In a reciprocal CBP-MORF transcript, exon 4 of the CBP gene was fused in frame with exon 16 of the MORF gene. This is the first reported case of t-MDS assocd. with t(10;16), and provides mol. evidence that the novel MORF-CBP and/or CBP-MORF fusion protein(s) might play an important role in the development of t-MDS.
431
Taki, T.; Sako, M.; Tsuchida, M.; Hayashi, Y. Blood 1997, 89, 3945
Google Scholar
There is no corresponding record for this reference.
432
Sobulo, O. M.; Borrow, J.; Tomek, R.; Reshmi, S.; Harden, A.; Schlegelberger, B.; Housman, D.; Doggett, N. A.; Rowley, J. D.; Zeleznik-Le, N. J. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 8732
Google Scholar
There is no corresponding record for this reference.
433
Satake, N.; Ishida, Y.; Otoh, Y.; Hinohara, S.; Kobayashi, H.; Sakashita, A.; Maseki, N.; Kaneko, Y. Genes, Chromosomes Cancer 1997, 20, 60
Google Scholar
433
Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation
Satake, Noriko; Ishida, Yasushi; Otoh, Yoshiko; Hinohara, Shin-Ichi; Kobayashi, Hirofumi; Sakashita, Akiko; Maseki, Nobuo; Kaneko, Yasuhiko
Genes, Chromosomes & Cancer (1997), 20 (1), 60-63CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss)
CBP, which is located on 16p13 and encodes a transcriptional adaptor/coactivator protein, has been shown to fuse by the t(8;16)(p11;p13) translocation to MOZ on 8p11 in acute myeloid leukemia. The authors found a t(11;16)(q23;p13) in a child with therapy-related chronic myelomonocytic leukemia. Subsequent reverse transcriptase-polymerase chain reaction and direct sequencing analyses revealed the MLL-CBP fusion transcript in CMML cells. Because 11q23 translocations involving MLL and t(8;16) involving MOZ and CBP have been reported in therapy-related leukemias, both the MLL and CBP genes may be targets for topoisomerase II inhibitors. Accordingly, the authors believe that most t(11;16)-assocd. leukemias may develop in patients who have been treated with cytotoxic chemotherapy for primary malignant diseases.
434
Ida, K.; Kitabayashi, I.; Taki, T.; Taniwaki, M.; Noro, K.; Yamamoto, M.; Ohki, M.; Hayashi, Y. Blood 1997, 90, 4699
Google Scholar
There is no corresponding record for this reference.
435
Wang, J.; Iwasaki, H.; Krivtsov, A.; Febbo, P. G.; Thorner, A. R.; Ernst, P.; Anastasiadou, E.; Kutok, J. L.; Kogan, S. C.; Zinkel, S. S.; Fisher, J. K.; Hess, J. L.; Golub, T. R.; Armstrong, S. A.; Akashi, K.; Korsmeyer, S. J. EMBO J. 2005, 24, 368
Google Scholar
There is no corresponding record for this reference.
436
Wang, L.; Gural, A.; Sun, X. J.; Zhao, X.; Perna, F.; Huang, G.; Hatlen, M. A.; Vu, L.; Liu, F.; Xu, H.; Asai, T.; Xu, H.; Deblasio, T.; Menendez, S.; Voza, F.; Jiang, Y.; Cole, P. A.; Zhang, J.; Melnick, A.; Roeder, R. G.; Nimer, S. D. Science 2011, 333, 765
Google Scholar
There is no corresponding record for this reference.
437
Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
Google Scholar
There is no corresponding record for this reference.
438
Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
Google Scholar
There is no corresponding record for this reference.
439
Pattabiraman, D. R.; Sun, J.; Dowhan, D. H.; Ishii, S.; Gonda, T. J. Mol. Cancer Res. 2009, 7, 1477
Google Scholar
439
Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability
Pattabiraman, Diwakar R.; Sun, Jane; Dowhan, Dennis H.; Ishii, Shunsuke; Gonda, Thomas J.
Molecular Cancer Research (2009), 7 (9), 1477-1486CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)
The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the neg. regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for mol. targeting of Myb in leukemia. (Mol Cancer Res 2009;7(9):1477-86).
440
Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
Google Scholar
440
p300/CBP and cancer
Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
441
Varier, R. A.; Kundu, T. K. Curr. Pharm. Des. 2006, 12, 1975
Google Scholar
441
Chromatin modifications (acetylation/ deacetylation/ methylation) as new targets for HIV therapy
Varier, Radhika A.; Kundu, Tapas K.
Current Pharmaceutical Design (2006), 12 (16), 1975-1993CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
A review. Human immunodeficiency virus (HIV) is one of the most deadly threats to the human race. Though the developed countries have been able to control the epidemic by utilizing the discovery of very expensive diagnostics, the situation is dangerously alarming in developing and underdeveloped countries. The development of highly active antiretroviral drugs has improved the survival and quality of life, but prolonged treatment results in viral load rebound to pretherapy levels. Recent advances in the understanding of eukaryotic and genome-integrated viral gene expression showed that regulation of chromatin function is closely linked to the multiplication of HIV. Therefore, a new therapeutic approach has been initiated targeting the chromatin-modifying enzymes mainly histone acetyltransferases and deacetylases which may lead to a better and economical anti- HIV combinatorial therapeutics. In this review, the authors have discussed the mechanisms of HIV gene expression in the chromatin context and its potentiality to be exploited as a new therapeutic target.
442
Mujtaba, S.; Zhou, M. M. Methods 2011, 53, 97
Google Scholar
There is no corresponding record for this reference.
443
Sakane, N.; Kwon, H. S.; Pagans, S.; Kaehlcke, K.; Mizusawa, Y.; Kamada, M.; Lassen, K. G.; Chan, J.; Greene, W. C.; Schnoelzer, M.; Ott, M. PLoS Pathog. 2011, 7, e1002184
Google Scholar
There is no corresponding record for this reference.
444
Mujtaba, S.; Zhou, M. M. Methods 2011, 53, 97
Google Scholar
There is no corresponding record for this reference.
445
Allouch, A.; Di Primio, C.; Alpi, E.; Lusic, M.; Arosio, D.; Giacca, M.; Cereseto, A. Cell Host Microbe 2011, 9, 484
Google Scholar
445
The TRIM Family Protein KAP1 Inhibits HIV-1 Integration
Allouch, Awatef; Di Primio, Cristina; Alpi, Emanuele; Lusic, Marina; Arosio, Daniele; Giacca, Mauro; Cereseto, Anna
Cell Host & Microbe (2011), 9 (6), 484-495CODEN: CHMECB; ISSN:1931-3128. (Cell Press)
Summary: The integration of viral cDNA into the host genome is a crit. step in the life cycle of HIV-1. This step is catalyzed by integrase (IN), a viral enzyme that is pos. regulated by acetylation via the cellular histone acetyl transferase (HAT) p300. To investigate the relevance of IN acetylation, we searched for cellular proteins that selectively bind acetylated IN and identified KAP1, a protein belonging to the TRIM family of antiviral proteins. KAP1 binds acetylated IN and induces its deacetylation through the formation of a protein complex which includes the deacetylase HDAC1. Modulation of intracellular KAP1 levels in different cell types including T cells, the primary HIV-1 target, revealed that KAP1 curtails viral infectivity by selectively affecting HIV-1 integration. This study identifies KAP1 as a cellular factor restricting HIV-1 infection and underscores the relevance of IN acetylation as a crucial step in the viral infectious cycle.
446
Terreni, M.; Valentini, P.; Liverani, V.; Gutierrez, M. I.; Di Primio, C.; Di Fenza, A.; Tozzini, V.; Allouch, A.; Albanese, A.; Giacca, M.; Cereseto, A. Retrovirology 2010, 7, 18
Google Scholar
There is no corresponding record for this reference.
447
Zou, W.; Wang, Z.; Liu, Y.; Fan, Y.; Zhou, B. Y.; Yang, X. F.; He, J. J. Glia 2010, 58, 1640
Google Scholar
There is no corresponding record for this reference.
448
Kauppi, M.; Murphy, J. M.; de Graaf, C. A.; Hyland, C. D.; Greig, K. T.; Metcalf, D.; Hilton, A. A.; Nicola, N. A.; Kile, B. T.; Hilton, D. J.; Alexander, W. S. Blood 2008, 112, 3148
Google Scholar
There is no corresponding record for this reference.
449
Hilton, D. J.; Kile, B. T.; Alexander, W. S. Blood 2009, 113, 5599
Google Scholar
There is no corresponding record for this reference.
450
Yanazume, T.; Morimoto, T.; Wada, H.; Kawamura, T.; Hasegawa, K. Mol. Cell. Biochem. 2003, 248, 115
Google Scholar
There is no corresponding record for this reference.
451
Gusterson, R. J.; Jazrawi, E.; Adcock, I. M.; Latchman, D. S. J. Biol. Chem. 2003, 278, 6838
Google Scholar
There is no corresponding record for this reference.
452
Zhou, X. Y.; Shibusawa, N.; Naik, K.; Porras, D.; Temple, K.; Ou, H.; Kaihara, K.; Roe, M. W.; Brady, M. J.; Wondisford, F. E. Nat. Med. 2004, 10, 633
Google Scholar
452
Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein
Zhou, Xiao Yan; Shibusawa, Nobuyuki; Naik, Karuna; Porras, Delia; Temple, Karla; Ou, Hesheng; Kaihara, Kelly; Roe, Michael W.; Brady, Matthew J.; Wondisford, Fredric E.
Nature Medicine (New York, NY, United States) (2004), 10 (6), 633-637CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concns. and is regulated by opposing stimulatory (cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, the authors show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose prodn. The authors propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.
453
Cha-Molstad, H.; Saxena, G.; Chen, J.; Shalev, A. J. Biol. Chem. 2009, 284, 16898
Google Scholar
There is no corresponding record for this reference.
454
Bricambert, J.; Miranda, J.; Benhamed, F.; Girard, J.; Postic, C.; Dentin, R. J. Clin. Invest. 2010, 120, 4316
Google Scholar
There is no corresponding record for this reference.
455
Schnell, U.; Dijk, F.; Sjollema, K. A.; Giepmans, B. N. Nat. Methods 2012, 9, 152
Google Scholar
455
Immunolabeling artifacts and the need for live-cell imaging
Schnell, Ulrike; Dijk, Freark; Sjollema, Klaas A.; Giepmans, Ben N. G.
Nature Methods (2012), 9 (2), 152-158CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
A review. Fluorescent fusion proteins have revolutionized examn. of proteins in living cells. Still, studies using these proteins are met with criticism because proteins are modified and ectopically expressed, in contrast to immunofluorescence studies. However, introducing immunoreagents inside cells can cause protein extn. or relocalization, not reflecting the in vivo situation. Here we discuss pitfalls of immunofluorescence labeling that often receive little attention and argue that immunostaining expts. in dead, permeabilized cells should be complemented with live-cell imaging when scrutinizing protein localization.
456
McNeil, P. L. J. Cell Sci. 1987, 88, 669
Google Scholar
456
Glass beads load macromolecules into living cells
McNeil P L; Warder E
Journal of cell science (1987), 88 ( Pt 5) (), 669-78 ISSN:0021-9533.
We describe and characterize an exceptionally rapid and simple new technique for loading large numbers of cultured cells with large macromolecules. The culture medium of the cell monolayer is replaced by a small volume of the macromolecule to be loaded. Glass beads (75-500 micron diameter) are then sprinkled onto the cells, the cells are washed free of beads and exogenous macromolecules, and 'bead-loading' is completed. The conditions for bead-loading can readily be modified to accommodate cell type and loading objectives: for example, the amount of loading per cell increases if bead size is increased or if beads are agitated after sprinkling onto the monolayer, but at the expense of increased cell loss. As many as 97% of a population of bovine aortic endothelial (BAE) cells were loaded with a 10,000 Mr dextran; and 79% with a 150,000 Mr dextran using bead-loading. Various cell lines have been loaded using glass beads. Moreover, bead-loading has the advantage of producing loaded cells that remain adherent and well-spread, thus minimizing recovery time and permitting immediate microscopic examination.
457
Hayashi-Takanaka, Y.; Yamagata, K.; Wakayama, T.; Stasevich, T. J.; Kainuma, T.; Tsurimoto, T.; Tachibana, M.; Shinkai, Y.; Kurumizaka, H.; Nozaki, N.; Kimura, H. Nucleic Acids Res. 2011, 39, 6475
Google Scholar
There is no corresponding record for this reference.
458
Hayashi-Takanaka, Y.; Yamagata, K.; Nozaki, N.; Kimura, H. J. Cell Biol. 2009, 187, 781
Google Scholar
There is no corresponding record for this reference.
459
Johansen, K. M.; Johansen, J. Chromosome Res. 2006, 14, 393
Google Scholar
459
Regulation of chromatin structure by histone H3S10 phosphorylation
Johansen, Kristen M.; Johansen, Jorgen
Chromosome Research (2006), 14 (4), 393-404CODEN: CRRSEE; ISSN:0967-3849. (Springer)
A review. The epigenetic phospho-serine 10 modification of histone H3 has been a puzzle due to its assocn. with two apparently opposed chromatin states. It is found at elevated levels on the highly condensed, transcriptionally inactive mitotic chromosomes yet is also correlated with the more extended chromatin configuration of active genes, euchromatic interband regions, and activated heat shock puffs of Drosophila polytene chromosomes. In addn., phosphorylation of histone H3S10 is up-regulated on the hypertranscribed male X chromosome. Here we review the cellular effects of histone H3S10 phosphorylation and discuss a model for its involvement in regulating chromatin organization and heterochromatization that would be applicable to both interphase and mitotic chromosomes.
460
Stasevich, T. J.; Hayashi-Takanaka, Y.; Sato, Y.; Maehara, K.; Ohkawa, Y.; Sakata-Sogawa, K.; Tokunaga, M.; Nagase, T.; Nozaki, N.; McNally, J. G.; Kimura, H. Nature 2014, 516, 272
Google Scholar
There is no corresponding record for this reference.
461
Rothbauer, U.; Zolghadr, K.; Tillib, S.; Nowak, D.; Schermelleh, L.; Gahl, A.; Backmann, N.; Conrath, K.; Muyldermans, S.; Cardoso, M. C.; Leonhardt, H. Nat. Methods. 2006, 3, 887
Google Scholar
461
Targeting and tracing antigens in live cells with fluorescent nanobodies
Rothbauer, Ulrich; Zolghadr, Kourosh; Tillib, Sergei; Nowak, Danny; Schermelleh, Lothar; Gahl, Anja; Backmann, Natalija; Conrath, Katja; Muyldermans, Serge; Cardoso, M. Cristina; Leonhardt, Heinrich
Nature Methods (2006), 3 (11), 887-889CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
The authors fused the epitope-recognizing fragment of heavy-chain antibodies from Camelidae sp. with fluorescent proteins to generate fluorescent, antigen-binding nanobodies (chromobodies) that can be expressed in living cells. The authors demonstrate that chromobodies can recognize and trace antigens in different subcellular compartments throughout S phase and mitosis. Chromobodies should enable new functional studies, as potentially any antigenic structure can be targeted and traced in living cells in this fashion.
462
Sato, Y.; Mukai, M.; Ueda, J.; Muraki, M.; Stasevich, T. J.; Horikoshi, N.; Kujirai, T.; Kita, H.; Kimura, T.; Hira, S.; Okada, Y.; Hayashi-Takanaka, Y.; Obuse, C.; Kurumizaka, H.; Kawahara, A.; Yamagata, K.; Nozaki, N.; Kimura, H. Sci. Rep. 2013, 3, 2436
Google Scholar
462
Genetically encoded system to track histone modification in vivo
Sato Yuko; Mukai Masanori; Ueda Jun; Muraki Michiko; Stasevich Timothy J; Horikoshi Naoki; Kujirai Tomoya; Kita Hiroaki; Kimura Taisuke; Hira Seiji; Okada Yasushi; Hayashi-Takanaka Yoko; Obuse Chikashi; Kurumizaka Hitoshi; Kawahara Atsuo; Yamagata Kazuo; Nozaki Naohito; Kimura Hiroshi
Scientific reports (2013), 3 (), 2436 ISSN:.
Post-translational histone modifications play key roles in gene regulation, development, and differentiation, but their dynamics in living organisms remain almost completely unknown. To address this problem, we developed a genetically encoded system for tracking histone modifications by generating fluorescent modification-specific intracellular antibodies (mintbodies) that can be expressed in vivo. To demonstrate, an H3 lysine 9 acetylation specific mintbody (H3K9ac-mintbody) was engineered and stably expressed in human cells. In good agreement with the localization of its target acetylation, H3K9ac-mintbody was enriched in euchromatin, and its kinetics measurably changed upon treatment with a histone deacetylase inhibitor. We also generated transgenic fruit fly and zebrafish stably expressing H3K9ac-mintbody for in vivo tracking. Dramatic changes in H3K9ac-mintbody localization during Drosophila embryogenesis could highlight enhanced acetylation at the start of zygotic transcription around mitotic cycle 7. Together, this work demonstrates the broad potential of mintbody and lays the foundation for epigenetic analysis in vivo.
463
Vincenz, C.; Kerppola, T. K. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 16572
Google Scholar
There is no corresponding record for this reference.
464
Forster, T. H. Ann. Phys. 1948, 437, 55
Google Scholar
There is no corresponding record for this reference.
465
Helms, V. Fluorescence Resonance Energy Transfer. Principles of Computational Cell Biology; Wiley-VCH: Weinheim, 2008; p 202, ISBN 978-3-527-31555-0.
Google Scholar
There is no corresponding record for this reference.
466
Kanno, T.; Kanno, Y.; Siegel, R. M.; Jang, M. K.; Lenardo, M. J.; Ozato, K. Mol. Cell 2004, 13, 33
Google Scholar
There is no corresponding record for this reference.
467
Sasaki, K.; Ito, T.; Nishino, N.; Khochbin, S.; Yoshida, M. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 16257
Google Scholar
There is no corresponding record for this reference.
468
Ito, T.; Umehara, T.; Sasaki, K.; Nakamura, Y.; Nishino, N.; Terada, T.; Shirouzu, M.; Padmanabhan, B.; Yokoyama, S.; Ito, A.; Yoshida, M. Chem. Biol. 2011, 18, 495
Google Scholar
468
Real-Time Imaging of Histone H4K12-Specific Acetylation Determines the Modes of Action of Histone Deacetylase and Bromodomain Inhibitors
Ito, Tamaki; Umehara, Takashi; Sasaki, Kazuki; Nakamura, Yoshihiro; Nishino, Norikazu; Terada, Takaho; Shirouzu, Mikako; Padmanabhan, Balasundaram; Yokoyama, Shigeyuki; Ito, Akihiro; Yoshida, Minoru
Chemistry & Biology (Cambridge, MA, United States) (2011), 18 (4), 495-507CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
Histone acetylation constitutes an epigenetic mark for transcriptional regulation. Here we developed a fluorescent probe to visualize acetylation of histone H4 Lys12 (H4K12) in living cells using fluorescence resonance energy transfer (FRET) and the binding of the BRD2 bromodomain to acetylated H4K12. Using this probe designated as Histac-K12, we demonstrated that histone H4K12 acetylation is retained in mitosis and that some histone deacetylase (HDAC) inhibitors continue to inhibit cellular HDAC activity even after their removal from the culture. In addn., a small mol. that interferes with ability of the bromodomain to bind to acetylated H4K12 could be assessed using Histac-K12 in cells. Thus, Histac-K12 will serve as a powerful tool not only to understand the dynamics of H4K12-specific acetylation but also to characterize small mols. that modulate the acetylation or interaction status of histones.
469
Carrillo, L. D.; Krishnamoorthy, L.; Mahal, L. K. J. Am. Chem. Soc. 2006, 128, 14768
Google Scholar
There is no corresponding record for this reference.
470
Newman, R. H.; Zhang, J. Mol. BioSyst. 2008, 4, 496
Google Scholar
470
Visualization of phosphatase activity in living cells with a FRET-based calcineurin activity sensor
Newman, Robert H.; Zhang, Jin
Molecular BioSystems (2008), 4 (6), 496-501CODEN: MBOIBW; ISSN:1742-206X. (Royal Society of Chemistry)
Protein kinases and phosphatases are organized into complex intracellular signaling networks designed to coordinate their activities in both space and time. In order to better understand the mol. mechanisms underlying the regulation of signal transduction networks, it is important to define the spatiotemporal dynamics of both protein kinases and phosphatases within their endogenous environment. Herein, we report the development of a genetically-encoded protein biosensor designed to specifically probe the activity of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. Our reporter design utilizes a phosphatase activity-dependent mol. switch based on the N-terminal regulatory domain of the nuclear factor of activated T-cells as a specific substrate of calcineurin, sandwiched between cyan fluorescent protein and yellow fluorescent protein. Using this reporter, calcineurin activity can be monitored as dephosphorylation-induced increases in fluorescence resonance energy transfer and can be simultaneously imaged with intracellular calcium dynamics. The successful design of a prototype phosphatase activity sensor lays a foundation for studying targeting and compartmentation of phosphatases.
471
Nagai, Y.; Miyazaki, M.; Aoki, R.; Zama, T.; Inouye, S.; Hirose, K.; Iino, M.; Hagiwara, M. Nat. Biotechnol. 2000, 18, 313
Google Scholar
There is no corresponding record for this reference.
472
Ting, A. Y.; Kain, K. H.; Klemke, R. L.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 15003
Google Scholar
There is no corresponding record for this reference.
473
Kurokawa, K.; Mochizuki, N.; Ohba, Y.; Mizuno, H.; Miyawaki, A.; Matsuda, M. J. Biol. Chem. 2001, 276, 31305
Google Scholar
There is no corresponding record for this reference.
474
Lin, C. W.; Jao, C. Y.; Ting, A. Y. J. Am. Chem. Soc. 2004, 126, 5982
Google Scholar
There is no corresponding record for this reference.
475
Lin, C. W.; Ting, A. Y. Angew. Chem., Int. Ed. 2004, 43, 2940
Google Scholar
There is no corresponding record for this reference.
476
Yoshida, M.; Kijima, M.; Akita, M.; Beppu, T. J. Biol. Chem. 1990, 265, 17174
Google Scholar
There is no corresponding record for this reference.
477
Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57
Google Scholar
477
The hallmarks of cancer
Hanahan, Douglas; Weinberg, Robert A.
Cell (Cambridge, Massachusetts) (2000), 100 (1), 57-70CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
A review is given with many refs. on principles governing the transformation of normal human cells into malignant cancers. The authors suggest that research over the past decades has revealed a small no. of mol., biochem., and cellular traits (acquired capabilities) shared by most and perhaps all types of cancer. Topics included are the acquired capabilities self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis followed by genome instability as an enabling characteristic and alternative pathways to cancer.
478
Hanahan, D.; Weinberg, R. A. Cell 2011, 144, 646
Google Scholar
478
Hallmarks of cancer: the next generation
Hanahan, Douglas; Weinberg, Robert A.
Cell (Cambridge, MA, United States) (2011), 144 (5), 646-674CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
A review. The hallmarks of cancer comprise six biol. capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metab. and evading immune destruction. In addn. to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment.". Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
479
Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
Google Scholar
There is no corresponding record for this reference.
480
Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
Google Scholar
There is no corresponding record for this reference.
481
Santer, F. R.; Höschele, P. P.; Oh, S. J.; Erb, H. H.; Bouchal, J.; Cavarretta, I. T.; Parson, W.; Meyers, D. J.; Cole, P. A.; Culig, Z. Mol. Cancer Ther. 2011, 10, 1644
Google Scholar
481
Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines
Santer, Frederic R.; Hoeschele, Philipp P. S.; Oh, Su Jung; Erb, Holger H. H.; Bouchal, Jan; Cavarretta, Ilaria T.; Parson, Walther; Meyers, David J.; Cole, Philip A.; Culig, Zoran
Molecular Cancer Therapeutics (2011), 10 (9), 1644-1655CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
Inhibitors of histone deacetylases have been approved for clin. application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chem. inhibition of the acetyltransferase activity by a newly developed small mol., C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-κB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. Mol Cancer Ther; 10(9); 1644-55.
482
Wang, Y.; Toh, H. C.; Chow, P.; Chung, A. Y.; Meyers, D. J.; Cole, P. A.; Ooi, L. L.; Lee, C. G. FASEB J. 2012, 26, 3032
Google Scholar
There is no corresponding record for this reference.
483
Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
Google Scholar
There is no corresponding record for this reference.
484
Santer, F. R.; Höschele, P. P.; Oh, S. J.; Erb, H. H.; Bouchal, J.; Cavarretta, I. T.; Parson, W.; Meyers, D. J.; Cole, P. A.; Culig, Z. Mol. Cancer Ther. 2011, 10, 1644
Google Scholar
484
Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines
Santer, Frederic R.; Hoeschele, Philipp P. S.; Oh, Su Jung; Erb, Holger H. H.; Bouchal, Jan; Cavarretta, Ilaria T.; Parson, Walther; Meyers, David J.; Cole, Philip A.; Culig, Zoran
Molecular Cancer Therapeutics (2011), 10 (9), 1644-1655CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
Inhibitors of histone deacetylases have been approved for clin. application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chem. inhibition of the acetyltransferase activity by a newly developed small mol., C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-κB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. Mol Cancer Ther; 10(9); 1644-55.
485
Wang, L.; Gural, A.; Sun, X. J.; Zhao, X.; Perna, F.; Huang, G.; Hatlen, M. A.; Vu, L.; Liu, F.; Xu, H.; Asai, T.; Xu, H.; Deblasio, T.; Menendez, S.; Voza, F.; Jiang, Y.; Cole, P. A.; Zhang, J.; Melnick, A.; Roeder, R. G.; Nimer, S. D. Science 2011, 333, 765
Google Scholar
There is no corresponding record for this reference.
486
Liu, Y.; Wang, L.; Predina, J.; Han, R.; Beier, U. H.; Wang, L. C.; Kapoor, V.; Bhatti, T. R.; Akimova, T.; Singhal, S.; SBrindle, P. K.; Cole, P. A.; Albelda, S. M.; Hancock, W. W. Nat. Med. 2013, 19, 1173
Google Scholar
486
Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity
Liu, Yujie; Wang, Liqing; Predina, Jarrod; Han, Rongxiang; Beier, Ulf H.; Wang, Liang-Chuan S.; Kapoor, Veena; Bhatti, Tricia R.; Akimova, Tatiana; Singhal, Sunil; Brindle, Paul K.; Cole, Philip A.; Albelda, Steven M.; Hancock, Wayne W.
Nature Medicine (New York, NY, United States) (2013), 19 (9), 1173-1177CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
Forkhead box P3 (Foxp3)+ T regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3+ Treg cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that exptl. depleting Foxp3+ Treg cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacol. inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3+ Treg cells increased T cell receptor-induced apoptosis in Treg cells, impaired Treg cell suppressive function and peripheral Treg cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3+ Treg cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-mol. inhibitors can diminish Treg cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.
487
Min, S. W.; Cho, S. H.; Zhou, Y.; Schroeder, S.; Haroutunian, V.; Seeley, W. W.; Huang, E. J.; Shen, Y.; Masliah, E.; Mukherjee, C.; Meyers, D.; Cole, P. A.; Ott, M.; Gan, L. Neuron 2010, 67, 953
Erratum in: Neuron2010, 68, 801
Google Scholar
There is no corresponding record for this reference.
488
Mali, P.; Chou, B. K.; Yen, J.; Ye, Z.; Zou, J.; Dowey, S.; Brodsky, R. A.; Ohm, J. E.; Yu, W.; Baylin, S. B.; Yusa, K.; Bradley, A.; Meyers, D. J.; Mukherjee, C.; Cole, P. A.; Cheng, L. Stem Cells 2010, 28, 713
Google Scholar
There is no corresponding record for this reference.
489
Xu, C. R.; Cole, P. A.; Meyers, D. J.; Kormish, J.; Dent, S.; Zaret, K. S. Science 2011, 332, 963
Google Scholar
There is no corresponding record for this reference.
490
Marek, R.; Coelho, C. M.; Sullivan, R. K.; Baker-Andresen, D.; Li, X.; Ratnu, V.; Dudley, K. J.; Meyers, D.; Mukherjee, C.; Cole, P. A.; Sah, P.; Bredy, T. W. J. Neurosci. 2011, 31, 7486
Google Scholar
490
Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300
Marek, Roger; Coelho, Carlos M.; Sullivan, Robert K. P.; Baker-Andresen, Danay; Li, Xiang; Ratnu, Vikram; Dudley, Kevin J.; Meyers, David; Mukherjee, Chandrani; Cole, Philip A.; Sah, Pankaj; Bredy, Timothy W.
Journal of Neuroscience (2011), 31 (20), 7486-7491CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examd. the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here, the authors report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. These results also demonstrated that the HAT p300 was highly expressed within pyramidal neurons of the ILPFC and that the small-mol. p300-specific inhibitor (C 646) infused into the ILPFC immediately after weak extinction training enhanced the consolidation of fear extinction memory. C 646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that did not evoke long-lasting LTP. These data suggested that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a redn. in the function of this HAT is required for the formation of fear extinction memory.
491
Knight, Z. A.; Shokat, K. M. Cell 2007, 128, 425
Google Scholar
There is no corresponding record for this reference.
492
Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
Google Scholar
492
Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
493
Kasper, L. H.; Lerach, S.; Wang, J.; Wu, S.; Jeevan, T.; Brindle, P. K. EMBO J. 2010, 29, 3660
Google Scholar
There is no corresponding record for this reference.
494
Phan, H. M.; Xu, A. W.; Coco, C.; Srajer, G.; Wyszomierski, S.; Evrard, Y. A.; Eckner, R.; Dent, S. Y. Dev. Dyn. 2005, 233, 1337
Google Scholar
There is no corresponding record for this reference.
495
Huang, Y.; Vasilatos, S. N.; Boric, L.; Shaw, P. G.; Davidson, N. E. Breast Cancer Res. Treat. 2012, 131, 777– 89
Google Scholar
495
Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells
Huang, Yi; Vasilatos, Shauna N.; Boric, Lamia; Shaw, Patrick G.; Davidson, Nancy E.
Breast Cancer Research and Treatment (2012), 131 (3), 777-789CODEN: BCTRD6; ISSN:0167-6806. (Springer)
Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are assocd. with aberrant gene expression in breast cancer development. However, the precise mol. mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD+ dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacol. inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer.
496
Han, H.; Yang, X.; Pandiyan, K.; Liang, G. PLoS One 2013, 8, e75136
Google Scholar
There is no corresponding record for this reference.
497
Prusevich, P.; Kalin, J. H.; Ming, S. A.; Basso, M.; Givens, J.; Li, X.; Hu, J.; Taylor, M. S.; Cieniewicz, A. M.; Hsiao, P. Y.; Huang, R.; Roberson, H.; Adejola, N.; Avery, L. B.; Casero, R. A., Jr.; Taverna, S. D.; Qian, J.; Tackett, A. J.; Ratan, R. R.; McDonald, O. G.; Feinberg, A. P.; Cole, P. A. ACS Chem. Biol. 2014, 9, 1284
Google Scholar
There is no corresponding record for this reference.
498
Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
Google Scholar
There is no corresponding record for this reference.
499
Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K. Eur. J. Pharm. Sci. 2010, 41, 571
Google Scholar
499
Codrug: An efficient approach for drug optimization
Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K.
European Journal of Pharmaceutical Sciences (2010), 41 (5), 571-588CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
A review. Codrug or mutual prodrug is an approach where various effective drugs, which are assocd. with some drawbacks, can be modified by attaching with other drugs of same or different categories directly or via a linkage. More appropriately one can say combining two different pharmacophores with similar or different pharmacol. activities elicit synergistic action or help to target the parent drug to specific site/organ/cells resp. This approach is commonly used to improve physicochem., biopharmaceutical and drug delivery properties of therapeutic agents.

Cited By

Click to copy section linkSection link copied!

Explore this article's citation statements on scite.ai

This article is cited by 416 publications.

Yanrui Suo, Xu Qian, Zhaoping Xiong, Xiaohong Liu, Chao Wang, Baiyang Mu, Xinyuan Wu, Weiwei Lu, Meiying Cui, Jiaxiang Liu, Yujie Chen, Mingyue Zheng, Xiaojie Lu. Enhancing the Predictive Power of Machine Learning Models through a Chemical Space Complementary DEL Screening Strategy. Journal of Medicinal Chemistry 2024, 67 (21) , 18969-18980. https://doi.org/10.1021/acs.jmedchem.4c01416
Zonglong Chen, Hong Yang, Yan Zhang, Xiaodong Lyu, Qiongyu Shi, Cheng Zhang, Xingcan Wang, Zekun Wang, Ying Zhang, Yue Deng, Yujie Wang, Yuting Huang, Yong Xu, Xun Huang, Yingxia Li. Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma. Journal of Medicinal Chemistry 2024, 67 (20) , 18606-18628. https://doi.org/10.1021/acs.jmedchem.4c01984
Mengjun Ma, Mengyao Li, Chengwei Zhang, Zixuan Yang, Xiaoyu Chen, Penghui Lu, Shuangshuang Nie, Siqi Zhang, Shumin Ma, Chong Qin. Discovery of a Highly Potent PROTAC Degrader of p300/CBP Proteins for the Treatment of Enzalutamide-Resistant Prostate Cancer. Journal of Medicinal Chemistry 2024, 67 (19) , 17290-17318. https://doi.org/10.1021/acs.jmedchem.4c01100
Iván Cheng-Sánchez, Katherine Gosselé, Leonardo Palaferri, Eleen Laul, Gionata Riccabella, Rajiv K. Bedi, Yaozong Li, Anna Müller, Ivan Corbeski, Amedeo Caflisch, Cristina Nevado. Structure-Based Design of CBP/EP300 Degraders: When Cooperativity Overcomes Affinity. JACS Au 2024, 4 (9) , 3466-3474. https://doi.org/10.1021/jacsau.4c00292
Li-Yun Chen, Soumya Jyoti Singha Roy, Appaso M. Jadhav, Wesley W. Wang, Pei-Hsin Chen, Timothy Bishop, Michael A. Erb, Christopher G. Parker. Functional Investigations of p53 Acetylation Enabled by Heterobifunctional Molecules. ACS Chemical Biology 2024, 19 (9) , 1918-1929. https://doi.org/10.1021/acschembio.4c00438
Xuemin Chen, McKenna C. Crawford, Ying Xiong, Anver Basha Shaik, Kiall F. Suazo, Ludwig G. Bauer, Manini S. Penikalapati, Joycelyn H. Williams, Kilian V. M. Huber, Thorkell Andressen, Rolf E. Swenson, Jordan L. Meier. Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300. JACS Au 2024, 4 (8) , 3094-3103. https://doi.org/10.1021/jacsau.4c00442
Yanrui Suo, Kaige Li, Xing Ling, Kenian Yan, Weiwei Lu, Jinfeng Yue, Xiaohua Chen, Zhiqiang Duan, Xiaojie Lu. Discovery Small-Molecule p300 Inhibitors Derived from a Newly Developed Indazolone-Focused DNA-Encoded Library. Bioconjugate Chemistry 2024, 35 (8) , 1251-1257. https://doi.org/10.1021/acs.bioconjchem.4c00307
Raj V. Nithun, Yumi Minyi Yao, Omer Harel, Shaimaa Habiballah, Ariel Afek, Muhammad Jbara. Site-Specific Acetylation of the Transcription Factor Protein Max Modulates Its DNA Binding Activity. ACS Central Science 2024, 10 (6) , 1295-1303. https://doi.org/10.1021/acscentsci.4c00686
Tianbang Wu, Jiankang Hu, Xiaofan Zhao, Cheng Zhang, Ruibo Dong, Qingqing Hu, Hongrui Xu, Hui Shen, Xiaohan Zhang, Yan Zhang, Bin Lin, Xishan Wu, Qiuping Xiang, Yong Xu. Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia. Journal of Medicinal Chemistry 2024, 67 (11) , 9194-9213. https://doi.org/10.1021/acs.jmedchem.4c00335
Jiankang Hu, Hongrui Xu, Tianbang Wu, Cheng Zhang, Hui Shen, Ruibo Dong, Qingqing Hu, Qiuping Xiang, Shuang Chai, Guolong Luo, Xiaoshan Chen, Yumin Huang, Xiaofan Zhao, Chao Peng, Xishan Wu, Bin Lin, Yan Zhang, Yong Xu. Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity. Journal of Medicinal Chemistry 2024, 67 (9) , 6952-6986. https://doi.org/10.1021/acs.jmedchem.3c02195
Zhixiang Chen, Mi Wang, Dimin Wu, Longchuan Bai, Tianfeng Xu, Hoda Metwally, Yu Wang, Donna McEachern, Lijie Zhao, Ruiting Li, John Takyi-Williams, Meilin Wang, Lu Wang, Qiuxia Li, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression. Journal of Medicinal Chemistry 2024, 67 (7) , 5275-5304. https://doi.org/10.1021/acs.jmedchem.3c02124
Iván Cheng-Sánchez, Katherine A. Gosselé, Leonardo Palaferri, Mariia S. Kirillova, Cristina Nevado. Discovery and Characterization of Active CBP/EP300 Degraders Targeting the HAT Domain. ACS Medicinal Chemistry Letters 2024, 15 (3) , 355-361. https://doi.org/10.1021/acsmedchemlett.3c00490
Qi Chang, Jiayi Li, Yue Deng, Ruilin Zhou, Bingwei Wang, Yujie Wang, Mingming Zhang, Xun Huang, Yingxia Li. Discovery of Novel PROTAC Degraders of p300/CBP as Potential Therapeutics for Hepatocellular Carcinoma. Journal of Medicinal Chemistry 2024, 67 (4) , 2466-2486. https://doi.org/10.1021/acs.jmedchem.3c01468
Aparajita Ghosh, Ambati Himaja, Swati Biswas, Onkar Kulkarni, Balaram Ghosh. Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer. Molecular Pharmaceutics 2023, 20 (12) , 5981-6009. https://doi.org/10.1021/acs.molpharmaceut.3c00610
McKenna C. Crawford, Deepika R. Tripu, Samuel A. Barritt, Yihang Jing, Diamond Gallimore, Stephen C. Kales, Natarajan V. Bhanu, Ying Xiong, Yuhong Fang, Kamaria A. T. Butler, Christopher A. LeClair, Nathan P. Coussens, Anton Simeonov, Benjamin A. Garcia, Christian C. Dibble, Jordan L. Meier. Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors. ACS Chemical Biology 2023, 18 (10) , 2249-2258. https://doi.org/10.1021/acschembio.3c00293
Md Kabir, Ning Sun, Xiaoping Hu, Tiphaine C. Martin, Jingjie Yi, Yue Zhong, Yan Xiong, H. Ümit Kaniskan, Wei Gu, Ramon Parsons, Jian Jin. Acetylation Targeting Chimera Enables Acetylation of the Tumor Suppressor p53. Journal of the American Chemical Society 2023, 145 (27) , 14932-14944. https://doi.org/10.1021/jacs.3c04640
Matthew Jones, Philipp Grosche, Andreas Floersheimer, Jérome André, Raphael Gattlen, Dieter Oser, Juliette Tinchant, Roman Wille, Barbara Chie-Leon, Marc Gerspacher, Peter Ertl, Nils Ostermann, Eva Altmann, Eusebio Manchado, Thomas Vorherr, Patrick Chène. Design and Biochemical Characterization of Peptidic Inhibitors of the Myb/p300 Interaction. Biochemistry 2023, 62 (7) , 1321-1329. https://doi.org/10.1021/acs.biochem.2c00690
Zhipeng A. Wang, Jonathan W. Markert, Samuel D. Whedon, Maheeshi Yapa Abeywardana, Kwangwoon Lee, Hanjie Jiang, Carolay Suarez, Hening Lin, Lucas Farnung, Philip A. Cole. Structural Basis of Sirtuin 6-Catalyzed Nucleosome Deacetylation. Journal of the American Chemical Society 2023, 145 (12) , 6811-6822. https://doi.org/10.1021/jacs.2c13512
Ryutaro Kanada, Yoshiko Kagoshima, Takashi Suzuki, Akifumi Nakamura, Hideaki Funami, Jun Watanabe, Masayoshi Asano, Mizuki Takahashi, Osamu Ubukata, Kanae Suzuki, Tomoya Aikawa, Kazumi Sato, Megumi Goto, Genzui Setsu, Kentaro Ito, Kawori Kihara, Mutsumi Kuroha, Takashi Kohno, Hideaki Ogiwara, Takeshi Isoyama, Yuichi Tominaga, Saito Higuchi, Hiroyuki Naito. Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor. Journal of Medicinal Chemistry 2023, 66 (1) , 695-715. https://doi.org/10.1021/acs.jmedchem.2c01641
Xinrong Tian, Dominic Suarez, Douglas Thomson, William Li, Elizabeth A. King, Louis LaFrance, Jeffrey Boehm, Linda Barton, Christina Di Marco, Cuthbert Martyr, Reema Thalji, Jesus Medina, Steven Knight, Dirk Heerding, Enoch Gao, Eldridge Nartey, Ted Cecconie, Christopher Nixon, Guofeng Zhang, Thomas J. Berrodin, Christopher Phelps, Amish Patel, Xiaopeng Bai, Ken Lind, Ninad Prabhu, Jeffrey Messer, Zhengrong Zhu, Lisa Shewchuk, Rob Reid, Alan P. Graves, Charles McHugh, Biju Mangatt. Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening. Journal of Medicinal Chemistry 2022, 65 (21) , 14391-14408. https://doi.org/10.1021/acs.jmedchem.2c00670
Liwen Hua, Qiuyue Zhang, Xinyue Zhu, Ruoning Wang, Qidong You, Lei Wang. Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors. Journal of Medicinal Chemistry 2022, 65 (12) , 8091-8112. https://doi.org/10.1021/acs.jmedchem.2c00316
Mary E. Tarantino, Sarah Delaney. Kinetic Analysis of the Effect of N-Terminal Acetylation on Thymine DNA Glycosylase. Biochemistry 2022, 61 (10) , 895-908. https://doi.org/10.1021/acs.biochem.1c00823
Zhipeng A. Wang, Samuel D. Whedon, Mingxuan Wu, Siyu Wang, Edward A. Brown, Ananya Anmangandla, Liam Regan, Kwangwoon Lee, Jianfeng Du, Jun Young Hong, Louise Fairall, Taylor Kay, Hening Lin, Yingming Zhao, John W. R. Schwabe, Philip A. Cole. Histone H2B Deacylation Selectivity: Exploring Chromatin’s Dark Matter with an Engineered Sortase. Journal of the American Chemical Society 2022, 144 (8) , 3360-3364. https://doi.org/10.1021/jacs.1c13555
Wesley W. Wang, Li-Yun Chen, Jacob M. Wozniak, Appaso M. Jadhav, Hayden Anderson, Taylor E. Malone, Christopher G. Parker. Targeted Protein Acetylation in Cells Using Heterobifunctional Molecules. Journal of the American Chemical Society 2021, 143 (40) , 16700-16708. https://doi.org/10.1021/jacs.1c07850
Alex Muthengi, Virangika K. Wimalasena, Hailemichael O. Yosief, Melissa J. Bikowitz, Logan H. Sigua, Tingjian Wang, Deyao Li, Zied Gaieb, Gagan Dhawan, Shuai Liu, Jon Erickson, Rommie E. Amaro, Ernst Schönbrunn, Jun Qi, Wei Zhang. Development of Dimethylisoxazole-Attached Imidazo[1,2-a]pyridines as Potent and Selective CBP/P300 Inhibitors. Journal of Medicinal Chemistry 2021, 64 (9) , 5787-5801. https://doi.org/10.1021/acs.jmedchem.0c02232
Jonathan E. Wilson, Gaurav Patel, Chirag Patel, Francois Brucelle, Annissa Huhn, Anna S. Gardberg, Florence Poy, Nico Cantone, Archana Bommi-Reddy, Robert J. Sims, III, Richard T. Cummings, Julian R. Levell. Discovery of CPI-1612: A Potent, Selective, and Orally Bioavailable EP300/CBP Histone Acetyltransferase Inhibitor. ACS Medicinal Chemistry Letters 2020, 11 (6) , 1324-1329. https://doi.org/10.1021/acsmedchemlett.0c00155
Fangrui Wu, Yuanda Hua, Salma Kaochar, Shenyou Nie, Yi-Lun Lin, Yuan Yao, Jingyu Wu, Xiaowei Wu, Xiaoyong Fu, Rachel Schiff, Christel M. Davis, Matthew Robertson, Erik A. Ehli, Cristian Coarfa, Nicholas Mitsiades, Yongcheng Song. Discovery, Structure–Activity Relationship, and Biological Activity of Histone-Competitive Inhibitors of Histone Acetyltransferases P300/CBP. Journal of Medicinal Chemistry 2020, 63 (9) , 4716-4731. https://doi.org/10.1021/acs.jmedchem.9b02164
Robert E. Thompson, Tom W. Muir. Chemoenzymatic Semisynthesis of Proteins. Chemical Reviews 2020, 120 (6) , 3051-3126. https://doi.org/10.1021/acs.chemrev.9b00450
Yaxi Yang, Rukang Zhang, Zhaojun Li, Lianghe Mei, Shili Wan, Hong Ding, Zhifeng Chen, Jing Xing, Huijin Feng, Jie Han, Hualiang Jiang, Mingyue Zheng, Cheng Luo, Bing Zhou. Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors. Journal of Medicinal Chemistry 2020, 63 (3) , 1337-1360. https://doi.org/10.1021/acs.jmedchem.9b01721
Beth E. Zucconi, Jessica L. Makofske, David J. Meyers, Yousang Hwang, Mingxuan Wu, Mitzi I. Kuroda, Philip A. Cole. Combination Targeting of the Bromodomain and Acetyltransferase Active Site of p300/CBP. Biochemistry 2019, 58 (16) , 2133-2143. https://doi.org/10.1021/acs.biochem.9b00160
Jonathan H. Shrimp, Carissa Grose, Stephanie R. T. Widmeyer, Abigail L. Thorpe, Ajit Jadhav, and Jordan L. Meier . Chemical Control of a CRISPR-Cas9 Acetyltransferase. ACS Chemical Biology 2018, 13 (2) , 455-460. https://doi.org/10.1021/acschembio.7b00883
Ibraheem Ali, Ryan J. Conrad, Eric Verdin, and Melanie Ott . Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Chemical Reviews 2018, 118 (3) , 1216-1252. https://doi.org/10.1021/acs.chemrev.7b00181
Michael R. Michaelides, Arthur Kluge, Michael Patane, John H. Van Drie, Ce Wang, T. Matthew Hansen, Roberto M. Risi, Robert Mantei, Carmen Hertel, Kannan Karukurichi, Alexandre Nesterov, David McElligott, Peter de Vries, J. William Langston, Philip A. Cole, Ronen Marmorstein, Hong Liu, Loren Lasko, Kenneth D. Bromberg, Albert Lai, and Edward A. Kesicki . Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases. ACS Medicinal Chemistry Letters 2018, 9 (1) , 28-33. https://doi.org/10.1021/acsmedchemlett.7b00395
Sarah M. Bronner, Jeremy Murray, F. Anthony Romero, Kwong Wah Lai, Vickie Tsui, Patrick Cyr, Maureen H. Beresini, Gladys de leon Boenig, Zhongguo Chen, Edna F. Choo, Kevin R. Clark, Terry D. Crawford, Hariharan Jayaram, Susan Kaufman, Ruina Li, Yingjie Li, Jiangpeng Liao, Xiaorong Liang, Wenfeng Liu, Justin Ly, Jonathan Maher, John Wai, Fei Wang, Aijun Zheng, Xiaoyu Zhu, and Steven Magnuson . A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors. Journal of Medicinal Chemistry 2017, 60 (24) , 10151-10171. https://doi.org/10.1021/acs.jmedchem.7b01372
Tingjun Chen, Dan Gao, Roushu Zhang, Guihua Zeng, Hao Yan, Eunju Lim, and Fu-Sen Liang . Chemically Controlled Epigenome Editing through an Inducible dCas9 System. Journal of the American Chemical Society 2017, 139 (33) , 11337-11340. https://doi.org/10.1021/jacs.7b06555
Zhen Han, Chau-wen Chou, Xiangkun Yang, Michael G. Bartlett, and Y. George Zheng . Profiling Cellular Substrates of Lysine Acetyltransferases GCN5 and p300 with Orthogonal Labeling and Click Chemistry. ACS Chemical Biology 2017, 12 (6) , 1547-1555. https://doi.org/10.1021/acschembio.7b00114
Mostafa M. Hamed, Sarah S. Darwish, Jennifer Herrmann, Ashraf H. Abadi, and Matthias Engel . First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents. Journal of Medicinal Chemistry 2017, 60 (7) , 2853-2868. https://doi.org/10.1021/acs.jmedchem.6b01774
Beth E. Zucconi, Birgit Luef, Wei Xu, Ryan A. Henry, Ilana M. Nodelman, Gregory D. Bowman, Andrew J. Andrews, and Philip A. Cole . Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112. Biochemistry 2016, 55 (27) , 3727-3734. https://doi.org/10.1021/acs.biochem.6b00480
David C. Montgomery, Julie M. Garlick, Rhushikesh A. Kulkarni, Steven Kennedy, Abdellah Allali-Hassani, Yin-Ming Kuo, Andrew J. Andrews, Hong Wu, Masoud Vedadi, and Jordan L. Meier . Global Profiling of Acetyltransferase Feedback Regulation. Journal of the American Chemical Society 2016, 138 (20) , 6388-6391. https://doi.org/10.1021/jacs.6b03036
Cheryl E. McCullough and Ronen Marmorstein . Molecular Basis for Histone Acetyltransferase Regulation by Binding Partners, Associated Domains, and Autoacetylation. ACS Chemical Biology 2016, 11 (3) , 632-642. https://doi.org/10.1021/acschembio.5b00841
Roman P. Simon, Dina Robaa, Zayan Alhalabi, Wolfgang Sippl, and Manfred Jung . KATching-Up on Small Molecule Modulators of Lysine Acetyltransferases. Journal of Medicinal Chemistry 2016, 59 (4) , 1249-1270. https://doi.org/10.1021/acs.jmedchem.5b01502
Xueying Yuan, Jeffrey M. Rosen. Histone acetylation modulators in breast cancer. Breast Cancer Research 2025, 27 (1) https://doi.org/10.1186/s13058-025-02006-9
Lili Li, Huabiao Zhou, Miaomiao Li, Wenbo Liu, Yuxuan Li, Hanyang Xu, Jiemei Jiang, Yan Yang, Yongfang Gong. Salvianolic acid B ameliorates hepatic fibrosis via inhibiting p300/CBP. European Journal of Pharmacology 2025, 998 , 177495. https://doi.org/10.1016/j.ejphar.2025.177495
Rahma Benhassoun, Anne-Pierre Morel, Victoria Jacquot, Alain Puisieux, Maria Ouzounova. The epipliancy journey: Tumor initiation at the mercy of identity crisis and epigenetic drift. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 2025, 1880 (3) , 189307. https://doi.org/10.1016/j.bbcan.2025.189307
Francesco Fiorentino, Filippo Spriano, Daniela Tomaselli, Giorgia Risi, Emanuele Fabbrizi, Valeria Pecci, Simona Nanni, Francesco Bertoni, Dante Rotili, Antonello Mai. Development of C646‐Based Proteolysis Targeting Chimeras Degraders of the Lysine Acetyltransferases CBP and p300. ChemMedChem 2025, 10 https://doi.org/10.1002/cmdc.202400792
Jiasheng Geng, Weina Lu, Qinglong Kong, Jiao Lv, Yue Liu, Guowei Zu, Yanmei Chen, Caiying Jiang, Zhengying You, Zuoming Nie. Validation of selective catalytic BmCBP inhibitors that regulate the Bm30K ‐24 protein expression in silkworm, Bombyx mori. Insect Molecular Biology 2025, 34 (2) , 322-334. https://doi.org/10.1111/imb.12974
Schilin Wen, Javiera Santander, Daniel Barria, Luis A. Salazar, Cristian Sandoval, Consuelo Arias, Verónica Iturriaga. Epigenetic Biomarkers in Temporomandibular Joint Osteoarthritis: An Emerging Target in Treatment. International Journal of Molecular Sciences 2025, 26 (8) , 3668. https://doi.org/10.3390/ijms26083668
Keqiang Rao, Xinchao Zhang, Yi Luo, Qiang Xia, Yuting Jin, Jing He. Lactylation orchestrates ubiquitin-independent degradation of cGAS and promotes tumor growth. Cell Reports 2025, 44 (4) , 115441. https://doi.org/10.1016/j.celrep.2025.115441
Jiaxin Tian, Tongyu Zhang, Ruidan Zhang, Sijia Hao, Jingyu Dong, Yiyan Chen, Jinpeng Zhou, Yang Tian. Lactylation in CNS disorders: mechanisms, cellular function, and disease relevance. Frontiers in Cell and Developmental Biology 2025, 13 https://doi.org/10.3389/fcell.2025.1566921
Chao Ma, Wangang Zhang, Lujuan Xing. Differences in protein lactylation between pale, soft and exudative and red, firm and non-exudative pork. Meat Science 2025, 221 , 109736. https://doi.org/10.1016/j.meatsci.2024.109736
Joseph Adu‐Amankwaah, Qiang You, Xiaoer Liu, Jiayi Jiang, Dongqi Yang, Kuntao Liu, Jinxiang Yuan, Yanfang Wang, Qinghua Hu, Rubin Tan. Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies. MedComm 2025, 6 (3) https://doi.org/10.1002/mco2.70134
Felix Osten, Alea K. Bodenschatz, Karina Ivaskevica, Simon Kröhn, Birgit Piep, Tim Holler, Jana Teske, Judith Montag, Bogdan Iorga, Natalie Weber, Robert Zweigerdt, Theresia Kraft, Joachim D. Meissner. Differential impact of substrates on myosin heavy and light chain expression in human stem cell-derived cardiomyocytes at single-cell level. Journal of Muscle Research and Cell Motility 2025, 20 https://doi.org/10.1007/s10974-025-09690-2
Longxia Xu, Hongwen Xuan, Xiaobing Shi. Dysregulation of the p300/CBP histone acetyltransferases in human cancer. Epigenomics 2025, 17 (3) , 193-208. https://doi.org/10.1080/17501911.2024.2447807
Nana Ma, Lairong Wang, Meijuan Meng, Yan Wang, Ran Huo, Guangjun Chang, Xiangzhen Shen. D-sodium lactate promotes the activation of NF-κB signaling pathway induced by lipopolysaccharide via histone lactylation in bovine mammary epithelial cells. Microbial Pathogenesis 2025, 199 , 107198. https://doi.org/10.1016/j.micpath.2024.107198
Ming-Ming Zhou, Philip A. Cole. Targeting lysine acetylation readers and writers. Nature Reviews Drug Discovery 2025, 24 (2) , 112-133. https://doi.org/10.1038/s41573-024-01080-6
Yilan Yang, Jiatao Liao, Zhe Pan, Jin Meng, Li Zhang, Wei Shi, Xiaofang Wang, Xiaomeng Zhang, Zhirui Zhou, Jurui Luo, Xingxing Chen, Zhaozhi Yang, Xin Mei, Jinli Ma, Zhen Zhang, Yi‐Zhou Jiang, Zhi‐Min Shao, Fei Xavier Chen, Xiaoli Yu, Xiaomao Guo. Dual Inhibition of CDK4/6 and CDK7 Suppresses Triple‐Negative Breast Cancer Progression via Epigenetic Modulation of SREBP1‐Regulated Cholesterol Metabolism. Advanced Science 2025, 12 (5) https://doi.org/10.1002/advs.202413103
Jian-kang Hu, Xin Tang, Guo-long Luo, Cheng Zhang, Tian-bang Wu, Chao Wang, Hui Shen, Xiao-fan Zhao, Xi-shan Wu, Jeff B. Smaill, Yong Xu, Yan Zhang, Qiu-ping Xiang. Discovery of 5-imidazole-3-methylbenz[d]isoxazole derivatives as potent and selective CBP/p300 bromodomain inhibitors for the treatment of acute myeloid leukemia. Acta Pharmacologica Sinica 2025, 85 https://doi.org/10.1038/s41401-025-01478-x
Megan J Ritter, Izuki Amano, Anthony N Hollenberg. Transcriptional Cofactors for Thyroid Hormone Receptors. Endocrinology 2025, 166 (2) https://doi.org/10.1210/endocr/bqae164
Nolan D. Swain, Y. George Zheng. Design of a Bioluminescent Assay Platform for Quantitative Measurement of Histone Acetyltransferase Enzymatic Activity. ChemBioChem 2025, 26 (1) https://doi.org/10.1002/cbic.202400692
Yao Deng, Guanxi Wen, Yongtao Yin, Dandan Chen, Difei Li, Rongchang Chen. Pharmacological inhibition of P300 with C646 ameliorates LPS-induced acute lung injury by modulating CXCL1 in M1 alveolar macrophages. International Immunopharmacology 2025, 144 , 113674. https://doi.org/10.1016/j.intimp.2024.113674
Graham P. Marsh, Mark S. Cooper, Sean Goggins, Stephen J. Reynolds, Dean F. Wheeler, Joel O. Cresser-Brown, Robert E. Arnold, Emily G. Babcock, Gareth Hughes, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple. Development of p300-targeting degraders with enhanced selectivity and onset of degradation. RSC Medicinal Chemistry 2025, 550 https://doi.org/10.1039/D4MD00969J
Swarna Beesetti. Ubiquitin Ligases in Control: Regulating NLRP3 Inflammasome Activation. Frontiers in Bioscience-Landmark 2025, 30 (3) https://doi.org/10.31083/FBL25970
Xuan Zhang, Lei Sun. Activated PRDM1-CREBBP contributes to preeclampsia by regulating apoptosis and invasion of the human trophoblast cells. iScience 2024, 27 (12) , 111484. https://doi.org/10.1016/j.isci.2024.111484
Noha A. M. Shendy, Melissa Bikowitz, Logan H. Sigua, Yang Zhang, Audrey Mercier, Yousef Khashana, Stephanie Nance, Qi Liu, Ian M. Delahunty, Sarah Robinson, Vanshita Goel, Matthew G. Rees, Melissa A. Ronan, Tingjian Wang, Mustafa Kocak, Jennifer A. Roth, Yingzhe Wang, Burgess B. Freeman, Brent A. Orr, Brian J. Abraham, Martine F. Roussel, Ernst Schonbrunn, Jun Qi, Adam D. Durbin. Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-47102-0
Priya Mittal, Jacquelyn A. Myers, Raymond D. Carter, Sandi Radko-Juettner, Hayden A. Malone, Wojciech Rosikiewicz, Alexis N. Robertson, Zhexin Zhu, Ishwarya V. Narayanan, Baranda S. Hansen, Meadow Parrish, Natarajan V. Bhanu, Robert J. Mobley, Jerold E. Rehg, Beisi Xu, Yiannis Drosos, Shondra M. Pruett-Miller, Mats Ljungman, Benjamin A. Garcia, Gang Wu, Janet F. Partridge, Charles W. M. Roberts. PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-51566-5
Shuangshuang Sun, Zhe Xu, Liying He, Yihui Shen, Yuqing Yan, Xubing Lv, Xujing Zhu, Wei Li, Wei-Ya Tian, Yongjun Zheng, Sen Lin, Yadong Sun, Lei Li. Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-52729-0
Julien Van Gils, Slim Karkar, Aurélien Barre, Seyta Ley-Ngardigal, Sophie Nothof, Stéphane Claverol, Caroline Tokarski, Jean-Philippe Trani, Raphael Chevalier, Natacha Broucqsault, Claire El Yazidi, Didier Lacombe, Patricia Fergelot, Frédérique Magdinier. Transcriptome and acetylome profiling identify crucial steps of neuronal differentiation in Rubinstein-Taybi syndrome. Communications Biology 2024, 7 (1) https://doi.org/10.1038/s42003-024-06939-3
Ashraf K. Shahib, Mojgan Rastegar, Andre J. van Wijnen, James R. Davie. Neurodevelopmental functions and activities of the KAT3 class of lysine acetyltransferases. Biochemistry and Cell Biology 2024, 102 (6) , 430-447. https://doi.org/10.1139/bcb-2024-0156
Ruimin He, Yifan Liu, Weijie Fu, Xuan He, Shuang Liu, Desheng Xiao, Yongguang Tao. Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression. Molecular Cancer 2024, 23 (1) https://doi.org/10.1186/s12943-024-02172-y
Yao Wang, Ping Li, Yuan Xu, Linyu Feng, Yongkang Fang, Guini Song, Li Xu, Zhou Zhu, Wei Wang, Qi Mei, Minjie Xie. Lactate metabolism and histone lactylation in the central nervous system disorders: impacts and molecular mechanisms. Journal of Neuroinflammation 2024, 21 (1) https://doi.org/10.1186/s12974-024-03303-4
Qun Wei, Cailing Gan, Meng Sun, Yuting Xie, Hongyao Liu, Taixiong Xue, Conghui Deng, Chunheng Mo, Tinghong Ye. BRD4: an effective target for organ fibrosis. Biomarker Research 2024, 12 (1) https://doi.org/10.1186/s40364-024-00641-6
Simon Maria Kienle, Tobias Schneider, Christine Bernecker, Janina Bracker, Andreas Marx, Michael Kovermann, Martin Scheffner, Katrin Stuber. Biochemical and Structural Consequences of NEDD8 Acetylation. ChemBioChem 2024, 25 (22) https://doi.org/10.1002/cbic.202400478
Xueying Yuan, Xiaoxin Hao, Hilda L. Chan, Na Zhao, Diego A. Pedroza, Fengshuo Liu, Kang Le, Alex J. Smith, Sebastian J. Calderon, Nadia Lieu, Michael J. Soth, Philip Jones, Xiang H.F. Zhang, Jeffrey M. Rosen. CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer. JCI Insight 2024, 9 (20) https://doi.org/10.1172/jci.insight.182621
Chloe P. Whitworth, Wen Y. Aw, Elizabeth L. Doherty, Chenchen Handler, Yogeshwari Ambekar, Aanya Sawhney, Giuliano Scarcelli, William J. Polacheck. P300 Modulates Endothelial Mechanotransduction of Fluid Shear Stress. Cellular and Molecular Bioengineering 2024, 17 (5) , 507-523. https://doi.org/10.1007/s12195-024-00805-2
Sharon Y.R. Dent. KAT tales: Functions of Gcn5 and PCAF lysine acetyltransferases in SAGA and ATAC. Journal of Biological Chemistry 2024, 300 (10) , 107744. https://doi.org/10.1016/j.jbc.2024.107744
Runhua Du, Yanmei Gao, Cong Yan, Xuelian Ren, Shankang Qi, Guobin Liu, Xinlong Guo, Xiaohan Song, Hanmin Wang, Jingxin Rao, Yi Zang, Mingyue Zheng, Jia Li, He Huang. Sirtuin 1/sirtuin 3 are robust lysine delactylases and sirtuin 1-mediated delactylation regulates glycolysis. iScience 2024, 27 (10) , 110911. https://doi.org/10.1016/j.isci.2024.110911
Qi Liu, Aimee L. Qi, Adam D. Durbin, Jun Qi. Chemical Targeting of Histone Acetyltransferases. 2024, 266-306. https://doi.org/10.1039/9781837674916-00266
. Drug Discovery for Chromatin Readers, Writers, Erasers, Remodelers and Epitranscriptomic Targets. 2024https://doi.org/10.1039/9781837674916-part3
Emiliano Bolesani, Dorothee Bornhorst, Lavanya M Iyer, Dorota Zawada, Nina Friese, Michael Morgan, Lucas Lange, David M Gonzalez, Nadine Schrode, Andreas Leffler, Julian Wunder, Annika Franke, Lika Drakhlis, Robert Sebra, Axel Schambach, Alexander Goedel, Nicole C Dubois, Gergana Dobreva, Alessandra Moretti, Laura C Zelaráyan, Salim Abdelilah-Seyfried, Robert Zweigerdt. Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo. Cardiovascular Research 2024, 120 (11) , 1295-1311. https://doi.org/10.1093/cvr/cvae118
Ye Chen, Tian Lan. N-terminal domain of androgen receptor is a major therapeutic barrier and potential pharmacological target for treating castration resistant prostate cancer: a comprehensive review. Frontiers in Pharmacology 2024, 15 https://doi.org/10.3389/fphar.2024.1451957
Shuhong Tian, Keyan Zhong, Zhaoxin Yang, Jian Fu, Yangbo Cai, Min Xiao. Investigating the mechanism of tricyclic decyl benzoxazole -induced apoptosis in liver Cancer cells through p300-mediated FOXO3 activation. Cellular Signalling 2024, 121 , 111280. https://doi.org/10.1016/j.cellsig.2024.111280
Jason P. Smith, Robert Paxton, Silvia Medrano, Nathan C. Sheffield, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez. Inhibition of Renin Expression Is Regulated by an Epigenetic Switch From an Active to a Poised State. Hypertension 2024, 81 (9) , 1869-1882. https://doi.org/10.1161/HYPERTENSIONAHA.124.22886
Jingyi Cai, Yudi Deng, Ziyang Min, Chaoyuan Li, Zhihe Zhao, Dian Jing. Deciphering the dynamics: Exploring the impact of mechanical forces on histone acetylation. The FASEB Journal 2024, 38 (15) https://doi.org/10.1096/fj.202400907RR
Hitoshi Ohtani, Minmin Liu, Gangning Liang, H Josh Jang, Peter A Jones. Efficient activation of hundreds of LTR12C elements reveals cis -regulatory function determined by distinct epigenetic mechanisms. Nucleic Acids Research 2024, 52 (14) , 8205-8217. https://doi.org/10.1093/nar/gkae498
Zijian Yang, Yingqi Zheng, Qiang Gao. Lysine lactylation in the regulation of tumor biology. Trends in Endocrinology & Metabolism 2024, 35 (8) , 720-731. https://doi.org/10.1016/j.tem.2024.01.011
Aaron Waddell, Nicole Grbic, Kassidy Leibowitz, William Austin Wyant, Sabah Choudhury, Kihyun Park, Marianne Collard, Philip A. Cole, Rhoda M. Alani. p300 KAT Regulates SOX10 Stability and Function in Human Melanoma. Cancer Research Communications 2024, 4 (8) , 1894-1907. https://doi.org/10.1158/2767-9764.CRC-24-0124
Xiaorui Su, Yuxuan Li, Yupeng Ren, Mingbo Cao, Gaoyuan Yang, Jing Luo, Ziyi Hu, Haixia Deng, Meihai Deng, Bo Liu, Zhicheng Yao. A new strategy for overcoming drug resistance in liver cancer: Epigenetic regulation. Biomedicine & Pharmacotherapy 2024, 176 , 116902. https://doi.org/10.1016/j.biopha.2024.116902
Dabo Pan, Yaxuan Huang, Dewen Jiang, Yonghao Zhang, Mingkai Wu, Minzhen Han, Xiaojie Jin. Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation. Current Pharmaceutical Design 2024, 30 (25) , 1985-1994. https://doi.org/10.2174/0113816128298051240529113313
Didier Lacombe, Agnès Bloch-Zupan, Cecilie Bredrup, Edward B Cooper, Sofia Douzgou Houge, Sixto García-Miñaúr, Hülya Kayserili, Lidia Larizza, Vanesa Lopez Gonzalez, Leonie A Menke, Donatella Milani, Francesco Saettini, Cathy A Stevens, Lloyd Tooke, Jill A Van der Zee, Maria M Van Genderen, Julien Van-Gils, Jane Waite, Jean-Louis Adrien, Oliver Bartsch, Pierre Bitoun, Antonia H M Bouts, Anna M Cueto-González, Elena Dominguez-Garrido, Floor A Duijkers, Patricia Fergelot, Elizabeth Halstead, Sylvia A Huisman, Camilla Meossi, Jo Mullins, Sarah M Nikkel, Chris Oliver, Elisabetta Prada, Alessandra Rei, Ilka Riddle, Cristina Rodriguez-Fonseca, Rebecca Rodríguez Pena, Janet Russell, Alicia Saba, Fernando Santos-Simarro, Brittany N Simpson, David F Smith, Markus F Stevens, Katalin Szakszon, Emmanuelle Taupiac, Nadia Totaro, Irene Valenzuena Palafoll, Daniëlle C M Van Der Kaay, Michiel P Van Wijk, Klea Vyshka, Susan Wiley, Raoul C Hennekam. Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement. Journal of Medical Genetics 2024, 61 (6) , 503-519. https://doi.org/10.1136/jmg-2023-109438
Mélanie Lavaud, Robel Tesfaye, Léa Lassous, Bénédicte Brounais, Marc Baud'huin, Franck Verrecchia, François Lamoureux, Steven Georges, Benjamin Ory. Super-enhancers: drivers of cells’ identities and cells’ debacles. Epigenomics 2024, 16 (9) , 681-700. https://doi.org/10.2217/epi-2023-0409
Qiuzi Dai, Zigao Yuan, Qinsheng Sun, Zhuolin Ao, Binsheng He, Yuyang Jiang. Discovery of novel nucleoside derivatives as selective lysine acetyltransferase p300 inhibitors for cancer therapy. Bioorganic & Medicinal Chemistry Letters 2024, 104 , 129742. https://doi.org/10.1016/j.bmcl.2024.129742
Yue Min, Hong Yu, Qi Li. Transcriptional and post-translational regulation of MITF mediated by bHLH domain during the melanogenesis and melanocyte proliferation in Crassostrea gigas. International Journal of Biological Macromolecules 2024, 266 , 131138. https://doi.org/10.1016/j.ijbiomac.2024.131138
Magdalena Strachowska, Agnieszka Robaszkiewicz. Characteristics of anticancer activity of CBP/p300 inhibitors – Features of their classes, intracellular targets and future perspectives of their application in cancer treatment. Pharmacology & Therapeutics 2024, 257 , 108636. https://doi.org/10.1016/j.pharmthera.2024.108636
Dustin C. Becht, Akinori Kanai, Soumi Biswas, Mohamed Halawa, Lei Zeng, Khan L. Cox, Michael G. Poirier, Ming-Ming Zhou, Xiaobing Shi, Akihiko Yokoyama, Tatiana G. Kutateladze. The winged helix domain of MORF binds CpG islands and the TAZ2 domain of p300. iScience 2024, 27 (4) , 109367. https://doi.org/10.1016/j.isci.2024.109367
Tsuyoshi Konuma, Ming-Ming Zhou. Distinct Histone H3 Lysine 27 Modifications Dictate Different Outcomes of Gene Transcription. Journal of Molecular Biology 2024, 436 (7) , 168376. https://doi.org/10.1016/j.jmb.2023.168376
Azharul Islam, Anirban Chakraborty, Altaf H Sarker, Uma K Aryal, Lang Pan, Gulshan Sharma, Istvan Boldogh, Tapas Hazra. Site-specific acetylation of polynucleotide kinase 3′-phosphatase regulates its distinct role in DNA repair pathways. Nucleic Acids Research 2024, 52 (5) , 2416-2433. https://doi.org/10.1093/nar/gkae002
Yun-Bin Lee, Hyun-Woo Rhee. Spray-type modifications: an emerging paradigm in post-translational modifications. Trends in Biochemical Sciences 2024, 49 (3) , 208-223. https://doi.org/10.1016/j.tibs.2024.01.008
Panhong Gou, Wenchao Zhang. Protein lysine acetyltransferase CBP/p300: A promising target for small molecules in cancer treatment. Biomedicine & Pharmacotherapy 2024, 171 , 116130. https://doi.org/10.1016/j.biopha.2024.116130
Ruizhi Lai, Zhiqian Lin, Chunyan Yang, Li Hai, Zhongzhen Yang, Li Guo, Ruifang Nie, Yong Wu. Novel berberine derivatives as p300 histone acetyltransferase inhibitors in combination treatment for breast cancer. European Journal of Medicinal Chemistry 2024, 266 , 116116. https://doi.org/10.1016/j.ejmech.2023.116116
Ning Wang, Xiaoyu Su, David Sams, Nanduri R. Prabhakar, Jayasri Nanduri. P300/CBP Regulates HIF-1–Dependent Sympathetic Activation and Hypertension by Intermittent Hypoxia. American Journal of Respiratory Cell and Molecular Biology 2024, 70 (2) , 110-118. https://doi.org/10.1165/rcmb.2022-0481OC

Load more citations

Download PDF

Get e-Alerts

Chemical Reviews

Cite this: Chem. Rev. 2015, 115, 6, 2419–2452

Click to copy citationCitation copied!

https://doi.org/10.1021/cr500452k

Published January 16, 2015

Request reuse permissions

Article Views

Altmetric

Citations

416

Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

Abstract
High Resolution Image
Download MS PowerPoint Slide
Figure 1
Figure 1. Reversible acetylation of the epsilon amine group of lysine side chains.
High Resolution Image
Download MS PowerPoint Slide
Figure 2
Figure 2. Major metabolic processes that produce or consume acetyl-CoA. Processes occurring in the cytoplasm are indicated using purple font, and processes occurring in the mitochondrion are indicated using orange font. Note that PDH can also be nuclear. This figure was adapted in part from Albaugh et al. (30)
High Resolution Image
Download MS PowerPoint Slide
Figure 3
Figure 3. Domain structure of p300/CBP. Exon–intron gene diagrams are shown for p300 and CBP (top). Below are example protein structures for the bromodomain (PDB 3I3J, 2.33 Å), catalytic HAT domain (PDB 3BIY, 1.7 Å), ZZ zinc finger (PDB 1TOT), and TAZ2 domain (PDB 3IO2, 2.5 Å). All structures were produced using purified p300, except the ZZ zinc finger, which used purified CBP. p300/CBP proteins are colored with a rainbow, with blue at the N-terminus and red at the C-terminus, and residues included in the structure are listed below each. Zinc ions are black spheres. All structures are based on X-ray crystallography, except the ZZ zinc finger structures from solution NMR. The p300 bromodomain structure shown here is remarkably similar to an independently generated CBP bromodomain structure (not shown, PDB 3DWY, 1.98 Å). Below is a model for full-length p300/CBP with all domains shown, and is a compilation based on several recent analyses.: (94, 95) three cysteine/histidine-rich (C/H) domains are shown in turquoise, three zinc fingers are shown in yellow, and the catalytic acetyltransferase domain is shown in orange, with its autoacetylated regulatory loop drawn above, which corresponds to residues 1523–1554. A few examples of proteins that bind p300/CBP are listed below the protein model, with the particular domain involved in binding indicated with a black line. Below that, amino acid similarity is indicated, for comparing p300 and CBP sequences within either the catalytic BHC region (from the bromodomain to the C/H3 domain) or the entire protein. At the bottom, commonly purified active p300 variants are indicated, including p300 acetyltransferase/HAT domain, BHC enzyme (bromodomain-HAT-C/H3), and full-length protein. It should be noted that p300 HAT has a deletion in residues 1529–1560.
High Resolution Image
Download MS PowerPoint Slide
Figure 4
Figure 4. p300/CBP is central to many important signaling pathways. These include pathways that respond to intracellular signals (turquoise), extracellular signals (purple), and intercellular signals (blue). These pathways control the key cellular functions via altering expression of target genes, through the action of p300/CBP in the nucleus.
High Resolution Image
Download MS PowerPoint Slide
Figure 5
Figure 5. p300/CBP functions as a scaffold, bridge, and acetyltransferase. The acetyltransferase reactions are illustrated by turquoise arrows, indicating acetylation of histone and nonhistone substrates (in yellow), as well as autoacetylation of the p300/CBP acetyltransferase domain. The bridge function is illustrated by turquoise squares, representing DNA-binding proteins that bring DNA elements into proximity with p300/CBP through their interactions. The scaffold function is illustrated by orange squares, representing a protein complex being recruited by p300/CBP. These functions together allow for gene expression.
High Resolution Image
Download MS PowerPoint Slide
Figure 6
Figure 6. p300 acetyltransferase domain structure bound to Lys-CoA. (A) Secondary structures of p300 acetyltransferase domain. (B) L1 loop and an acidic surface. (C) Parts of Lys-CoA bisubstrate analog (gray) and four p300 residues of interest (green). Generated in PyMol based on Protein Databank entry 3BIY, published by Liu et al. (143)
High Resolution Image
Download MS PowerPoint Slide
Figure 7
Figure 7. Acetyl transfer catalysis by p300. (A) The p300 active site is drawn in green, and histone H4 substrate in blue, with important residues indicated. CoA is drawn in black, and binds in a specific tunnel. (B) Four steps in a proposed p300 mechanism. acetyl-CoA binds, then peptidyl-lysine binds. The hydrophobic indole of W1436 promotes an uncharged lysine and positions it for attack. The lysine attacks the carbonyl of acetyl-CoA, while Y1467 acts as a general acid to protonate the leaving group. Acetyl-lysine-containing product leaves quickly, then CoASH departs slowly.
High Resolution Image
Download MS PowerPoint Slide
Figure 8
Figure 8. Bisubstrate inhibitors of acetyltransferases.
High Resolution Image
Download MS PowerPoint Slide
Figure 9
Figure 9. Natural products implicated as modulators of acetyltransferases.
High Resolution Image
Download MS PowerPoint Slide
Figure 10
Figure 10. Synthetic inhibitors of acetyltransferases.
High Resolution Image
Download MS PowerPoint Slide
Figure 11
Figure 11. C646 modeled in the acetyltransferase active site. (A) C646 is shown in magenta, computationally docked in the crystal structure of the acetyltransferase active site, which was generated as a cocrystal with Lys-CoA. Several residues that coordinate CoA binding are predicted to similarly coordinate C646 binding, as shown in aqua stick representations of the side chains. (B) The structure of C646, shown in an orientation similar to that in the docked model above.
High Resolution Image
Download MS PowerPoint Slide
Figure 12
Figure 12. Structures of CBP bromodomain bound to ligands. The purified CBP bromodomain (residues 1081–1197, shown in a rainbow blue to red) is shown bound to (A) histone H4 residues 14–28 acetylated at K20 (PDB 2RNY); (B) p53 residues 367–386 acetylated at K382 (PDB 1JSP); (C) the compound ischemin (PDB 2L84); and (D) the compound dimethylisoxazole (PDB 3SVH). Peptide ligands are shown in gray (A,B) or stick models colored by atom (C,D and acetyl-lysines in A,B). All structures are based on solution NMR except for (D), which is from X-ray crystallography (1.8 Å).
High Resolution Image
Download MS PowerPoint Slide
Figure 13
Figure 13. Structures of p300/CBP TAZ2 domain bound to ligands. The TAZ2 domain is shown colored in a rainbow (blue to red, residues included listed below each) bound to various ligands: STAT1 (A, PDB 2KA6); E1A (B, PDB 2KJE); p53 (C, PDB 2K8F); MEF2-DNA complex (D, PDB 3P57), and C/EBPε (PDB 3T92). All structures are based on solution NMR except for two from X-ray crystallography: that in (D) (2.192 Å) and that in (E) (1.5 Å). All structures were produced using purified p300, except the (A) and (B), which used purified CBP. Zinc ions are black spheres, protein ligands are gray, and DNA is yellow. The crystal structure with MEF2 revealed binding in three possible conformations with TAZ2, and one example is shown here.
High Resolution Image
Download MS PowerPoint Slide
Figure 14
Figure 14. Models for targeting influenced by p300-ligand binding. In these models, p300 is shown in green, the histone octamer is shown in yellow, DNA is shown with a red strand, and p300 ligands are indicated with an “L”. In (A), a ligand targets p300 to a gene or other DNA element due to the DNA binding affinity of the ligand. In (B), a ligand targets p300 to a protein complex due to the protein binding affinity of the ligand. In (C), two ligands bridged by p300 allow for chromatin (bound by the purple ligand) to come into proximity with a chromatin-modifying enzyme (the orange ligand). In (D), two ligands compete for the same site within p300, and the one ligand could be seen as a competitive inhibitor for the p300 association with the other.
High Resolution Image
Download MS PowerPoint Slide
Figure 15
Figure 15. Mastermind-Notch-CSL-DNA core complex. The complex formed by DNA, CSL, Notch (ANK repeats and RAM region purified separately), and Mastermind N-terminal helix is shown with two different view angles. The X-ray crystal structure was generated at 3.85 Å, and this figure was produced in PyMol using Protein Databank entry 3V79. Proteins are shown as ribbons, with the surfaces at 70% transparency. DNA is shown as stick models colored by atom.
High Resolution Image
Download MS PowerPoint Slide
Figure 16
Figure 16. Model for Mastermind activation of p300. In this model, p300 (green) initially has inhibited acetyltransferase activity due to an autoinhibitory loop (orange, left). This is relieved upon recruitment by the Notch-Mastermind-CSL complex. Mastermind (purple) binds to the p300 C/H3 domain, and also to Notch intracellular domain (magenta) and CSL (red). p300 autoacetylation, Mastermind acetylation, and histone acetylation are then catalyzed by p300 (turquoise ▲).
High Resolution Image
Download MS PowerPoint Slide
Figure 17
Figure 17. Inhibitors of the p300/CBP bromodomain.
High Resolution Image
Download MS PowerPoint Slide
Figure 18
Figure 18. Inhibitors of the other p300/CBP domains.
High Resolution Image
Download MS PowerPoint Slide
Figure 19
Figure 19. Diseases of potential therapeutic application for a p300/CBP inhibitor. No p300/CBP inhibitor has yet made it into clinical trials, but the biology of p300/CBP action and documented effects of p300/CBP disruption lead us to hypothesize a beneficial therapeutic potential for a p300/CBP inhibitor in many diseases.
High Resolution Image
Download MS PowerPoint Slide
Beverley M. Dancy
High Resolution Image
Download MS PowerPoint Slide
Beverley M. Dancy, originally from Cape Town, was introduced to research in the laboratory of Greg J. Hermann at Lewis & Clark College. Her graduate studies with Philip A. Cole, centered on p300 acetyltransferase inhibition, earned her a Ph.D. in Pharmacology and Molecular Sciences from the Johns Hopkins University School of Medicine in 2013. As a postdoctoral fellow in the Morgan-Sedensky laboratory, she investigated enzymes and pathways involved in mitochondrial disease, and in 2014 she will begin a fellowship at the National Institutes of Health Laboratory of Cardiac Energetics, with Robert S. Balaban. Dr. Dancy is interested in developing molecular tools and imaging technologies for understanding the consequences of disease at the molecular, cellular, and organismal levels. In addition to research, she is passionate about bridging the gap between science research and a broader audience through communication and engagement.
Philip A. Cole
High Resolution Image
Download MS PowerPoint Slide
Philip A. Cole was born in Paterson, NJ and graduated from Yale University with a B.S. in Chemistry in 1984 and then spent a year as a Churchill Scholar at the University of Cambridge, England. Cole went on to obtain M.D. and Ph.D. degrees from Johns Hopkins University where he pursued research in bioorganic chemistry in 1991. Cole then entered postdoctoral fellowship training at Harvard Medical School prior to joining the Rockefeller University in 1996 as a junior lab head. In 1999, Cole moved back to Johns Hopkins as the Marshall-Maren professor and director of pharmacology. His research interests are in the area of protein post-translational modifications and chemical biology.
References
This article references 499 other publications.
1. 1
  Waddington, C. H. Endeavour 1942, 18
  There is no corresponding record for this reference.
2. 2
  Klar, A. J. Trends Genet. 1998, 14, 299
  2
  Propagating epigenetic states through meiosis: where Mendel's gene is more than a DNA moiety
  Klar, Amar J. S.
  Trends in Genetics (1998), 14 (8), 299-301CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)
  A review, with 21 refs., on epigenetic inheritance as illustrated by Drosophila and Schizosaccharomyces pombe.
3. 3
  Redon, C.; Pilch, D.; Rogakou, E.; Sedelnikova, O.; Newrock, K.; Bonner, W. Curr. Opin. Genet. Dev. 2002, 12, 162
  There is no corresponding record for this reference.
4. 4
  Dawson, M. A.; Kouzarides, T. Cell 2012, 150, 12
  4
  Cancer Epigenetics: From Mechanism to Therapy
  Dawson, Mark A.; Kouzarides, Tony
  Cell (Cambridge, MA, United States) (2012), 150 (1), 12-27CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  A review. The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biol. processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clin. and preclin. results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.
5. 5
  Mukherjee, S.; Hao, Y. H.; Orth, K. Trends Biochem. Sci. 2007, 32, 210
  There is no corresponding record for this reference.
6. 6
  Moellering, R. E.; Cravatt, B. F. Science 2013, 341, 549
  There is no corresponding record for this reference.
7. 7
  Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
  7
  Histone modifiers in cancer: friends or foes?
  Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
  Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
  A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
8. 8
  Xing, S.; Poirier, Y. Trends Plant Sci. 2012, 17, 423
  8
  The protein acetylome and the regulation of metabolism
  Xing, Shufan; Poirier, Yves
  Trends in Plant Science (2012), 17 (7), 423-430CODEN: TPSCF9; ISSN:1360-1385. (Elsevier Ltd.)
  A review. Acetyl-CoA (CoA) is a central metabolite involved in numerous anabolic and catabolic pathways, as well as in protein acetylation. Beyond histones, a large no. of metabolic enzymes are acetylated in both animal and bacteria, and the protein acetylome is now emerging in plants. Protein acetylation is influenced by the cellular level of both acetyl-CoA and NAD+, and regulates the activity of several enzymes. Acetyl-CoA is thus ideally placed to act as a key mol. linking the energy balance of the cell to the regulation of gene expression and metabolic pathways via the control of protein acetylation. Better knowledge over how to influence acetyl-CoA levels and the acetylation process promises to be an invaluable tool to control metabolic pathways.
9. 9
  Daugherty, M.; Polanuyer, B.; Farrell, M.; Scholle, M.; Lykidis, A.; de Crécy-Lagard, V.; Osterman, A. J. Biol. Chem. 2002, 277, 21431
  There is no corresponding record for this reference.
10. 10
  Robinson, P. J.; An, W.; Routh, A.; Martino, F.; Chapman, L.; Roeder, R. G.; Rhodes, D. J. Mol. Biol. 2008, 381, 816
  10
  30 nm Chromatin Fibre Decompaction Requires both H4-K16 Acetylation and Linker Histone Eviction
  Robinson, Philip J. J.; An, Woojin; Routh, Andrew; Martino, Fabrizio; Chapman, Lynda; Roeder, Robert G.; Rhodes, Daniela
  Journal of Molecular Biology (2008), 381 (4), 816-825CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
  The mechanism by which chromatin is decondensed to permit access to DNA is largely unknown. Here, using a model nucleosome array reconstituted from recombinant histone octamers, we have defined the relative contribution of the individual histone octamer N-terminal tails as well as the effect of a targeted histone tail acetylation on the compaction state of the 30 nm chromatin fiber. This study goes beyond previous studies as it is based on a nucleosome array that is very long (61 nucleosomes) and contains a stoichiometric concn. of bound linker histone, which is essential for the formation of the 30 nm chromatin fiber. We find that compaction is regulated in two steps: Introduction of H4 acetylated to 30% on K16 inhibits compaction to a greater degree than deletion of the H4 N-terminal tail. Further decompaction is achieved by removal of the linker histone.
11. 11
  Neumann, H.; Peak-Chew, S. Y.; Chin, J. W. Nat. Chem. Biol. 2008, 4, 232
  11
  Genetically encoding Nε-acetyllysine in recombinant proteins
  Neumann, Heinz; Peak-Chew, Sew Y.; Chin, Jason W.
  Nature Chemical Biology (2008), 4 (4), 232-234CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  Nε-acetylation of lysine is a reversible post-translational modification with a regulatory role that rivals that of phosphorylation in eukaryotes. No general methods exist to synthesize proteins contg. Nε-acetyllysine at defined sites. The site-specific incorporation of Nε-acetyllysine in recombinant proteins produced in Escherichia coli was achieved via the evolution of an orthogonal Nε-acetyllysyl-tRNA synthetase/tRNACUA pair. This strategy should find wide applications in defining the cellular role of this modification.
12. 12
  Guo, J.; Wang, J.; Lee, J. S.; Schultz, P. G. Angew. Chem., Int. Ed. 2008, 47, 6399
  There is no corresponding record for this reference.
13. 13
  Muir, T. W.; Sondhi, D.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6705
  13
  Expressed protein ligation: A general method for protein engineering
  Muir, Tom W.; Sondhi, Dolan; Cole, Philip A.
  Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 6705-6710CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  A protein semisynthesis method-expressed protein ligation-is described that involves the chemoselective addn. of a peptide to a recombinant protein. This method was used to ligate a phosphotyrosine peptide to the C terminus of the protein tyrosine kinase C-terminal Src kinase (Csk). By intercepting a thioester generated in the recombinant protein with an N-terminal cysteine contg. synthetic peptide, near quant. chem. ligation of the peptide to the protein was achieved. The semisynthetic tail-phosphorylated Csk showed evidence of an intramol. phosphotyrosine-Src homol. 2 interaction and an unexpected increase in catalytic phosphoryl transfer efficiency toward a physiol. relevant substrate compared with the non-tail-phosphorylated control. This work illustrates that expressed protein ligation is a simple and powerful new method in protein engineering to introduce sequences of unnatural amino acids, posttranslational modifications, and biophys. probes into proteins of any size.
14. 14
  Karukurichi, K. R.; Wang, L.; Uzasci, L.; Manlandro, C. M.; Wang, Q.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 1222
  There is no corresponding record for this reference.
15. 15
  Huang, R.; Holbert, M. A.; Tarrant, M. K.; Curtet, S.; Colquhoun, D. R.; Dancy, B. M.; Dancy, B. C.; Hwang, Y.; Tang, Y.; Meeth, K.; Marmorstein, R.; Cole, R. N.; Khochbin, S.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 9986
  There is no corresponding record for this reference.
16. 16
  Johns, E. W.; Phillips, D. M.; Simson, P.; Butler, J. A. Biochem. J. 1961, 80, 189
  There is no corresponding record for this reference.
17. 17
  Phillips, D. M. Biochem. J. 1963, 87, 258
  There is no corresponding record for this reference.
18. 18
  Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
  18
  Histone modifiers in cancer: friends or foes?
  Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
  Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
  A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
19. 19
  Close, P.; Creppe, C.; Gillard, M.; Ladang, A.; Chapelle, J. P.; Nguyen, L.; Chariot, A. Cell. Mol. Life Sci. 2010, 67, 1255
  19
  The emerging role of lysine acetylation of non-nuclear proteins
  Close, Pierre; Creppe, Catherine; Gillard, Magali; Ladang, Aurelie; Chapelle, Jean-Paul; Nguyen, Laurent; Chariot, Alain
  Cellular and Molecular Life Sciences (2010), 67 (8), 1255-1264CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)
  A review. The acetylation of protein Lys residues is a post-translational modification that critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. More recent reports have also demonstrated that numerous proteins located outside the nucleus are also acetylated and that this modification has profound consequences on their functions. This review describes the latest findings on the protein substrates acetylated outside the nucleus and on the acetylases and deacetylates that catalyze these modifications. Protein acetylation is emerging as a major mechanism by which key proteins are regulated in many physiol. processes such as migration, metab., and aging as well as in pathol. circumstances such as cancer and neurodegenerative disorders.
20. 20
  Glozak, M. A.; Sengupta, N.; Zhang, X.; Seto, E. Gene 2005, 363, 15
  There is no corresponding record for this reference.
21. 21
  Norris, K. L.; Lee, J. Y.; Yao, T. P. Sci. Signaling 2009, 2, pe76
  21
  Acetylation goes global: the emergence of acetylation biology
  Norris Kristi L; Lee Joo-Yong; Yao Tso-Pang
  Science signaling (2009), 2 (97), pe76 ISSN:.
  For the first 30 years since its discovery, reversible protein acetylation has been studied and understood almost exclusively in the context of histone modification and gene transcription. With the discovery of non-histone acetylated proteins and acetylation-modifying enzymes in cellular compartments outside the nucleus, the regulatory potential of reversible acetylation has slowly been recognized in the last decade. However, the scope of protein acetylation involvement in complex biological processes remains uncertain. The recent development of new technology has enabled, for the first time, the identification and quantification of the acetylome, acetylation events at the whole-proteome level. These efforts have uncovered a stunning complexity of the acetylome that potentially rivals that of the phosphoproteome. The remarkably ubiquitous and conserved nature of protein acetylation revealed by these new studies suggests the regulatory power of this dynamic modification. The establishment of comprehensive acetylomes will change the landscape of protein acetylation, where an exciting research frontier awaits.
22. 22
  Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman, M.; Walther, T. C.; Olsen, J. V.; Mann, M. Science 2009, 325, 834
  22
  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
  Choudhary, Chunaram; Kumar, Chanchal; Gnad, Florian; Nielsen, Michael L.; Rehman, Michael; Walther, Tobias C.; Olsen, Jesper V.; Mann, Matthias
  Science (Washington, DC, United States) (2009), 325 (5942), 834-840CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Lysine acetylation is a reversible posttranslational modification of proteins and plays a key role in regulating gene expression. Technol. limitations have so far prevented a global anal. of lysine acetylation's cellular roles. We used high-resoln. mass spectrometry to identify 3600 lysine acetylation sites on 1750 proteins and quantified acetylation changes in response to the deacetylase inhibitors suberoylanilide hydroxamic acid and MS-275. Lysine acetylation preferentially targets large macromol. complexes involved in diverse cellular processes, such as chromatin remodeling, cell cycle, splicing, nuclear transport, and actin nucleation. Acetylation impaired phosphorylation-dependent interactions of 14-3-3 and regulated the yeast cyclin-dependent kinase Cdc28. Our data demonstrate that the regulatory scope of lysine acetylation is broad and comparable with that of other major posttranslational modifications.
23. 23
  Chen, Y.; Zhao, W.; Yang, J. S.; Cheng, Z.; Luo, H.; Lu, Z.; Tan, M.; Gu, W.; Zhao, Y. Mol. Cell. Proteomics 2012, 11, 1048
  23
  Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways
  Chen, Yue; Zhao, Wenhui; Yang, Jeong Soo; Cheng, Zhongyi; Luo, Hao; Lu, Zhike; Tan, Minjia; Gu, Wei; Zhao, Yingming
  Molecular and Cellular Proteomics (2012), 11 (10), 1048-1062CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
  Despite the progress in identifying many Lys acetylation (Kac) proteins, Kac substrates for Kac-regulatory enzymes remain largely unknown, presenting a major knowledge gap in Kac biol. Here, we identified and quantified 4623 Kac sites in 1800 Kac proteins in SIRT1+/+ and SIRT1-/- MEF cells, representing the first study to reveal an enzyme-regulated Kac subproteome and the largest Lys acetylome reported to date from a single study. Four hundred eighty-five Kac sites were enhanced by more than 100% after SIRT1 knockout. Our results indicate that SIRT1 regulates the Kac states of diverse cellular pathways. Interestingly, we found that a no. of acetyltransferases and major acetyltransferase complexes are targeted by SIRT1. Moreover, we showed that the activities of the acetyltransferases are regulated by SIRT1-mediated deacetylation. Taken together, our results reveal the Lys acetylome in response to SIRT1, provide new insights into mechanisms of SIRT1 function, and offer biomarker candidates for the clin. evaluation of SIRT1-activator compds.
24. 24
  Zhao, S.; Xu, W.; Jiang, W.; Yu, W.; Lin, Y.; Zhang, T.; Yao, J.; Zhou, L.; Zeng, Y.; Li, H.; Li, Y.; Shi, J.; An, W.; Hancock, S. M.; He, F.; Qin, L.; Chin, J.; Yang, P.; Chen, X.; Lei, Q.; Xiong, Y.; Guan, K. L. Science 2010, 327, 1000
  There is no corresponding record for this reference.
25. 25
  Albaugh, B. N.; Arnold, K. M.; Denu, J. M. ChemBioChem 2011, 12, 290
  There is no corresponding record for this reference.
26. 26
  Sutendra, G.; Kinnaird, A.; Dromparis, P.; Paulin, R.; Stenson, T. H.; Haromy, A.; Hashimoto, K.; Zhang, N.; Flaim, E.; Michelakis, E. D. Cell 2014, 158, 84
  There is no corresponding record for this reference.
27. 27
  Begley, T. P.; Kinsland, C.; Strauss, E. Vitam. Horm. 2001, 61, 157
  27
  The biosynthesis of coenzyme A in bacteria
  Begley, Tadhg P.; Kinsland, Cynthia; Strauss, Erick
  Vitamins and Hormones (San Diego, CA, United States) (2001), 61 (), 157-171CODEN: VIHOAQ; ISSN:0083-6729. (Academic Press)
  A review with 50 refs. CoA (I) and enzyme-bound phosphopantetheine (II) function as acyl carriers and as carbonyl activating groups for Claisen reactions as well as for amide-, ester-, and thioester-forming reactions in the cell. These cofactors play a key role in the biosynthesis and breakdown of fatty acids and in the biosynthesis of polyketides and nonribosomal peptides. CoA is biosynthesized in bacteria in nine steps. The biosynthesis begins with the decarboxylation of aspartate to give β-alanine. Pantoic acid is formed by the hydroxymethylation of α-ketoisovalerate followed by redn. These intermediates are then condensed to give pantothenic acid. Phosphorylation of pantothenic acid followed by condensation with cysteine and decarboxylation gives 4'-phosphopantetheine. Adenylation and phosphorylation of 4'-phosphopantetheine completes the biosynthesis of CoA. This review will focus on the mechanistic enzymol. of CoA biosynthesis in bacteria. (c) 2001 Academic Press.
28. 28
  Xing, S.; Poirier, Y. Trends Plant Sci. 2012, 17, 423
  28
  The protein acetylome and the regulation of metabolism
  Xing, Shufan; Poirier, Yves
  Trends in Plant Science (2012), 17 (7), 423-430CODEN: TPSCF9; ISSN:1360-1385. (Elsevier Ltd.)
  A review. Acetyl-CoA (CoA) is a central metabolite involved in numerous anabolic and catabolic pathways, as well as in protein acetylation. Beyond histones, a large no. of metabolic enzymes are acetylated in both animal and bacteria, and the protein acetylome is now emerging in plants. Protein acetylation is influenced by the cellular level of both acetyl-CoA and NAD+, and regulates the activity of several enzymes. Acetyl-CoA is thus ideally placed to act as a key mol. linking the energy balance of the cell to the regulation of gene expression and metabolic pathways via the control of protein acetylation. Better knowledge over how to influence acetyl-CoA levels and the acetylation process promises to be an invaluable tool to control metabolic pathways.
29. 29
  Wellen, K. E.; Thompson, C. B. Nat. Rev. Mol. Cell Biol. 2012, 13, 270
  29
  A two-way street: reciprocal regulation of metabolism and signalling
  Wellen, Kathryn E.; Thompson, Craig B.
  Nature Reviews Molecular Cell Biology (2012), 13 (4), 270-276CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
  A review. It is becoming increasingly clear that cellular signaling and metab. are not just sep. entities but rather are tightly linked. Although nutrient metab. is known to be regulated by signal transduction, an emerging paradigm is that signaling and transcriptional networks can be modulated by nutrient-sensitive protein modifications, such as acetylation and glycosylation, which depend on the availability of acetyl-CoA and sugar donors such as UDP-N-acetylglucosamine (UDP-GlcNAc), resp. The integration of metabolic and signaling cues allows cells to modulate activities such as metab., cell survival and proliferation according to their intracellular metabolic resources.
30. 30
  Albaugh, B. N.; Arnold, K. M.; Denu, J. M. ChemBioChem 2011, 12, 290
  There is no corresponding record for this reference.
31. 31
  Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Proc. Natl. Acad. Sci. U.S.A. 1964, 51, 786
  31
  Acetylation and methylation of histones and their possible role in the regulation of ribonucleic acid (RNA) synthesis
  Allfrey, V. G.; Faulkner, R.; Mirsky, A. E.
  Proceedings of the National Academy of Sciences of the United States of America (1964), 51 (5), 786-94CODEN: PNASA6; ISSN:0027-8424.
  Isolated calf thymus nuclei was incubated with 14C-labeled Na acetate. Evidence that acetate was incorporated as acetyl groups attached to histones included: (1) following chromatography the label was eluted together with basic proteins; (2) acetyl-labeled histones were sepd. by electrophoresis; (3) acetate-14C was not removed from histones by org. solvents; (4) over 75% of the label remained after histones were treated with trichloroacetic acid. Most extensive acetate uptake occurred with arginine-rich histones. Puromycin did not inhibit the acetylation, indicating histones were modified by acetylation after completion of the polypeptide chain. Acetylation lowered the histone effectiveness as inhibitor of the RNA polymerase reaction, and a dynamic and reversible mechanism was suggested for activation as well as repression of RNA synthesis.
32. 32
  Hebbes, T. R.; Thorne, A. W.; Crane-Robinson, C. EMBO J. 1988, 7, 1395
  There is no corresponding record for this reference.
33. 33
  Hebbes, T. R.; Clayton, A. L.; Thorne, A. W.; Crane-Robinson, C. EMBO J. 1994, 13, 1823
  There is no corresponding record for this reference.
34. 34
  Braunstein, M.; Rose, A. B.; Holmes, S. G.; Allis, C. D.; Broach, J. R. Genes Dev. 1993, 7, 592
  34
  Transcriptional silencing in yeast is associated with reduced nucleosome acetylation
  Braunstein, Miriam; Rose, Alan B.; Holmes, Scott G.; Allis, C. David; Broach, James R.
  Genes & Development (1993), 7 (4), 592-604CODEN: GEDEEP; ISSN:0890-9369.
  Two classes of sequences in the yeast Saccharomyces cerevisiae are subject to transcription silencing: the silent mating-type cassettes and telomers. The silencing of these regions is shown to be strictly assocd. with acetylation of the ε-amino groups of lysines in the N-terminal domains of 3 of the 4 core histones. Both the silent mating-type cassettes and the Y domains of telomeres are packaged in nucleosomes in vivo that are hypoacetylated relative to those packaging active genes. This difference in acetylation is eliminated by genetic inactivation of silencing:. The silent cassettes from sir2, sir3, or sir4 cells show the same level of acetylation as other active genes. The correspondence of silencing and hypoacetylation of the mating-type cassettes is obsd. even for an allele lacking a promoter, indicating that silencing per se, rather than the absence of transcription, is correlated with hypoacetylation. Finally, overexpression of Sir2p, a protein required for transcriptional silencing in yeast, yields substantial histone deacetylation in vivo. These studies fortify the hypothesis that silencing in yeast results from heterochromatin formation and argue that the silencing proteins participate in this formation.
35. 35
  Turner, B. M.; Birley, A. J.; Lavender, J. Cell 1992, 69, 375
  There is no corresponding record for this reference.
36. 36
  Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Proc. Natl. Acad. Sci. U.S.A. 1964, 51, 786
  36
  Acetylation and methylation of histones and their possible role in the regulation of ribonucleic acid (RNA) synthesis
  Allfrey, V. G.; Faulkner, R.; Mirsky, A. E.
  Proceedings of the National Academy of Sciences of the United States of America (1964), 51 (5), 786-94CODEN: PNASA6; ISSN:0027-8424.
  Isolated calf thymus nuclei was incubated with 14C-labeled Na acetate. Evidence that acetate was incorporated as acetyl groups attached to histones included: (1) following chromatography the label was eluted together with basic proteins; (2) acetyl-labeled histones were sepd. by electrophoresis; (3) acetate-14C was not removed from histones by org. solvents; (4) over 75% of the label remained after histones were treated with trichloroacetic acid. Most extensive acetate uptake occurred with arginine-rich histones. Puromycin did not inhibit the acetylation, indicating histones were modified by acetylation after completion of the polypeptide chain. Acetylation lowered the histone effectiveness as inhibitor of the RNA polymerase reaction, and a dynamic and reversible mechanism was suggested for activation as well as repression of RNA synthesis.
37. 37
  Mutskov, V.; Gerber, D.; Angelov, D.; Ausio, J.; Workman, J.; Dimitrov, S. Mol. Cell. Biol. 1998, 18, 6293
  37
  Persistent interactions of core histone tails with nucleosomal DNA following acetylation and transcription factor binding
  Mutskov, Vesco; Gerber, Delphine; Angelov, Dimitri; Ausio, Juan; Workman, Jerry; Dimitrov, Stefan
  Molecular and Cellular Biology (1998), 18 (11), 6293-6304CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  In this study, we examd. the effect of acetylation of the NH2 tails of core histones on their binding to nucleosomal DNA in the absence or presence of bound transcription factors. To do this, we used a novel UV laser-induced protein-DNA crosslinking technique, combined with immunochem. and mol. biol. approaches. Nucleosomes contg. one or five GAL4 binding sites were reconstituted with hypo-acetylated or hyper-acetylated core histones. Within these reconstituted particles, UV laser-induced histone-DNA crosslinking was found to occur only via the non-structured histone tails and thus presented a unique tool for studying histone tail interactions with nucleosomal DNA. Importantly, these studies demonstrated that the NH2 tails were not released from nucleosomal DNA upon histone acetylation, although some weakening of their interactions was obsd. at elevated ionic strengths. Moreover, the binding of up to five GAL4-AH dimers to nucleosomes occupying the central 90 bp occurred without displacement of the histone NH2 tails from DNA. GAL4-AH binding perturbed the interaction of each histone tail with nucleosomal DNA to different degrees. However, in all cases, greater than 50% of the interactions between the histone tails and DNA was retained upon GAL4-AH binding, even if the tails were highly acetylated. These data illustrate an interaction of acetylated or non-acetylated histone tails with DNA that persists in the presence of simultaneously bound transcription factors.
38. 38
  Zeng, L.; Zhou, M. M. FEBS Lett. 2002, 513, 124
  There is no corresponding record for this reference.
39. 39
  Taverna, S. D.; Li, H.; Ruthenburg, A. J.; Allis, C. D.; Patel, D. J. Nat. Struct. Mol. Biol. 2007, 14, 1025
  39
  How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
  Taverna, Sean D.; Li, Haitao; Ruthenburg, Alexander J.; Allis, C. David; Patel, Dinshaw J.
  Nature Structural & Molecular Biology (2007), 14 (11), 1025-1040CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  A review. Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), esp. on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their assocd. complexes, has been predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here, the authors summarize key features in the mol. recognition of histone PTMs by a diverse family of 'reader pockets' (including bromodomains, Royal superfamily modules, PHD fingers, WD40 protein repeats, 14-3-3 proteins, and BRCT domains), highlighting specific readout mechanisms for individual marks, common themes, and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biol. and disease, notably cancer.
40. 40
  Botuyan, M. V.; Lee, J.; Ward, I. M.; Kim, J. E.; Thompson, J. R.; Chen, J.; Mer, G. Cell 2006, 127, 1361
  There is no corresponding record for this reference.
41. 41
  Lee, J.; Thompson, J. R.; Botuyan, M. V.; Mer, G. Nat. Struct. Mol. Biol. 2008, 15, 109
  41
  Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor
  Lee, Joseph; Thompson, James R.; Botuyan, Maria Victoria; Mer, Georges
  Nature Structural & Molecular Biology (2008), 15 (1), 109-111CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  The lysine demethylase JMJD2A has the unique property of binding trimethylated peptides from two different histone sequences (H3K4me3 and H4K20me3) through its tudor domains. Here we show using X-ray crystallog. and calorimetry that H3K4me3 and H4K20me3, which are recognized with similar affinities by JMJD2A, adopt radically different binding modes, to the extent that we were able to design single point mutations in JMJD2A that inhibited the recognition of H3K4me3 but not H4K20me3 and vice versa.
42. 42
  Guo, Y.; Nady, N.; Qi, C.; Allali-Hassani, A.; Zhu, H.; Pan, P.; Adams-Cioaba, M. A.; Amaya, M. F.; Dong, A.; Vedadi, M.; Schapira, M.; Read, R. J.; Arrowsmith, C. H.; Min, J. Nucleic Acids Res. 2009, 37, 2204
  There is no corresponding record for this reference.
43. 43
  Li, H.; Fischle, W.; Wang, W.; Duncan, E. M.; Liang, L.; Murakami-Ishibe, S.; Allis, C. D.; Patel, D. J. Mol. Cell 2007, 28, 677
  There is no corresponding record for this reference.
44. 44
  Li, H.; Ilin, S.; Wang, W.; Duncan, E. M.; Wysocka, J.; Allis, C. D.; Patel, D. J. Nature 2006, 442, 91
  There is no corresponding record for this reference.
45. 45
  Jenuwein, T.; Allis, C. D. Science 2001, 293, 1074
  45
  Translating the histone code
  Jenuwein, Thomas; Allis, C. David
  Science (Washington, DC, United States) (2001), 293 (5532), 1074-1080CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  The review. Chromatin, the physiol. template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-assocd. proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all; chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathol. development.
46. 46
  Bernstein, E.; Hake, S. B. Biochem. Cell Biol. 2006, 84, 505
  46
  The nucleosome: a little variation goes a long way
  Bernstein, Emily; Hake, Sandra B.
  Biochemistry and Cell Biology (2006), 84 (4), 505-517CODEN: BCBIEQ; ISSN:0829-8211. (National Research Council of Canada)
  A review. Changes in the overall structure of chromatin are essential for the proper regulation of cellular processes, including gene activation and silencing, DNA repair, chromosome segregation during mitosis and meiosis, X chromosome inactivation in female mammals, and chromatin compaction during apoptosis. Such alterations of the chromatin template occur through at least 3 interrelated mechanisms: post-translational modifications of histones, ATP-dependent chromatin remodeling, and the incorporation (or replacement) of specialized histone variants into chromatin. Of these mechanisms, the exchange of variants into and out of chromatin is the least well understood. However, the exchange of conventional histones for variant histones has distinct and profound consequences within the cell. This review focuses on the growing no. of mammalian histone variants, their particular biol. functions and unique features, and how they may affect the structure of the nucleosome. The authors propose that a given nucleosome might not consist of heterotypic variants, but rather, that only specific histone variants come together to form a homotypic nucleosome, a hypothesis that the authors refer to as the nucleosome code. Such nucleosomes might in turn participate in marking specific chromatin domains that may contribute to epigenetic inheritance.
47. 47
  Schreiber, S. L.; Bernstein, B. E. Cell 2002, 111, 771
  There is no corresponding record for this reference.
48. 48
  Ernst, J.; Kellis, M. Nat. Biotechnol. 2010, 28, 817
  There is no corresponding record for this reference.
49. 49
  Jenuwein, T.; Allis, C. D. Science 2001, 293, 1074
  49
  Translating the histone code
  Jenuwein, Thomas; Allis, C. David
  Science (Washington, DC, United States) (2001), 293 (5532), 1074-1080CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  The review. Chromatin, the physiol. template of all eukaryotic genetic information, is subject to a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA. Distinct histone amino-terminal modifications can generate synergistic or antagonistic interaction affinities for chromatin-assocd. proteins, which in turn dictate dynamic transitions between transcriptionally active or transcriptionally silent chromatin states. The combinatorial nature of histone amino-terminal modifications thus reveals a "histone code" that considerably extends the information potential of the genetic code. We propose that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all; chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathol. development.
50. 50
  Feng, Y.; Wang, J.; Asher, S.; Hoang, L.; Guardiani, C.; Ivanov, I.; Zheng, Y. G. J. Biol. Chem. 2011, 286, 20323
  There is no corresponding record for this reference.
51. 51
  Nathan, D.; Ingvarsdottir, K.; Sterner, D. E.; Bylebyl, G. R.; Dokmanovic, M.; Dorsey, J. A.; Whelan, K. A.; Krsmanovic, M.; Lane, W. S.; Meluh, P. B.; Johnson, E. S.; Berger, S. L. Genes Dev. 2006, 20, 966
  There is no corresponding record for this reference.
52. 52
  Messner, S.; Altmeyer, M.; Zhao, H.; Pozivil, A.; Roschitzki, B.; Gehrig, P.; Rutishauser, D.; Huang, D.; Caflisch, A.; Hottiger, M. O. Nucleic Acids Res. 2010, 38, 6350
  There is no corresponding record for this reference.
53. 53
  Dhalluin, C.; Carlson, J. E.; Zeng, L.; He, C.; Aggarwal, A. K.; Zhou, M. M. Nature 1999, 399, 491
  There is no corresponding record for this reference.
54. 54
  Thorne, A. W.; Kmiciek, D.; Mitchelson, K.; Sautiere, P.; Crane-Robinson, C. Eur. J. Biochem. 1990, 193, 701
  54
  Patterns of histone acetylation
  Thorne, Alan W.; Kmiciek, Daniel; Mitchelson, Keith; Sautiere, Pierre; Crane-Robinson, Colyn
  European Journal of Biochemistry (1990), 193 (3), 701-13CODEN: EJBCAI; ISSN:0014-2956.
  The N-terminal domains of all four core histones are subject to reversible acetylation at certain lysine residues. This modification has been functionally linked to transcription, histone deposition at replication, and to histone removal during spermatogenesis. To increase understanding of the significance of this modification the specificity of site utilization in the monoacetyl, diacetyl, and triacetyl forms of histones H3, H4, and H2B (histone H2A has only a single modification site) was studied using pig thymus and HeLa cells as the source. The HeLa histones were extd. from cells grown both with and without butyrate treatment. For histone H3 there is a fairly strict order of site occupancy: Lys14, followed by Lys23, followed by Lys18 in both pig and HeLa histones. Since the order and specificity is the same when butyrate is added to the HeLa cell cultures, it is concluded that addn. of the fatty acid does not scramble the specificity of site utilization, but merely allows more of the natural forms of modified histone to accumulate. For histone H4, the monoacetyl form is exclusively modified at Lys16, but further addn. of acetyl groups is less specific and progresses through sites 12, 8 and 5 in an N-terminal direction. Similar results were obtained for H4 from both pig thymus and butyrate-treated HeLa cells. Histone H2B could be studied in detail only from butyrate-treated HeLa cells and a much lower level of site specificity was found: sites 12 and 15 were preferred to the more N- and C-terminal sites at Lys5 and Lys20. The data reinforces the view that lysine acetylation in core histones is a very specific phenomenon that plays several functionally distinct roles. The high degree of site specificity makes it unlikely that the structural effects of acetylation are mediated merely by a generalized redn. of charge in the histone N-terminal domains.
55. 55
  Zhang, K.; Williams, K. E.; Huang, L.; Yau, P.; Siino, J. S.; Bradbury, E. M.; Jones, P. R.; Minch, M. J.; Burlingame, A. L. Mol. Cell. Proteomics 2002, 1, 500
  55
  Histone acetylation and deacetylation: identification of acetylation and methylation sites of HeLa histone H4 by mass spectrometry
  Zhang, Kangling; Williams, Katherine E.; Huang, Lan; Yau, Peter; Siino, Joseph S.; Bradbury, E. Morton; Jones, Patrick R.; Minch, Michael J.; Burlingame, Alma L.
  Molecular and Cellular Proteomics (2002), 1 (7), 500-508CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology, Inc.)
  The acetylation isoforms of histone H4 from butyrate-treated HeLa cells were sepd. by C4 reverse-phase high pressure liq. chromatog. and by PAGE. Histone H4 bands were excised and digested in-gel with the endoprotease trypsin. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to characterize the level of acetylation, and nanoelectrospray tandem mass spectrometric anal. of the acetylated peptides was used to det. the exact sites of acetylation. Although there are 15 acetylation sites possible, only four acetylated peptide sequences were actually obsd. The tetra-acetylated form is modified at lysines 5, 8, 12, and 16, the tri-acetylated form is modified at lysines 8, 12, and 16, and the di-acetylated form is modified at lysines 12 and 16. The only significant amt. of the mono-acetylated form was found at position 16. These results are consistent with the hypothesis of a "zip" model whereby acetylation of histone H4 proceeds in the direction of from Lys-16 to Lys-5, and deacetylation proceeds in the reverse direction. Histone acetylation and deacetylation are coordinated processes leading to a non-random distribution of isoforms. Our results also revealed that lysine 20 is dimethylated in all modified isoforms, as well as the nonacetylated isoform of H4.
56. 56
  Clayton, A. L.; Hazzalin, C. A.; Mahadevan, L. C. Mol. Cell 2006, 23, 289
  There is no corresponding record for this reference.
57. 57
  Waterborg, J. H. Biochem. Cell Biol. 2002, 80, 363
  57
  Dynamics of histone acetylation in vivo. A function for acetylation turnover?
  Waterborg, Jakob H.
  Biochemistry and Cell Biology (2002), 80 (3), 363-378CODEN: BCBIEQ; ISSN:0829-8211. (National Research Council of Canada)
  A review. Histone acetylation discovered more than 40 yr ago is a reversible modification of lysines within the amino-terminal domain of core histones. Amino-terminal histone domains contribute to the compaction of genes into repressed chromatin fibers. It is thought that their acetylation causes localized relaxation of chromatin as a necessary but not sufficient condition for processes that repackage DNA such as transcription, replication, repair, recombination, and sperm formation. While increased histone acetylation enhances gene transcription and loss of acetylation represses and silences genes, the function of the rapid continuous or repetitive acetylation and deacetylation reactions with half-lives of just a few minutes remains unknown. Thirty years of in vivo measurements of acetylation turnover and rates of change in histone modification levels have been reviewed to identify common chromatin characteristics measured by distinct protocols. It has now become possible to look across a wider spectrum of organisms than ever before and identify common features. The rapid turnover rates in transcriptionally active and competent chromatin are one such feature. While ubiquitously obsd., we still do not know whether turnover itself is linked to chromatin transcription beyond its contribution to rapid changes towards hyper- or hypoacetylation of nucleosomes. However, recent expts. suggest that turnover may be linked directly to steps in gene transcription, interacting with nucleosome remodeling complexes.
58. 58
  Katan-Khaykovich, Y.; Struhl, K. Genes Dev. 2002, 16, 743
  There is no corresponding record for this reference.
59. 59
  Annunziato, A. T.; Eason, M. B.; Perry, C. A. Biochemistry 1995, 34, 2916
  There is no corresponding record for this reference.
60. 60
  Hendzel, M. J.; Davie, J. R. Biochem. J. 1991, 273, 753
  There is no corresponding record for this reference.
61. 61
  Hazzalin, C. A.; Mahadevan, L. C. PLoS Biol. 2005, 3, e393
  There is no corresponding record for this reference.
62. 62
  Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
  There is no corresponding record for this reference.
63. 63
  Taunton, J.; Hassig, C. A.; Schreiber, S. L. Science 1996, 272, 408
  63
  A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p
  Taunton, Jack; Hassig, Christian A.; Schreiber, Stuart L.
  Science (Washington, D. C.) (1996), 272 (5260), 408-11CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a human Jurkat T cell library. As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p, these results support a role for histone deacetylase as a key regulator of eukaryotic transcription.
64. 64
  Schiltz, R. L.; Mizzen, C. A.; Vassilev, A.; Cook, R. G.; Allis, C. D.; Nakatani, Y. J. Biol. Chem. 1999, 274, 1189
  There is no corresponding record for this reference.
65. 65
  Kimura, A.; Horikoshi, M. Genes Cells 1998, 3, 789
  65
  Tip60 acetylates six lysines of a specific class in core histones in vitro
  Kimura, Akatsuki; Horikoshi, Masami
  Genes to Cells (1998), 3 (12), 789-800CODEN: GECEFL; ISSN:1356-9597. (Blackwell Science Ltd.)
  Tip60, an HIV-1-Tat interactive protein, is a nuclear histone acetyltransferase (HAT) with unique histone substrate specificity. Since the acetylation of core histones at particular lysines mediates distinct effects on chromatin assembly and gene regulation, the identification of Lys site specificity of the HAT activity of Tip60 is an initial step in the anal. of its mol. function. Tip60 significantly acetylates N-terminal tail peptides of histones H2A, H3 and H4, but not H2B, consistent with substrate preference on intact histones. Preferred acetylation sites for Tip60 are Lys-5 of histone H2A, Lys-14 of histone H3, and Lys-5, Lys-8, Lys-12, Lys-16 of histone H4, detd. by a method which combined matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) measurements and Lys-C endopeptidase digestion, or a method detecting the incorporation of radiolabeled acetate into synthetic peptides. The Lys site specificity of Tip60 in histone N-terminal tail peptides in vitro was characterized by an assay measuring the mol. wt. of endopeptidase-digested peptides, or a previously described assay. These results agree well with the authors' proposed classification of Lys residues in core histones. The classification may be useful for an anal. of the relations between HATs and the substrates of other uncharacterized HATs.
66. 66
  Thompson, P. R.; Kurooka, H.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2001, 276, 33721
  There is no corresponding record for this reference.
67. 67
  Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
  There is no corresponding record for this reference.
68. 68
  Schiltz, R. L.; Mizzen, C. A.; Vassilev, A.; Cook, R. G.; Allis, C. D.; Nakatani, Y. J. Biol. Chem. 1999, 274, 1189
  There is no corresponding record for this reference.
69. 69
  McManus, K. J.; Hendzel, M. J. Mol. Cell. Biol. 2003, 23, 7611
  69
  Quantitative analysis of CBP- and P300-induced histone acetylations in vivo using native chromatin
  McManus, Kirk J.; Hendzel, Michael J.
  Molecular and Cellular Biology (2003), 23 (21), 7611-7627CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  In vivo, histone tails are involved in numerous interactions, including those with DNA, adjacent histones, and other, nonhistone proteins. The N-termini are also the substrates for a no. of enzymes, including histone acetyltransferases (HATs), histone deacetylases, and histone methyltransferases. Traditional biochem. approaches defining the substrate specificity profiles of HATs have been performed using purified histone tails, recombinant histones, or purified mononucleosomes as substrates. It is clear that the in vivo presentation of the substrate cannot be accurately represented by using these in vitro approaches. Because of the difficulty in translating in vitro results into in vivo situations, the authors developed a novel single-cell HAT assay that provides quant. measurements of endogenous HAT activity. The HAT assay is performed under in vivo conditions by using the native chromatin structure as the physiol. substrate. The assay combines the spatial resolving power of laser scanning confocal microscopy with simple statistical analyses to characterize CREB binding protein (CBP)- and P300-induced changes in global histone acetylation levels at specific lysine residues. Here the authors show that CBP and P300 exhibit unique substrate specificity profiles, consistent with the developmental and functional differences between the two HATs.
70. 70
  Kasper, L. H.; Lerach, S.; Wang, J.; Wu, S.; Jeevan, T.; Brindle, P. K. EMBO J. 2010, 29, 3660
  There is no corresponding record for this reference.
71. 71
  Dawson, M. A.; Kouzarides, T. Cell 2012, 150, 12
  71
  Cancer Epigenetics: From Mechanism to Therapy
  Dawson, Mark A.; Kouzarides, Tony
  Cell (Cambridge, MA, United States) (2012), 150 (1), 12-27CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  A review. The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15 years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biol. processes that are fundamental to the genesis of cancer. Here, we present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clin. and preclin. results seen with epigenetic drugs against chromatin regulators, signifies that it is time to embrace the central role of epigenetics in cancer.
72. 72
  Yee, S. P.; Branton, P. E. Virology 1985, 147, 142
  There is no corresponding record for this reference.
73. 73
  Whyte, P.; Williamson, N. M.; Harlow, E. Cell 1989, 56, 67
  There is no corresponding record for this reference.
74. 74
  Eckner, R.; Ewen, M. E.; Newsome, D.; Gerdes, M.; DeCaprio, J. A.; Lawrence, J. B.; Livingston, D. M. Genes Dev. 1994, 8, 869
  There is no corresponding record for this reference.
75. 75
  Chrivia, J. C.; Kwok, R. P.; Lamb, N.; Hagiwara, M.; Montminy, M. R.; Goodman, R. H. Nature 1993, 365, 855
  There is no corresponding record for this reference.
76. 76
  Arany, Z.; Sellers, W. R.; Livingston, D. M.; Eckner, R. Cell 1994, 77, 799
  There is no corresponding record for this reference.
77. 77
  Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
  There is no corresponding record for this reference.
78. 78
  Brownell, J. E.; Zhou, J.; Ranalli, T.; Kobayashi, R.; Edmondson, D. G.; Roth, S. Y.; Allis, C. D. Cell 1996, 84, 843
  78
  Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation
  Brownell, James E.; Zhou, Jianxin; Ranalli, Tamara; Kobayashi, Ryuji; Edmondson, Diane G.; Roth, Sharon Y.; Allis, C. David
  Cell (Cambridge, Massachusetts) (1996), 84 (6), 843-51CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  We report the cloning of a transcription-assocd. histone acetyltransferase type A (HAT A). This Tetrahymena enzyme is strikingly homologous to the yeast protein Gcn5, a putative transcriptional adaptor, and we demonstrate that recombinant Gcn5p possesses HAT activity. Both the ciliate enzyme and Gcn5p contain potential active site residues found in other acetyltransferases and a highly conserved bromodomain. The presence of this domain in nuclear A-type HATs, but not in cytoplasmic B-type HATs, suggests a mechanism whereby HAT A is directed to chromatin to facilitate transcriptional activation. These findings shed light on the biochem. function of the evolutionarily conserved Gcn5p-Ada complex, directly linking histone acetylation to gene activation, and indicate that histone acetylation is a targeted phenomenon.
79. 79
  Brownell, J. E.; Allis, C. D. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6364
  There is no corresponding record for this reference.
80. 80
  Kleff, S.; Andrulis, E. D.; Anderson, C. W.; Sternglanz, R. J. Biol. Chem. 1995, 270, 24674
  There is no corresponding record for this reference.
81. 81
  Bannister, A. J.; Kouzarides, T. Nature 1996, 384, 641
  There is no corresponding record for this reference.
82. 82
  Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
  There is no corresponding record for this reference.
83. 83
  Eckner, R. Biol. Chem. 1996, 377, 685
  There is no corresponding record for this reference.
84. 84
  Taddei, A.; Gasser, S. M. Genetics 2012, 192, 107
  There is no corresponding record for this reference.
85. 85
  Rando, O. J.; Chang, H. Y. Annu. Rev. Biochem. 2009, 78, 245
  85
  Genome-wide views of chromatin structure
  Rando, Oliver J.; Chang, Howard Y.
  Annual Review of Biochemistry (2009), 78 (), 245-271CODEN: ARBOAW; ISSN:0066-4154. (Annual Reviews Inc.)
  A review. Eukaryotic genomes are packaged into a nucleoprotein complex known as chromatin, which affects most processes that occur on DNA. Along with genetic and biochem. studies of resident chromatin proteins and their modifying enzymes, mapping of chromatin structure in vivo is one of the main pillars in our understanding of how chromatin relates to cellular processes. In this review, we discuss the use of genomic technologies to characterize chromatin structure in vivo, with a focus on data from budding yeast and humans. The picture emerging from these studies is the detailed chromatin structure of a typical gene, where the typical behavior gives insight into the mechanisms and deep rules that establish chromatin structure. Important deviation from the archetype is also obsd., usually as a consequence of unique regulatory mechanisms at special genomic loci. Chromatin structure shows substantial conservation from yeast to humans, but mammalian chromatin has addnl. layers of complexity that likely relate to the requirements of multicellularity such as the need to establish faithful gene regulatory mechanisms for cell differentiation.
86. 86
  Bordoli, L.; Netsch, M.; Lüthi, U.; Lutz, W.; Eckner, R. Nucleic Acids Res. 2001, 29, 589
  There is no corresponding record for this reference.
87. 87
  Tang, Y.; Holbert, M. A.; Wurtele, H.; Meeth, K.; Rocha, W.; Gharib, M.; Jiang, E.; Thibault, P.; Verreault, A.; Cole, P. A.; Marmorstein, R. Nat. Struct. Mol. Biol. 2008, 15, 998
  87
  Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. [Erratum to document cited in CA149:217962]
  Tang, Yong; Holbert, Marc A.; Wurtele, Hugo; Meeth, Katrina; Rocha, Walter; Gharib, Marlene; Jiang, Eva; Thibault, Pierre; Verreault, Alain; Cole, Philip A.; Marmorstein, Ronen
  Nature Structural & Molecular Biology (2008), 15 (9), 998CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  On page 738, the author name "Verreault" was mistakenly spelled as "Verrault". The error has been cor. in the HTML and PDF versions of the article.
88. 88
  Bordoli, L.; Netsch, M.; Lüthi, U.; Lutz, W.; Eckner, R. Nucleic Acids Res. 2001, 29, 589
  There is no corresponding record for this reference.
89. 89
  Giles, R. H.; Dauwerse, H. G.; van Ommen, G. J.; Breuning, M. H. Am. J. Hum. Genet. 1998, 63, 1240
  89
  Do human chromosomal bands 16p13 and 22q11-13 share ancestral origins?
  Giles R H; Dauwerse H G; van Ommen G J; Breuning M H
  American journal of human genetics (1998), 63 (4), 1240-2 ISSN:0002-9297.
  There is no expanded citation for this reference.
90. 90
  Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
  90
  p300/CBP proteins: HATs for transcriptional bridges and scaffolds
  Chan, Ho Man; La Thangue, Nicholas B.
  Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
  A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
91. 91
  Ogryzko, V. V.; Schiltz, R. L.; Russanova, V.; Howard, B. H.; Nakatani, Y. Cell 1996, 87, 953
  There is no corresponding record for this reference.
92. 92
  Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
  There is no corresponding record for this reference.
93. 93
  Bedford, D. C.; Brindle, Ph. Aging (N. Y.) 2012, 4, 247
  93
  Is histone acetylation the most important physiological function for CBP and p300?
  Bedford David C; Brindle Paul K
  Aging (2012), 4 (4), 247-55 ISSN:.
  Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription.
94. 94
  Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
  There is no corresponding record for this reference.
95. 95
  Bedford, D. C.; Brindle, P. K. Aging (N. Y.) 2012, 4, 247
  95
  Is histone acetylation the most important physiological function for CBP and p300?
  Bedford David C; Brindle Paul K
  Aging (2012), 4 (4), 247-55 ISSN:.
  Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network "hubs" with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription.
96. 96
  Arany, Z.; Newsome, D.; Oldread, E.; Livingston, D. M.; Eckner, R. Nature 1995, 374, 81
  There is no corresponding record for this reference.
97. 97
  Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
  There is no corresponding record for this reference.
98. 98
  Lundblad, J. R.; Kwok, R. P.; Laurance, M. E.; Harter, M. L.; Goodman, R. H. Nature 1995, 374, 85
  There is no corresponding record for this reference.
99. 99
  Radhakrishnan, I.; Pérez-Alvarado, G. C.; Parker, D.; Dyson, H. J.; Montminy, M. R.; Wright, P. E. Cell 1997, 91, 741
  There is no corresponding record for this reference.
100. 100
  Kalkhoven, E. Biochem. Pharmacol. 2004, 68, 1145
  There is no corresponding record for this reference.
101. 101
  Nam, Y.; Sliz, P.; Song, L.; Aster, J. C.; Blacklow, S. C. Cell 2006, 124, 973
  There is no corresponding record for this reference.
102. 102
  Mayr, B.; Montminy, M. Nat. Rev. Mol. Cell Biol. 2001, 2, 599
  102
  Transcriptional regulation by the phosphorylation-dependent factor CREB
  Mayr, Bernhard; Montminy, Marc
  Nature Reviews Molecular Cell Biology (2001), 2 (8), 599-609CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)
  A review. The transcription factor CREB - for 'cAMP response element-binding protein' - functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signaling pathways.
103. 103
  Bourdeau, V.; Deschênes, J.; Métivier, R.; Nagai, Y.; Nguyen, D.; Bretschneider, N.; Gannon, F.; White, J. H.; Mader, S. Mol. Endocrinol. 2004, 18, 1411
  103
  Genome-wide identification of high-affinity estrogen response elements in human and mouse
  Bourdeau, Veronique; Deschenes, Julie; Metivier, Raphael; Nagai, Yoshihiko; Nguyen, Denis; Bretschneider, Nancy; Gannon, Frank; White, John H.; Mader, Sylvie
  Molecular Endocrinology (2004), 18 (6), 1411-1427CODEN: MOENEN; ISSN:0888-8809. (Endocrine Society)
  Although estrogen receptors (ERs) recognize 15-bp palindromic estrogen response elements (EREs) with maximal affinity in vitro, few near-consensus sequences have been characterized in estrogen target genes. Here we report the design of a genome-wide screen for high-affinity EREs and the identification of approx. 70,000 motifs in the human and mouse genomes. EREs are enriched in regions proximal to the transcriptional start sites, and approx. 1% of elements appear conserved in the flanking regions (-10 kb to +5 kb) of orthologous human and mouse genes. Conserved and nonconserved elements were also found, often in multiple occurrences, in more than 230 estrogen-stimulated human genes previously identified from expression studies. In genes contg. known EREs, we also identified addnl. distal elements, sometimes with higher in vitro binding affinity and/or better conservation between the species considered. Chromatin immunopptn. expts. in breast cancer cell lines indicate that most novel elements present in responsive genes bind ERα in vivo, including some EREs located up to approx. 10 kb from transcriptional start sites. Our results demonstrate that near-consensus EREs occur frequently in both genomes and that whereas chromatin structure likely modulates access to binding sites, far upstream elements can be evolutionarily conserved and bind ERs in vivo.
104. 104
  Saito, H.; Posas, F. Genetics 2012, 192, 289
  There is no corresponding record for this reference.
105. 105
  Sheikh-Hamad, D.; Di Mari, J.; Suki, W. N.; Safirstein, R.; Watts, B. A., III; Rouse, D. J. Biol. Chem. 1998, 273, 1832
  There is no corresponding record for this reference.
106. 106
  Chen, Y. J.; Wang, Y. N.; Chang, W. C. J. Biol. Chem. 2007, 282, 27215
  There is no corresponding record for this reference.
107. 107
  Jang, E. R.; Choi, J. D.; Lee, J. S. FEBS Lett. 2011, 585, 47
  There is no corresponding record for this reference.
108. 108
  Sakaguchi, K.; Herrera, J. E.; Saito, S.; Miki, T.; Bustin, M.; Vassilev, A.; Anderson, C. W.; Appella, E. Genes Dev. 1998, 12, 2831
  There is no corresponding record for this reference.
109. 109
  Iyer, N. G.; Chin, S. F.; Ozdag, H.; Daigo, Y.; Hu, D. E.; Cariati, M.; Brindle, K.; Aparicio, S.; Caldas, C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 7386
  There is no corresponding record for this reference.
110. 110
  Yuan, L. W.; Gambee, J. E. J. Biol. Chem. 2000, 275, 40946
  There is no corresponding record for this reference.
111. 111
  Yang, X. J.; Seto, E. Mol. Cell 2008, 31, 449
  There is no corresponding record for this reference.
112. 112
  Legube, G.; Trouche, D. EMBO Rep. 2003, 4, 944
  There is no corresponding record for this reference.
113. 113
  Schwartz, C.; Beck, K.; Mink, S.; Schmolke, M.; Budde, B.; Wenning, D.; Klempnauer, K. H. EMBO J. 2003, 22, 882
  There is no corresponding record for this reference.
114. 114
  Poizat, C.; Puri, P. L.; Bai, Y.; Kedes, L. Mol. Cell. Biol. 2005, 25, 2673
  114
  Phosphorylation-dependent degradation of p300 by doxorubicin-activated p38 mitogen-activated protein kinase in cardiac cells
  Poizat, Coralie; Puri, Pier Lorenzo; Bai, Yan; Kedes, Larry
  Molecular and Cellular Biology (2005), 25 (7), 2673-2687CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  P300 and CBP are general transcriptional coactivators implicated in different cellular processes, including regulation of the cell cycle, differentiation, tumorigenesis, and apoptosis. Posttranslational modifications such as phosphorylation are predicted to select a specific function of p300/CBP in these processes; however, the identification of the kinases that regulate p300/CBP activity in response to individual stimuli and the physiol. significance of p300 phosphorylation have not been elucidated. Here we demonstrate that the cardiotoxic anticancer agent doxorubicin (adriamycin) induces the phosphorylation of p300 in primary neonatal cardiomyocytes. Hyperphosphorylation precedes the degrdn. of p300 and parallels apoptosis in response to doxorubicin. Doxorubicin-activated p38 kinases α and β assoc. with p300 and are implicated in the phosphorylation-mediated degrdn. of p300, as pharmacol. blockade of p38 prevents p300 degrdn. P38 phosphorylates p300 in vitro at both the N and C termini of the protein, and enforced activation of p38 by the constitutively active form of its upstream kinase (MKK6EE) triggers p300 degrdn. These data support the conclusion that p38 mitogen-activated protein kinase regulates p300 protein stability and function in cardiomyocytes undergoing apoptosis in response to doxorubicin.
115. 115
  Xu, W.; Chen, H.; Du, K.; Asahara, H.; Tini, M.; Emerson, B. M.; Montminy, M.; Evans, R. M. Science 2001, 294, 2507
  There is no corresponding record for this reference.
116. 116
  Ceschin, D. G.; Walia, M.; Wenk, S. S.; Duboé, C.; Gaudon, C.; Xiao, Y.; Fauquier, L.; Sankar, M.; Vandel, L.; Gronemeyer, H. Genes Dev. 2011, 25, 1132
  There is no corresponding record for this reference.
117. 117
  Ryan, C. M.; Kindle, K. B.; Collins, H. M.; Heery, D. M. Biochem. Biophys. Res. Commun. 2010, 391, 1136
  There is no corresponding record for this reference.
118. 118
  Kuo, H. Y.; Chang, C. C.; Jeng, J. C.; Hu, H. M.; Lin, D. Y.; Maul, G. G.; Kwok, R. P.; Shih, H. M. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 16973
  There is no corresponding record for this reference.
119. 119
  Karanam, B.; Jiang, L.; Wang, L.; Kelleher, N. L.; Cole, P. A. J. Biol. Chem. 2006, 281, 40292
  There is no corresponding record for this reference.
120. 120
  Karukurichi, K. R.; Wang, L.; Uzasci, L.; Manlandro, C. M.; Wang, Q.; Cole, P. A. J. Am. Chem. Soc. 2010, 132, 1222
  There is no corresponding record for this reference.
121. 121
  Thompson, P. R.; Wang, D.; Wang, L.; Fulco, M.; Pediconi, N.; Zhang, D.; An, W.; Ge, Q.; Roeder, R. G.; Wong, J.; Levrero, M.; Sartorelli, V.; Cotter, R. J.; Cole, P. A. Nat. Struct. Mol. Biol. 2004, 11, 308
  121
  Regulation of the p300 HAT domain via a novel activation loop
  Thompson, Paul R.; Wang, Dongxia; Wang, Ling; Fulco, Marcella; Pediconi, Natalia; Zhang, Dianzheng; An, Woojin; Ge, Qingyuan; Roeder, Robert G.; Wong, Jiemin; Levrero, Massimo; Sartorelli, Vittorio; Cotter, Robert J.; Cole, Philip A.
  Nature Structural & Molecular Biology (2004), 11 (4), 308-315CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is crit. for regulating gene expression in mammalian cells. However, the mol. events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to det. its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.
122. 122
  Karanam, B.; Wang, L.; Wang, D.; Liu, X.; Marmorstein, R.; Cotter, R.; Cole, P. A. Biochemistry 2007, 46, 8207
  There is no corresponding record for this reference.
123. 123
  Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
  123
  Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
  Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
  Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
124. 124
  Personal communication with Paul Brindle, see: http://www.stjude.org/stjude/v/index.jsp?vgnextoid=c30215f204294210VgnVCM1000001e0215acRCRD.
  There is no corresponding record for this reference.
125. 125
  Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
  There is no corresponding record for this reference.
126. 126
  Cohen, I.; Poręba, E.; Kamieniarz, K.; Schneider, R. Genes Cancer 2011, 2, 631
  126
  Histone modifiers in cancer: friends or foes?
  Cohen, Idan; Poreba, Elzbieta; Kamieniarz, Kinga; Schneider, Robert
  Genes & Cancer (2011), 2 (6), 631-647CODEN: GCEAAY; ISSN:1947-6019. (Sage Publications)
  A review. Covalent modifications of histories can regulate all DNA-dependent processes. In the last few years, it has become more and more evident that histone modifications are key players in the regulation of chromatin states and dynamics as well as in gene expression. Therefore, histone modifications and the enzymic machineries that set them are crucial regulators that can control cellular proliferation, differentiation, plasticity, and malignancy processes. This review discusses the biol. and biochem. of covalent histone posttranslational modifications (PTMs) and evaluates the dual role of their modifiers in cancer: as oncogenes that can initiate and amplify tumorigenesis or as tumor suppressors.
127. 127
  Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
  127
  p300/CBP proteins: HATs for transcriptional bridges and scaffolds
  Chan, Ho Man; La Thangue, Nicholas B.
  Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
  A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
128. 128
  Pan, C. Q.; Sudol, M.; Sheetz, M.; Low, B. C. Cell. Signalling 2012, 24, 2143
  128
  Modularity and functional plasticity of scaffold proteins as p(l)acemakers in cell signaling
  Pan, Catherine Qiurong; Sudol, Marius; Sheetz, Michael; Low, Boon Chuan
  Cellular Signalling (2012), 24 (11), 2143-2165CODEN: CESIEY; ISSN:0898-6568. (Elsevier Inc.)
  A review. Cells coordinate and integrate various functional modules that control their dynamics, intracellular trafficking, metab. and gene expression. Such capacity is mediated by specific scaffold proteins that tether multiple components of signaling pathways at plasma membrane, Golgi app., mitochondria, endoplasmic reticulum, nucleus and in more specialized subcellular structures such as focal adhesions, cell-cell junctions, endosomes, vesicles and synapses. Scaffold proteins act as "pacemakers" as well as "placemakers" that regulate the temporal, spatial and kinetic aspects of protein complex assembly by modulating the local concns., proximity, subcellular dispositions and biochem. properties of the target proteins through the intricate use of their modular protein domains. These regulatory mechanisms allow them to gate the specificity, integration and crosstalk of different signaling modules. In addn. to acting as phys. platforms for protein assembly, many professional scaffold proteins can also directly modify the properties of their targets while they themselves can be regulated by post-translational modifications and/or mech. forces. Furthermore, multiple scaffold proteins can form alliances of higher-order regulatory networks. Here, we highlight the emerging themes of scaffold proteins by analyzing their common and distinctive mechanisms of action and regulation, which underlie their functional plasticity in cell signaling. Understanding these mechanisms in the context of space, time and force should have ramifications for human physiol. and for developing new therapeutic approaches to control pathol. states and diseases.
129. 129
  Tanaka, Y.; Naruse, I.; Maekawa, T.; Masuya, H.; Shiroishi, T.; Ishii, S. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10215
  There is no corresponding record for this reference.
130. 130
  Kamei, Y.; Xu, L.; Heinzel, T.; Torchia, J.; Kurokawa, R.; Gloss, B.; Lin, S. C.; Heyman, R. A.; Rose, D. W.; Glass, C. K.; Rosenfeld, M. G. Cell 1996, 85, 403
  There is no corresponding record for this reference.
131. 131
  Hottiger, M. O.; Felzien, L. K.; Nabel, G. J. EMBO J. 1998, 17, 3124
  There is no corresponding record for this reference.
132. 132
  Yin, X.; Warner, D. R.; Roberts, E. A.; Pisano, M. M.; Greene, R. M. Biochem. Biophys. Res. Commun. 2005, 329, 1010
  There is no corresponding record for this reference.
133. 133
  Avantaggiati, M. L.; Ogryzko, V.; Gardner, K.; Giordano, A.; Levine, A. S.; Kelly, K. Cell 1997, 89, 1175
  There is no corresponding record for this reference.
134. 134
  Kamei, Y.; Xu, L.; Heinzel, T.; Torchia, J.; Kurokawa, R.; Gloss, B.; Lin, S. C.; Heyman, R. A.; Rose, D. W.; Glass, C. K.; Rosenfeld, M. G. Cell 1996, 85, 403
  There is no corresponding record for this reference.
135. 135
  Goodman, R. H.; Smolik, S. Genes Dev. 2000, 14, 1553
  135
  CBP/p300 in cell growth, transformation, and development
  Goodman, Richard H.; Smolik, Sarah
  Genes & Development (2000), 14 (13), 1553-1577CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)
  A review with several refs. This review discusses the involvement of CBP/p300 in cell growth and transformation, chromosomal translocations, involvement of cellular oncogenes, assocn. with viral oncoproteins, involvement with DNA and RNA tumor viruses, the regulation of CBP/p300 by phosphorylation, and usage in development of model systems.
136. 136
  Lee, C. W.; Sørensen, T. S.; Shikama, N.; La Thangue, N. B. Oncogene 1998, 16, 2695
  There is no corresponding record for this reference.
137. 137
  Nakajima, T.; Fukamizu, A.; Takahashi, J.; Gage, F. H.; Fisher, T.; Blenis, J.; Montminy, M. R. Cell 1996, 86, 465
  There is no corresponding record for this reference.
138. 138
  Thompson, P. R.; Wang, D.; Wang, L.; Fulco, M.; Pediconi, N.; Zhang, D.; An, W.; Ge, Q.; Roeder, R. G.; Wong, J.; Levrero, M.; Sartorelli, V.; Cotter, R. J.; Cole, P. A. Nat. Struct. Mol. Biol. 2004, 11, 308
  138
  Regulation of the p300 HAT domain via a novel activation loop
  Thompson, Paul R.; Wang, Dongxia; Wang, Ling; Fulco, Marcella; Pediconi, Natalia; Zhang, Dianzheng; An, Woojin; Ge, Qingyuan; Roeder, Robert G.; Wong, Jiemin; Levrero, Massimo; Sartorelli, Vittorio; Cotter, Robert J.; Cole, Philip A.
  Nature Structural & Molecular Biology (2004), 11 (4), 308-315CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is crit. for regulating gene expression in mammalian cells. However, the mol. events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to det. its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.
139. 139
  Muir, T. W.; Sondhi, D.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 6705
  139
  Expressed protein ligation: A general method for protein engineering
  Muir, Tom W.; Sondhi, Dolan; Cole, Philip A.
  Proceedings of the National Academy of Sciences of the United States of America (1998), 95 (12), 6705-6710CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  A protein semisynthesis method-expressed protein ligation-is described that involves the chemoselective addn. of a peptide to a recombinant protein. This method was used to ligate a phosphotyrosine peptide to the C terminus of the protein tyrosine kinase C-terminal Src kinase (Csk). By intercepting a thioester generated in the recombinant protein with an N-terminal cysteine contg. synthetic peptide, near quant. chem. ligation of the peptide to the protein was achieved. The semisynthetic tail-phosphorylated Csk showed evidence of an intramol. phosphotyrosine-Src homol. 2 interaction and an unexpected increase in catalytic phosphoryl transfer efficiency toward a physiol. relevant substrate compared with the non-tail-phosphorylated control. This work illustrates that expressed protein ligation is a simple and powerful new method in protein engineering to introduce sequences of unnatural amino acids, posttranslational modifications, and biophys. probes into proteins of any size.
140. 140
  Dancy, B. M.; Crump, N. T.; Peterson, D. J.; Mukherjee, C.; Bowers, E. M.; Ahn, Y. H.; Yoshida, M.; Zhang, J.; Mahadevan, L. C.; Meyers, D. J.; Boeke, J. D.; Cole, P. A. ChemBioChem 2012, 13, 2113
  There is no corresponding record for this reference.
141. 141
  Liu, X.; Wang, L.; Zhao, K.; Thompson, P. R.; Hwang, Y.; Marmorstein, R.; Cole, P. A. Nature 2008, 451, 846
  There is no corresponding record for this reference.
142. 142
  Hwang, Y.; Thompson, P. R.; Wang, L.; Jiang, L.; Kelleher, N. L.; Cole, P. A. Angew. Chem., Int. Ed. 2007, 46, 7621
  142
  A selective chemical probe for coenzyme A-requiring enzymes
  Hwang, Yousang; Thompson, Paul R.; Wang, Ling; Jiang, Lihua; Kelleher, Neil L.; Cole, Philip A.
  Angewandte Chemie, International Edition (2007), 46 (40), 7621-7624CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A CoA-based affinity probe with a sulfoxycarbamate functionality can selectively identify several acetyltransferases relative to other enzymes and proteins. It leaves behind a desthiobiotin tag that can be used for western blotting and mass spectrometric characterization.
143. 143
  Liu, X.; Wang, L.; Zhao, K.; Thompson, P. R.; Hwang, Y.; Marmorstein, R.; Cole, P. A. Nature 2008, 451, 846
  There is no corresponding record for this reference.
144. 144
  Tang, Y.; Holbert, M. A.; Wurtele, H.; Meeth, K.; Rocha, W.; Gharib, M.; Jiang, E.; Thibault, P.; Verreault, A.; Cole, P. A.; Marmorstein, R. Nat. Struct. Mol. Biol. 2008, 15, 998
  144
  Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. [Erratum to document cited in CA149:217962]
  Tang, Yong; Holbert, Marc A.; Wurtele, Hugo; Meeth, Katrina; Rocha, Walter; Gharib, Marlene; Jiang, Eva; Thibault, Pierre; Verreault, Alain; Cole, Philip A.; Marmorstein, Ronen
  Nature Structural & Molecular Biology (2008), 15 (9), 998CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  On page 738, the author name "Verreault" was mistakenly spelled as "Verrault". The error has been cor. in the HTML and PDF versions of the article.
145. 145
  Wang, L.; Tang, Y.; Cole, P. A.; Marmorstein, R. Curr. Opin. Struct. Biol. 2008, 18, 741
  145
  Structure and chemistry of the p300/CBP and Rtt109 histone acetyltransferases: implications for histone acetyltransferase evolution and function
  Wang, Ling; Tang, Yong; Cole, Philip A.; Marmorstein, Ronen
  Current Opinion in Structural Biology (2008), 18 (6), 741-747CODEN: COSBEF; ISSN:0959-440X. (Elsevier B.V.)
  A review. The recent crystal structure and assocd. biochem. studies of the metazoan-specific p300/CBP and fungal-specific Rtt109 histone acetyltransferases (HATs) have provided new insights into the ancestral relation between HATs and their functions. These studies point to a common HAT ancestor that has evolved around a common structural framework to form HATs with divergent catalytic and substrate-binding properties. These studies also point to the importance of regulatory loops within HATs and autoacetylation in HAT function. Implications for future studies are discussed.
146. 146
  Poux, A. N.; Cebrat, M.; Kim, C. M.; Cole, P. A.; Marmorstein, R. Proc. Natl. Acad. Sci. U.S.A. 2009, 99, 14065
  There is no corresponding record for this reference.
147. 147
  Yuan, H.; Rossetto, D.; Mellert, H.; Dang, W.; Srinivasan, M.; Johnson, J.; Hodawadekar, S.; Ding, E. C.; Speicher, K.; Abshiru, N.; Perry, R.; Wu, J.; Yang, C.; Zheng, Y. G.; Speicher, D. W.; Thibault, P.; Verreault, A.; Johnson, F. B.; Berger, S. L.; Sternglanz, R.; McMahon, S. B.; Côté, J.; Marmorstein, R. EMBO J. 2012, 31, 58
  There is no corresponding record for this reference.
148. 148
  Karukurichi, K. R.; Cole, P. A. Bioorg. Chem. 2011, 39, 42
  148
  Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs
  Karukurichi, Kannan R.; Cole, Philip A.
  Bioorganic Chemistry (2011), 39 (1), 42-47CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
  Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biol. pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a neg. charged surface on the enzyme to interact with the histone tail.
149. 149
  Cleland, W. W. Biochim. Biophys. Acta 1963, 67, 104
  There is no corresponding record for this reference.
150. 150
  Cleland, W. W. Biochim. Biophys. Acta 1963, 67, 104
  There is no corresponding record for this reference.
151. 151
  Segel, I. Enzyme Kinetics; Wiley Interscience: New York, 1975.
  There is no corresponding record for this reference.
152. 152
  Zheng, Y.; Thompson, P. R.; Cebrat, M.; Wang, L.; Devlin, M. K.; Alani, R. M.; Cole, P. A. Methods Enzymol. 2004, 376, 188
  There is no corresponding record for this reference.
153. 153
  Bowers, E. M.; Yan, G.; Mukherjee, C.; Orry, A.; Wang, L.; Holbert, M. A.; Crump, N. T.; Hazzalin, C. A.; Liszczak, G.; Yuan, H.; Larocca, C.; Saldanha, S. A.; Abagyan, R.; Sun, Y.; Meyers, D. J.; Marmorstein, R.; Mahadevan, L. C.; Alani, R. M.; Cole, P. A. Chem. Biol. 2010, 17, 471
  153
  Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor
  Bowers, Erin M.; Yan, Gai; Mukherjee, Chandrani; Orry, Andrew; Wang, Ling; Holbert, Marc A.; Crump, Nicholas T.; Hazzalin, Catherine A.; Liszczak, Glen; Yuan, Hua; Larocca, Cecilia; Saldanha, S. Adrian; Abagyan, Ruben; Sun, Yan; Meyers, David J.; Marmorstein, Ronen; Mahadevan, Louis C.; Alani, Rhoda M.; Cole, Philip A.
  Chemistry & Biology (Cambridge, MA, United States) (2010), 17 (5), 471-482CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  Summary: The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-site-directed small mol. inhibitor is not yet known. Here the authors use a structure-based, in silico screening approach to identify a com. available pyrazolone-contg. small mol. p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective vs. other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacol. probe and suggest that p300/CBP HAT is a worthy anticancer target.
154. 154
  Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
  There is no corresponding record for this reference.
155. 155
  Sagar, V.; Zheng, W.; Thompson, P. R.; Cole, P. A. Bioorg. Med. Chem. 2004, 12, 3383
  There is no corresponding record for this reference.
156. 156
  Karukurichi, K. R.; Cole, P. A. Bioorg. Chem. 2011, 39, 42
  156
  Probing the reaction coordinate of the p300/CBP histone acetyltransferase with bisubstrate analogs
  Karukurichi, Kannan R.; Cole, Philip A.
  Bioorganic Chemistry (2011), 39 (1), 42-47CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
  Histone and protein acetylation catalyzed by p300/CBP transcriptional coactivator regulates a variety of key biol. pathways. This study investigates the proposed Theorell-Chance or "hit-and-run" catalytic mechanism of p300/CBP histone acetyltransferase (HAT) using bisubstrate analogs. A range of histone peptide tail peptide-CoA conjugates with different length linkers were synthesized and evaluated as inhibitors of p300 HAT. We show that longer linkers between the histone tail peptide and the CoA substrate moieties appear to allow for dual engagement of the two binding surfaces. Results with D1625R/D1628R double mutant p300 HAT further confirm the requirement for a neg. charged surface on the enzyme to interact with the histone tail.
157. 157
  Cebrat, M.; Kim, C. M.; Thompson, P. R.; Daugherty, M.; Cole, P. A. Bioorg. Med. Chem. 2003, 11, 3307
  There is no corresponding record for this reference.
158. 158
  Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
  There is no corresponding record for this reference.
159. 159
  Chase, J. F.; Tubbs, P. K. Biochem. J. 1969, 111, 225
  There is no corresponding record for this reference.
160. 160
  Williams, J. W.; Northrop, D. B. J. Antibiot. 1979, 32, 1147
  There is no corresponding record for this reference.
161. 161
  Cullis, P. M.; Wolfenden, R.; Cousens, L. S.; Alberts, B. M. J. Biol. Chem. 1982, 257, 12165
  There is no corresponding record for this reference.
162. 162
  Erwin, B. G.; Persson, L.; Pegg, A. E. Biochemistry 1984, 23, 4250
  There is no corresponding record for this reference.
163. 163
  Khalil, E. M.; Cole, P. A. J. Am. Chem. Soc. 1998, 120, 6195
  There is no corresponding record for this reference.
164. 164
  Khalil, E. M.; De Angelis, J.; Ishii, M.; Cole, P. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 12418
  There is no corresponding record for this reference.
165. 165
  Kim, C. M.; Cole, P. A. J. Med. Chem. 2001, 44, 2479
  There is no corresponding record for this reference.
166. 166
  Yu, M.; Magalhães, M. L.; Cook, P. F.; Blanchard, J. S. Biochemistry 2006, 45, 14788
  There is no corresponding record for this reference.
167. 167
  Gao, F.; Yan, X.; Baettig, O. M.; Berghuis, A. M.; Auclair, K. Angew. Chem., Int. Ed. 2005, 44, 6859
  There is no corresponding record for this reference.
168. 168
  Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A. M.; Wright, G. D.; Auclair, K. J. Med. Chem. 2006, 49, 5273
  There is no corresponding record for this reference.
169. 169
  Gao, F.; Yan, X.; Zahr, O.; Larsen, A.; Vong, K.; Auclair, K. Bioorg. Med. Chem. Lett. 2008, 18, 5518
  There is no corresponding record for this reference.
170. 170
  Magalhães, M. L.; Vetting, M. W.; Gao, F.; Freiburger, L.; Auclair, K.; Blanchard, J. S. Biochemistry 2008, 47, 579
  There is no corresponding record for this reference.
171. 171
  Barnett, B. P.; Hwang, Y.; Taylor, M. S.; Kirchner, H.; Pfluger, P. T.; Bernard, V.; Lin, Y. Y.; Bowers, E. M.; Mukherjee, C.; Song, W. J.; Longo, P. A.; Leahy, D. J.; Hussain, M. A.; Tschöp, M. H.; Boeke, J. D.; Cole, P. A. Science 2010, 330, 1689
  There is no corresponding record for this reference.
172. 172
  Taylor, M. S.; Hwang, Y.; Hsiao, P. Y.; Boeke, J. D.; Cole, P. A. Methods Enzymol. 2012, 514, 205
  There is no corresponding record for this reference.
173. 173
  Parang, K.; Till, J. H.; Ablooglu, A. J.; Kohanski, R. A.; Hubbard, S. R.; Cole, P. A. Nat. Struct. Biol. 2001, 8, 37
  There is no corresponding record for this reference.
174. 174
  Shen, K.; Hines, A. C.; Schwarzer, D.; Pickin, K. A.; Cole, P. A. Biochim. Biophys. Acta 2005, 1754, 65
  There is no corresponding record for this reference.
175. 175
  Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
  There is no corresponding record for this reference.
176. 176
  Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
  There is no corresponding record for this reference.
177. 177
  Zheng, Y.; Thompson, P. R.; Cebrat, M.; Wang, L.; Devlin, M. K.; Alani, R. M.; Cole, P. A. Methods Enzymol. 2004, 376, 188
  There is no corresponding record for this reference.
178. 178
  De Angelis, J.; Gastel, J.; Klein, D. C.; Cole, P. A. J. Biol. Chem. 1998, 273, 3045
  There is no corresponding record for this reference.
179. 179
  Lau, O. D.; Courtney, A. D.; Vassilev, A.; Marzilli, L. A.; Cotter, R. J.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2000, 275, 21953
  There is no corresponding record for this reference.
180. 180
  Tanner, K. G.; Langer, M. R.; Denu, J. M. Biochemistry 2000, 39, 15652
  There is no corresponding record for this reference.
181. 181
  Tanner, K. G.; Langer, M. R.; Kim, Y.; Denu, J. M. J. Biol. Chem. 2000, 275, 22048
  There is no corresponding record for this reference.
182. 182
  Yan, Y.; Barlev, N. A.; Haley, R. H.; Berger, S. L.; Marmorstein, R. Mol. Cell 2000, 6, 1195
  There is no corresponding record for this reference.
183. 183
  Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
  There is no corresponding record for this reference.
184. 184
  Lau, O. D.; Kundu, T. K.; Soccio, R. E.; Ait-Si-Ali, S.; Khalil, E. M.; Vassilev, A.; Wolffe, A. P.; Nakatani, Y.; Roeder, R. G.; Cole, P. A. Mol. Cell 2000, 5, 589
  There is no corresponding record for this reference.
185. 185
  Lau, O. D.; Courtney, A. D.; Vassilev, A.; Marzilli, L. A.; Cotter, R. J.; Nakatani, Y.; Cole, P. A. J. Biol. Chem. 2000, 275, 21953
  There is no corresponding record for this reference.
186. 186
  Poux, A. N.; Cebrat, M.; Kim, C. M.; Cole, P. A.; Marmorstein, R. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14065
  There is no corresponding record for this reference.
187. 187
  Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
  There is no corresponding record for this reference.
188. 188
  Victor, M.; Bei, Y.; Gay, F.; Calvo, D.; Mello, C.; Shi, Y. EMBO Rep. 2002, 3, 50
  There is no corresponding record for this reference.
189. 189
  Huang, Z. Q.; Li, J.; Sachs, L. M.; Cole, P. A.; Wong, J. EMBO J. 2003, 22, 2146
  There is no corresponding record for this reference.
190. 190
  Costanzo, A.; Merlo, P.; Pediconi, N.; Fulco, M.; Sartorelli, V.; Cole, P. A.; Fontemaggi, G.; Fanciulli, M.; Schiltz, L.; Blandino, G.; Balsano, C.; Levrero, M. Mol. Cell 2002, 9, 175
  There is no corresponding record for this reference.
191. 191
  Kaehlcke, K.; Dorr, A.; Hetzer-Egger, C.; Kiermer, V.; Henklein, P.; Schnoelzer, M.; Loret, E.; Cole, P. A.; Verdin, E.; Ott, M. Mol. Cell 2003, 12, 167
  There is no corresponding record for this reference.
192. 192
  Polesskaya, A.; Naguibneva, I.; Fritsch, L.; Duquet, A.; Ait-Si-Ali, S.; Robin, P.; Vervisch, A.; Pritchard, L. L.; Cole, P.; Harel-Bellan, A. EMBO J. 2001, 20, 6816
  There is no corresponding record for this reference.
193. 193
  Bandyopadhyay, D.; Okan, N. A.; Bales, E.; Nascimento, L.; Cole, P. A.; Medrano, E. E. Cancer Res. 2002, 62, 6231
  There is no corresponding record for this reference.
194. 194
  Cebrat, M.; Kim, C. M.; Thompson, P. R.; Daugherty, M.; Cole, P. A. Bioorg. Med. Chem. 2003, 11, 3307
  There is no corresponding record for this reference.
195. 195
  Zheng, Y.; Balasubramanyam, K.; Cebrat, M.; Buck, D.; Guidez, F.; Zelent, A.; Alani, R. M.; Cole, P. A. J. Am. Chem. Soc. 2005, 127, 17182
  There is no corresponding record for this reference.
196. 196
  Guidez, F.; Howell, L.; Isalan, M.; Cebrat, M.; Alani, R. M.; Ivins, S.; Hormaeche, I.; McConnell, M. J.; Pierce, S.; Cole, P. A.; Licht, J.; Zelent, A. Mol. Cell. Biol. 2005, 25, 5552
  196
  Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein
  Guidez, Fabien; Howell, Louise; Isalan, Mark; Cebrat, Marek; Alani, Rhoda M.; Ivins, Sarah; Hormaeche, Itsaso; McConnell, Melanie J.; Pierce, Sarah; Cole, Philip A.; Licht, Jonathan; Zelent, Arthur
  Molecular and Cellular Biology (2005), 25 (13), 5552-5566CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-contg. corepressor complexes to specific DNA binding sites. PLZF assocs. with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C2-H2 zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be pos. regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.
197. 197
  Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
  There is no corresponding record for this reference.
198. 198
  Rosen, T.; Fordice, D. B. South Med. J. 1994, 87, 543
  198
  Cashew nut dermatitis
  Rosen T; Fordice D B
  Southern medical journal (1994), 87 (4), 543-6 ISSN:0038-4348.
  The urushiol dermatitis caused by plants of the Anacardiaceae family is the most common cause of acute allergic contact dermatitis. We have reported a case of cashew nut urushiol dermatitis due to ingestion of homemade cashew nut butter contaminated by cashew nut shell oil. With the precautions taken today to avoid contamination of food products with cashew urushiols, it is rare to find a case of cashew nut dermatitis in the United States. We have found no other report of contact dermatitis due to cashew nut butter. Moreover, though hinted at in the literature, there has been no previous detailed report of perianal contact dermatitis due to cashew ingestion. The fact that our patient was ill enough to require treatment with 3 weeks of systemic steroid therapy highlights the potential public health hazard of consumption of improperly prepared cashew products. However, the risk of cashew nut dermatitis today remains small, and this should not discourage cashew lovers from enjoying their treats. A final lesson to be learned from this case is that perianal eruptions may be due to materials deliberately applied to the anogenital region or to ingested antigens that remain sufficiently intact within the feces to affect perianal skin.
199. 199
  Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
  There is no corresponding record for this reference.
200. 200
  Ghizzoni, M.; Wu, J.; Gao, T.; Haisma, H. J.; Dekker, F. J.; George Zheng, Y. Eur. J. Med. Chem. 2012, 47, 337
  There is no corresponding record for this reference.
201. 201
  Wu, J.; Xie, N.; Wu, Z.; Zhang, Y.; Zheng, Y. G. Bioorg. Med. Chem. 2009, 17, 1381
  There is no corresponding record for this reference.
202. 202
  Chandregowda, V.; Kush, A.; Reddy, G. C. Eur. J. Med. Chem. 2009, 44, 2711
  There is no corresponding record for this reference.
203. 203
  Balasubramanyam, K.; Swaminathan, V.; Ranganathan, A.; Kundu, T. K. J. Biol. Chem. 2003, 278, 19134
  There is no corresponding record for this reference.
204. 204
  Devipriya, B.; Parameswari, A. R.; Rajalakshmi, G.; Palvannan, T.; Kumaradhas, P. Indian J. Biochem. Biophys. 2010, 47, 364
  204
  Exploring the binding affinities of p300 enzyme activators CTPB and CTB using docking method
  Devipriya, B.; Parameswari, A. Renuga; Rajalakshmi, G.; Palvannan, T.; Kumaradhas, P.
  Indian Journal of Biochemistry & Biophysics (2010), 47 (6), 364-369CODEN: IJBBBQ; ISSN:0301-1208. (National Institute of Science Communication and Information Resources)
  CREB binding protein (CBP) and E1A binding protein p300, also known as p300 are functionally related transcriptional co-activators (CoAs) and histone acetyltransferases (HATs). Some small mols., which target HATs can activate or inhibit the p300 enzyme potently. Here, the binding affinities are reported for two small mols. CTPB [N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide] and CTB [N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxybenzamide] with p300 using docking method to obtain the insight of their interaction with p300. These small mols. bind to the enzyme, subsequently causing a structural change in the enzyme, which is responsible for the HAT activation. CTB exhibits higher binding affinity than CTPB, and their lowest docked energies are -7.72, -1.18 kcal/mol, resp. In CTPB mol., phenolic hydroxyl of Tyr1397 interacts with the non-polar atoms C(5E) and C(5F), and forms polar-non polar interactions. Similar interactions have also been obsd. in CTB. The residues Tyr1446 and Cys1438 interact with the non-pentadecyl atoms. Further, the docking study predicts a N-H···O hydrogen bonding interaction between CTB and Leu1398, in which the H···O contact distance is 2.06 Å. The long pentadecyl chain of CTPB reduces the formation of hydrogen bond with the p300. The H-bond interaction could be the key factor for the better activation of CTB.
205. 205
  Mantelingu, K.; Kishore, A. H.; Balasubramanyam, K.; Kumar, G. V.; Altaf, M.; Swamy, S. N.; Selvi, R.; Das, C.; Narayana, C.; Rangappa, K. S.; Kundu, T. K. J. Phys. Chem. B 2007, 111, 4527
  There is no corresponding record for this reference.
206. 206
  Varier, R. A.; Swaminathan, V.; Balasubramanyam, K.; Kundu, T. K. Biochem. Pharmacol. 2004, 68, 1215
  There is no corresponding record for this reference.
207. 207
  Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163
  There is no corresponding record for this reference.
208. 208
  Goel, A.; Kunnumakkara, A. B.; Aggarwal, B. B. Biochem. Pharmacol. 2008, 75, 787
  There is no corresponding record for this reference.
209. 209
  Maheshwari, R. K.; Singh, A. K.; Gaddipati, J.; Srimal, R. C. Life Sci. 2006, 78, 2081
  There is no corresponding record for this reference.
210. 210
  Aggarwal, B. B.; Shishodia, S. Biochem. Pharmacol. 2006, 71, 1397
  210
  Molecular targets of dietary agents for prevention and therapy of cancer
  Aggarwal, Bharat B.; Shishodia, Shishir
  Biochemical Pharmacology (2006), 71 (10), 1397-1421CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)
  A review. While fruits and vegetables are recommended for prevention of cancer and other diseases, their active ingredients (at the mol. level) and their mechanisms of action less well understood. Extensive research during the last half century has identified various mol. targets that can potentially be used not only for the prevention of cancer but also for treatment. However, lack of success with targeted monotherapy resulting from bypass mechanisms has forced researchers to employ either combination therapy or agents that interfere with multiple cell-signaling pathways. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with several cell-signaling pathways. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts, and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apples, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), β-carotene (carrots), and dietary fiber. For instance, the cell-signaling pathways inhibited by curcumin alone include NF-κB, AP-1, STAT3, Akt, Bcl-2, Bcl-XL, caspases, PARP, IKK, EGFR, HER2, JNK, MAPK, COX2, and 5-LOX. The active principle identified in fruit and vegetables and the mol. targets modulated may be the basis for how these dietary agents not only prevent but also treat cancer and other diseases. This work reaffirms what Hippocrates said 25 centuries ago, let food be thy medicine and medicine be thy food.
211. 211
  Zhou, H.; Beevers, C. S.; Huang, S. Curr. Drug Targets 2011, 12, 332
  211
  The targets of curcumin
  Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile
  Current Drug Targets (2011), 12 (3), 332-347CODEN: CDTUAU; ISSN:1389-4501. (Bentham Science Publishers Ltd.)
  A review. Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal prepn. or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various mol. targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacol. aspects of curcumin as well as the underlying action mechanisms. The recently identified mol. targets and signaling pathways modulated by curcumin are also discussed here.
212. 212
  Han, X.; Xu, B.; Beevers, C. S.; Odaka, Y.; Chen, L.; Liu, L.; Luo, Y.; Zhou, H.; Chen, W.; Shen, T.; Huang, S. Carcinogenesis 2012, 33, 868
  There is no corresponding record for this reference.
213. 213
  Gupta, S. C.; Prasad, S.; Kim, J. H.; Patchva, S.; Webb, L. J.; Priyadarsini, I. K.; Aggarwal, B. B. Nat. Prod. Rep. 2011, 28, 1937
  213
  Multitargeting by curcumin as revealed by molecular interaction studies
  Gupta, Subash C.; Prasad, Sahdeo; Kim, Ji Hye; Patchva, Sridevi; Webb, Lauren J.; Priyadarsini, Indira K.; Aggarwal, Bharat B.
  Natural Product Reports (2011), 28 (12), 1937-1955CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
  A review. Curcumin (diferuloylmethane), the active ingredient in turmeric (Curcuma longa), is a highly pleiotropic mol. with anti-inflammatory, anti-oxidant, chemopreventive, chemosensitization, and radiosensitization activities. The pleiotropic activities attributed to curcumin come from its complex mol. structure and chem., as well as its ability to influence multiple signaling mols. Curcumin has been shown to bind by multiple forces directly to numerous signaling mols., such as inflammatory mols., cell survival proteins, protein kinases, protein reductases, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, FtsZ protofilaments, carrier proteins, and metal ions. Curcumin can also bind directly to DNA and RNA. Owing to its β-diketone moiety, curcumin undergoes keto-enol tautomerism that has been reported as a favorable state for direct binding. The functional groups on curcumin found suitable for interaction with other macromols. include the α, β-unsatd. β-diketone moiety, carbonyl and enolic groups of the β-diketone moiety, methoxy and phenolic hydroxyl groups, and the Ph rings. Various biophys. tools have been used to monitor direct interaction of curcumin with other proteins, including absorption, fluorescence, Fourier transform IR (FTIR) and CD (CD) spectroscopy, surface plasmon resonance, competitive ligand binding, Forster type fluorescence resonance energy transfer (FRET), radiolabeling, site-directed mutagenesis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), immunopptn., phage display biopanning, electron microscopy, 1-anilino-8-naphthalene-sulfonate (ANS) displacement, and co-localization. Mol. docking, the most commonly employed computational tool for calcg. binding affinities and predicting binding sites, has also been used to further characterize curcumin's binding sites. Furthermore, the ability of curcumin to bind directly to carrier proteins improves its soly. and bioavailability. In this review, we focus on how curcumin directly targets signaling mols., as well as the different forces that bind the curcumin-protein complex and how this interaction affects the biol. properties of proteins. We will also discuss various analogs of curcumin designed to bind selective targets with increased affinity.
214. 214
  Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
  There is no corresponding record for this reference.
215. 215
  Marcu, M. G.; Jung, Y. J.; Lee, S.; Chung, E. J.; Lee, M. J.; Trepel, J.; Neckers, L. Med. Chem. 2006, 2, 169
  215
  Curcumin is an inhibitor of p300 histone acetyltransferase
  Marcu, Monica G.; Jung, Yun-Jin; Lee, Sunmin; Chung, Eun-Joo; Lee, Min-Jung; Trepel, Jane; Neckers, Len
  Medicinal Chemistry (2006), 2 (2), 169-174CODEN: MCEHAJ; ISSN:1573-4064. (Bentham Science Publishers Ltd.)
  Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant mol. targets for drug development. In this study, we demonstrate that the small mol. natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that α, β unsatd. carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degrdn. of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addn. to inducing p300 degrdn. curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent assocn. with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compd. for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.
216. 216
  Balasubramanyam, K.; Varier, R. A.; Altaf, M.; Swaminathan, V.; Siddappa, N. B.; Ranga, U.; Kundu, T. K. J. Biol. Chem. 2004, 279, 51163
  There is no corresponding record for this reference.
217. 217
  Anand, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharmaceutics 2007, 4, 807
  217
  Bioavailability of Curcumin: Problems and Promises
  Anand, Preetha; Kunnumakkara, Ajaikumar B.; Newman, Robert A.; Aggarwal, Bharat B.
  Molecular Pharmaceutics (2007), 4 (6), 807-818CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
  A review. Curcumin, a polyphenolic compd. derived from dietary spice turmeric, possesses diverse pharmacol. effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clin. trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metab., and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogs of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurol. diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
218. 218
  Sharma, R. A.; Euden, S. A.; Platton, S. L.; Cooke, D. N.; Shafayat, A.; Hewitt, H. R.; Marczylo, T. H.; Morgan, B.; Hemingway, D.; Plummer, S. M.; Pirmohamed, M.; Gescher, A. J.; Steward, W. P. Clin. Cancer Res. 2004, 10, 6847
  218
  Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance
  Sharma, Ricky A.; Euden, Stephanie A.; Platton, Sharon L.; Cooke, Darren N.; Shafayat, Aisha; Hewitt, Heather R.; Marczylo, Timothy H.; Morgan, Bruno; Hemingway, David; Plummer, Simon M.; Pirmohamed, Munir; Gescher, Andreas J.; Steward, William P.
  Clinical Cancer Research (2004), 10 (20), 6847-6854CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) prodn., or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacol. of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to std. chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 mo. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liq. chromatog. and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclin. models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 prodn. induced ex vivo. Dose-limiting toxicity was not obsd. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 prodn. in blood samples taken 1 h after dose on days 1 and 29, resp., of treatment compared with levels obsd. immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 prodn. in blood and target tissue may indicate biol. activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
219. 219
  Mishra, S.; Kapoor, N.; Mubarak Ali, A.; Pardhasaradhi, B. V.; Kumari, A. L.; Khar, A.; Misra, K. Free Radical Biol. Med. 2005, 38, 1353
  219
  Differential apoptotic and redox regulatory activities of curcumin and its derivatives
  Mishra, Satyendra; Kapoor, Neha; Mubarak Ali, A.; Pardhasaradhi, B. V. V.; Kumari, A. Leela; Khar, Ashok; Misra, Krishna
  Free Radical Biology & Medicine (2005), 38 (10), 1353-1360CODEN: FRBMEH; ISSN:0891-5849. (Elsevier)
  We have synthesized different bioconjugates of curcumin, which were tested for their pro- and antioxidant properties. In the present study five representative derivs. of curcumin, i.e., 4,4'-di-(O-acetyl) curcumin, 4,4'-di-(O-glycinoyl) curcumin, 4,4'-di-(O-glycinoyl-di-N-piperoyl) curcumin, 4,4'-di-(O-piperoyl) curcumin, and 4,4'-(O,O-cystinoyl)-3,3'-dimethoxydiphenyl-1,6-heptadiene-3,5-dione, were used for testing their apoptotic potential on tumor cells. Dipiperoyl and diglycinoyl derivs. showed higher apoptotic activity at lower concns., whereas diacetyl curcumin had slightly lower apoptotic activity on tumor cells. On the other hand, diglycinoyl-dipiperoyl and cystinoyl heptadiene derivs. had lost their apoptotic potential significantly. The apoptotic activity of these derivs. correlated very well with the generation of ROS by the tumor cells, whereas GSH levels remained unaltered. Our studies also indicate down-regulation of Bcl-2 and participation of caspase-3 in the apoptotic death of tumor cells.
220. 220
  Weber, W. M.; Hunsaker, L. A.; Abcouwer, S. F.; Deck, L. M.; Vander Jagt, D. L. Bioorg. Med. Chem. 2005, 13, 3811
  There is no corresponding record for this reference.
221. 221
  Varier, R. A.; Swaminathan, V.; Balasubramanyam, K.; Kundu, T. K. Biochem. Pharmacol. 2004, 68, 1215
  There is no corresponding record for this reference.
222. 222
  Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.; Sadhale, P. P.; Kundu, T. K. J. Biol. Chem. 2004, 279, 33716
  There is no corresponding record for this reference.
223. 223
  Balasubramanyam, K.; Altaf, M.; Varier, R. A.; Swaminathan, V.; Ravindran, A.; Sadhale, P. P.; Kundu, T. K. J. Biol. Chem. 2004, 279, 33716
  There is no corresponding record for this reference.
224. 224
  Mantelingu, K.; Reddy, B. A.; Swaminathan, V.; Kishore, A. H.; Siddappa, N. B.; Kumar, G. V.; Nagashankar, G.; Natesh, N.; Roy, S.; Sadhale, P. P.; Ranga, U.; Narayana, C.; Kundu, T. K. Chem. Biol. 2007, 14, 645
  224
  Specific Inhibition of p300-HAT Alters Global Gene Expression and Represses HIV Replication
  Mantelingu, K.; Reddy, B. A. Ashok; Swaminathan, V.; Kishore, A. Hari; Siddappa, Nagadenahalli B.; Kumar, G. V. Pavan; Nagashankar, G.; Natesh, Nagashayana; Roy, Siddhartha; Sadhale, Parag P.; Ranga, Udaykumar; Narayana, Chandrabhas; Kundu, Tapas K.
  Chemistry & Biology (Cambridge, MA, United States) (2007), 14 (6), 645-657CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  Summary: Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-mol. inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells. We show that the specific inhibitor selectively represses the p300-mediated acetylation of p53 in vivo. Furthermore, inhibition of p300-HAT down regulates several genes but significantly a few important genes are also upregulated. Remarkably, these inhibitors were found to be nontoxic to T cells, inhibit histone acetylation of HIV infected cells, and consequently inhibit the multiplication of HIV.
225. 225
  Arif, M.; Pradhan, S. K.; Thanuja, G. R.; Vedamurthy, B. M.; Agrawal, S.; Dasgupta, D.; Kundu, T. K. J. Med. Chem. 2009, 52, 267
  There is no corresponding record for this reference.
226. 226
  Baggett, S.; Protiva, P.; Mazzola, E. P.; Yang, H.; Ressler, E. T.; Basile, M. J.; Weinstein, I. B.; Kennelly, E. J. J. Nat. Prod. 2005, 68, 354
  There is no corresponding record for this reference.
227. 227
  Gartner, M.; Müller, T.; Simon, J. C.; Giannis, A.; Sleeman, J. P. ChemBioChem 2005, 6, 171
  There is no corresponding record for this reference.
228. 228
  Dal Piaz, F.; Tosco, A.; Eletto, D.; Piccinelli, A. L.; Moltedo, O.; Franceschelli, S.; Sbardella, G.; Remondelli, P.; Rastrelli, L.; Vesci, L.; Pisano, C.; De Tommasi, N. ChemBioChem 2010, 11, 818
  There is no corresponding record for this reference.
229. 229
  Biel, M.; Kretsovali, A.; Karatzali, E.; Papamatheakis, J.; Giannis, A. Angew. Chem., Int. Ed. 2004, 43, 3974
  There is no corresponding record for this reference.
230. 230
  Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
  There is no corresponding record for this reference.
231. 231
  Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. J. Biol. Chem. 2009, 284, 24453
  There is no corresponding record for this reference.
232. 232
  Sandur, S. K.; Ichikawa, H.; Sethi, G.; Ahn, K. S.; Aggarwal, B. B. J. Biol. Chem. 2006, 281, 17023
  There is no corresponding record for this reference.
233. 233
  Padhye, S.; Dandawate, P.; Yusufi, M.; Ahmad, A.; Sarkar, F. H. Med. Res. Rev. 2012, 32, 1131
  233
  Perspectives on medicinal properties of plumbagin and its analogs
  Padhye, Subhash; Dandawate, Prasad; Yusufi, Mujahid; Ahmad, Aamir; Sarkar, Fazlul H.
  Medicinal Research Reviews (2012), 32 (6), 1131-1158CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
  A review. Plumbagin is one of the simplest plant secondary metabolite of three major phylogenic families viz. Plumbaginaceae, Droseraceae, and Ebenceae, and exhibits highly potent biol. activities, including antioxidant, antiinflammatory, anticancer, antibacterial, and antifungal activities. Recent investigations indicate that these activities arise mainly out of its ability to undergo redox cycling, generating reactive oxygen species and chelating trace metals in biol. system. The compd. is endowed with a property to inhibit the drug efflux mechanism in drug-resistant bacteria, thereby allowing intracellular accumulation of the potent drug mols. An interesting bioactivity exhibited by this compd. is the elimination of stringent, conjugative, multidrug-resistant plasmids from several bacterial strains including opportunistic bacteria, such as Acinetobacter baumannii. Moreover, plumbagin effectively induces apoptosis and causes cell cycle arrest, which is, in part, due to the inactivation of NF-κB in cancer cells. Therefore, it has been suggested that designing "hybrid drug mols." of plumbagin by combining it with other appropriate anticancer agents may lead to the generation of novel and potent anticancer drugs with pleiotropic action against human cancers. This comprehensive review is an attempt to understand the chem. of plumbagin and catalog its biol. activities reported to date.
234. 234
  Ravindra, K. C.; Selvi, B. R.; Arif, M.; Reddy, B. A.; Thanuja, G. R.; Agrawal, S.; Pradhan, S. K.; Nagashayana, N.; Dasgupta, D.; Kundu, T. K. J. Biol. Chem. 2009, 284, 24453
  There is no corresponding record for this reference.
235. 235
  Choi, K. C.; Jung, M. G.; Lee, Y. H.; Yoon, J. C.; Kwon, S. H.; Kang, H. B.; Kim, M. J.; Cha, J. H.; Kim, Y. J.; Jun, W. J.; Lee, J. M.; Yoon, H. G. Cancer Res. 2009, 69, 583
  There is no corresponding record for this reference.
236. 236
  Neukam, K.; Pastor, N.; Cortés, F. Mutat. Res. 2008, 654, 8
  236
  Tea flavanols inhibit cell growth and DNA topoisomerase II activity and induce endoreduplication in cultured Chinese hamster cells
  Neukam, Karin; Pastor, Nuria; Cortes, Felipe
  Mutation Research, Genetic Toxicology and Environmental Mutagenesis (2008), 654 (1), 8-12CODEN: MRGMFI; ISSN:1383-5718. (Elsevier B.V.)
  Tea polyphenols are promising chemopreventive anticancer agents, the properties of which have been studied both in vitro and in vivo, providing evidence that - within this group of compds. - the tea flavanols are able to inhibit carcinogenesis, an effect that in some cases could be correlated with increased cell apoptosis and decreased cell proliferation. Of four main tea flavanols, namely (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (+)-catechin (CA) and (-)-epicatechin (EC), it was found that EGCG was the most potent to inhibit dose dependently the topoisomerase II (TOPO II) catalytic activity isolated from hamster ovary AA8 cells. In the range of concns. that caused TOPO II inhibition, a high level of endoreduplication, a rare phenomenon that consists in two successive rounds of DNA replication without intervening mitosis, was obsd., while neither micronuclei nor DNA strand breaks (Comet assay) were detected at the same doses. We propose that the anticarcinogenic effect of tea flavanols can be partly explained by their potency and effectiveness to induce endoreduplication. Concerning such an induction, max. effect seems to require a pyrogallol structure at the B-ring. Addnl. substitution with a galloylic residue at the C3 hydroxyl group leads to further augmentation of the effect. Thus, we suggest that the chemopreventive properties of tea flavanols can be at least partly due to their ability to interfere with the cell cycle and block cell proliferation at early stages of mitosis.
237. 237
  Berger, S. J.; Gupta, S.; Belfi, C. A.; Gosky, D. M.; Mukhtar, H. Biochem. Biophys. Res. Commun. 2001, 288, 101
  There is no corresponding record for this reference.
238. 238
  Suzuki, K.; Yahara, S.; Hashimoto, F.; Uyeda, M. Biol. Pharm. Bull. 2001, 24, 1088
  238
  Inhibitory activities of (-)-epigallocatechin-3-O-gallate against topoisomerases I and II
  Suzuki, Keitarou; Yahara, Shoji; Hashimoto, Furnio; Uyeda, Masaru
  Biological & Pharmaceutical Bulletin (2001), 24 (9), 1088-1090CODEN: BPBLEO; ISSN:0918-6158. (Pharmaceutical Society of Japan)
  The substitution of gallic acid at the 3 position of (-)-epigallocatechin-3-O-gallate (EGCG) increased the inhibition against topoisomerase I from calf thymus gland and topoisomerase II from human placenta, and the substitution of a hydroxyl group at the 3' position increased the inhibition against the topoisomerase I. These results suggested that the 3 and 3' positions of the EGCG mol. play important roles in the process of inhibition of topoisomerases I and II. EGCG showed strong inhibition against topoisomerases I from wheat germ, calf thymus gland, and Vero cells, and showed weak or no inhibition against topoisomerases I from carcinoma cells such as A549, HeLaand COLO 201 cells. EGCG differentially inhibited the topoisomerases I from different sources.
239. 239
  Bandele, O. J.; Osheroff, N. Chem. Res. Toxicol. 2008, 21, 936
  There is no corresponding record for this reference.
240. 240
  Golden, E. B.; Lam, P. Y.; Kardosh, A.; Gaffney, K. J.; Cadenas, E.; Louie, S. G.; Petasis, N. A.; Chen, T. C.; Schönthal, A. H. Blood 2009, 113, 5927
  There is no corresponding record for this reference.
241. 241
  Ge, J.; Tan, B. X.; Chen, Y.; Yang, L.; Peng, X. C.; Li, H. Z.; Lin, H. J.; Zhao, Y.; Wei, M.; Cheng, K.; Li, L. H.; Dong, H.; Gao, F.; He, J. P.; Wu, Y.; Qiu, M.; Zhao, Y. L.; Su, J. M.; Hou, J. M.; Liu, J. Y. J. Mol. Med. 2011, 89, 595
  241
  Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability
  Ge, Jun; Tan, Ben-Xu; Chen, Ye; Yang, Li; Peng, Xing-Chen; Li, Hong-Ze; Lin, Hong-Jun; Zhao, Yu; Wei, Meng; Cheng, Ke; Li, Long-Hao; Dong, Hang; Gao, Feng; He, Jian-Ping; Wu, Yang; Qiu, Meng; Zhao, Ying-Lan; Su, Jing-Mei; Hou, Jian-Mei; Liu, Ji-Yan
  Journal of Molecular Medicine (Heidelberg, Germany) (2011), 89 (6), 595-602CODEN: JMLME8; ISSN:0946-2716. (Springer)
  Sunitinib, a novel oral multi-targeted tyrosine kinase inhibitor for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumor, has a good prospect for clin. application and is being investigated for the potential therapy of other tumors. We obsd. the phenomenon that drinking tea interfered with symptom control in an mRCC patient treated with sunitinib and speculated that green tea or its components might interact with sunitinib. This study was performed to investigate whether epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib. The interaction between EGCG and sunitinib was examd. in vitro and in vivo. 1H NMR (1H-NMR) spectroscopy and mass spectrometry (MS) were used to analyze the interaction between these two mols. and whether a new compd. was formed. Solns. of sunitinib and EGCG were intragastrically administered to rats to investigate whether the plasma concns. of sunitinib were affected by EGCG. In this study, we noticed that a ppt. was formed when the solns. of sunitinib and EGCG were mixed under both neutral and acidic conditions. 1H-NMR spectra indicated an interaction between EGCG and sunitinib, but no new compd. was obsd. by MS. Sticky semisolid contents were found in the stomachs of sunitinib and EGCG co-administrated mice. The and C max of plasma sunitinib were markedly reduced by co-administration of EGCG to rats. Our study firstly showed that EGCG interacted with sunitinib and reduced the bioavailability of sunitinib. This finding has significant practical implications for tea-drinking habit during sunitinib administration.
242. 242
  Strick, R.; Strissel, P. L.; Borgers, S.; Smith, S. L.; Rowley, J. D. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 4790
  There is no corresponding record for this reference.
243. 243
  Ruiz, P. A.; Braune, A.; Hölzlwimmer, G.; Quintanilla-Fend, L.; Haller, D. J. Nutr. 2007, 137, 1208
  243
  Quercetin inhibits TNF-induced NF-κB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells
  Ruiz, Pedro A.; Braune, Annett; Hoelzlwimmer, Gabriele; Quintanilla-Fend, Leticia; Haller, Dirk
  Journal of Nutrition (2007), 137 (5), 1208-1215CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutrition)
  Flavonoids may play an important role for adjunct nutritional therapy of chronic intestinal inflammation. In this study, we characterized the mol. mechanisms by which quercetin and its enteric bacterial metabolites, taxifolin, alphitonin, and 3, 4-dihydroxy-phenylacetic acid, inhibit tumor necrosis factor α (TNF)-induced proinflammatory gene expression in the murine small intestinal epithelial cell (IEC) line Mode-K as well as in heterozygous TNFΔARE/WT mice, a murine model of exptl. ileitis. Quercetin inhibited TNF-induced interferon-γ-inducible protein 10 (IP-10) and macrophage inflammatory protein 2 (MIP-2) gene expression in Mode-K cells with effective inhibitory concn. of 40 and 44 μmol/L, resp. Interestingly, taxifolin, alphitonin, and 3,4-dihydroxy-phenylacetic acid did not inhibit TNF responses in IEC, suggesting that microbial transformation of quercetin completely abolished its anti-inflammatory effect. At the mol. level, quercetin inhibited Akt phosphorylation but did not inhibit TNF-induced RelA/I-κB phosphorylation and IκB degrdn. or TNF-α-induced nuclear factor-κB transcriptional activity. Most important for understanding the mechanism involved, chromatin immunopptn. anal. revealed inhibitory effects of quercetin on phospho-RelA recruitment to the IP-10 and MIP-2 gene promoters. In addn., and consistent with the lack of cAMP response element binding protein (CBP)/p300 recruitment and phosphorylation/acetylation of histone 3 at the promoter binding site, quercetin inhibited histone acetyl transferase activity. The oral application of quercetin to heterozygous TNFΔARE/WT mice [10 mg/(d × kg body wt)] significantly inhibited IP-10 and MIP-2 gene expression in primary ileal epithelial cells but did not affect tissue pathol. These studies support an anti-inflammatory effect of quercetin in epithelial cells through mechanisms that inhibit cofactor recruitment at the chromatin of proinflammatory genes.
244. 244
  Chen, J.; Han, J.; Wang, J. Toxicol. Ind. Health 2013, 29, 360
  244
  Prevention of cytotoxicity of nickel by quercetin: the role of reactive oxygen species and histone acetylation
  Chen, Jie; Han, Jia; Wang, Jianmin
  Toxicology and Industrial Health (2013), 29 (4), 360-366CODEN: TIHEEC; ISSN:0748-2337. (Sage Publications)
  Excessive exposure to nickel may cause health effects on the blood, lung, nose, kidney, reproductive system, skin and the unborn child. In the present study, we found that Ni2+ exposure led to a time- and dosedependent proliferation arrest and death in human leukemia HL-60 cells. In the presence of 1 μM Ni2+, reactive oxygen species (ROS) generation (indicated by the level of malondialdehyde) increased to 323% and histone acetylation decreased to 32%. Interestingly, quercetin (QU) dose dependently prevented Ni2+-induced cell proliferation arrest and death from 0 to 80 μM but showed similar activity of scavenging ROS at the concns. of 20, 40 and 80 μM. When the effect of QU on histone acetylation was studied, QU significantly prevented Ni2+-induced histone hypoacetylation at 40 or 80 μM. Moreover, increase in histone acetylation by trichostatin A could also significantly enhance the protection effect of QU at 10 or 20 μM but not at higher concns. Thus, our results further confirmed the crit. role of ROS and histone hypoacetylation in the cytotoxicity of Ni2+ exposure and proved that QU is a potentially useful native dietary compd. to efficiently prevent Ni2+-caused cytotoxicity through both diminishing ROS generation and increasing histone acetylation.
245. 245
  Si, D.; Wang, Y.; Zhou, Y. H.; Guo, Y.; Wang, J.; Zhou, H.; Li, Z. S.; Fawcett, J. P. Drug Metab. Dispos. 2009, 37, 629
  There is no corresponding record for this reference.
246. 246
  Saaby, L.; Rasmussen, H. B.; Jäger, A. K. J. Ethnopharmacol. 2009, 121, 178
  There is no corresponding record for this reference.
247. 247
  Hilliard, J. J.; Krause, H. M.; Bernstein, J. I.; Fernandez, J. A.; Nguyen, V.; Ohemeng, K. A.; Barrett, J. F. Adv. Exp. Med. Biol. 1995, 390, 59
  There is no corresponding record for this reference.
248. 248
  Xiao, X.; Shi, D.; Liu, L.; Wang, J.; Xie, X.; Kang, T.; Deng, W. PLoS One 2011, 6, e22934
  There is no corresponding record for this reference.
249. 249
  O’Brien, E.; Dietrich, D. R. Crit. Rev. Toxicol. 2005, 35, 33
  249
  Ochratoxin A: The Continuing Enigma
  O'Brien, Evelyn; Dietrich, Daniel
  Critical Reviews in Toxicology (2005), 35 (1), 33-60CODEN: CRTXB2; ISSN:1040-8444. (Taylor & Francis, Inc.)
  A review. The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in lab. and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concn. in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiol. studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species- and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant exptl. data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.
250. 250
  Czakai, K.; Müller, K.; Mosesso, P.; Pepe, G.; Schulze, M.; Gohla, A.; Patnaik, D.; Dekant, W.; Higgins, J. M.; Mally, A. Toxicol. Sci. 2011, 122, 317
  250
  Perturbation of Mitosis through Inhibition of Histone Acetyltransferases: The Key to Ochratoxin A Toxicity and Carcinogenicity?
  Czakai, Kristin; Mueller, Katja; Mosesso, Pasquale; Pepe, Gaetano; Schulze, Markus; Gohla, Antje; Patnaik, Debasis; Dekant, Wolfgang; Higgins, Jonathan M. G.; Mally, Angela
  Toxicological Sciences (2011), 122 (2), 317-329CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)
  Ochratoxin A (OTA) is one of the most potent rodent renal carcinogens studied to date. Although controversial results regarding OTA genotoxicity have been published, it is now widely accepted that OTA is not a mutagenic, DNA-reactive carcinogen. Instead, increasing evidence from both in vivo and in vitro studies suggests that OTA may promote genomic instability and tumorigenesis through interference with cell division. The aim of the present study was to provide further support for disruption of mitosis as a key event in OTA toxicity and to understand how OTA mediates these effects. Immortalized human kidney epithelial cells (IHKE) were treated with OTA and monitored by differential interference contrast microscopy for 15 h. Image anal. confirmed that OTA at concns. ≥ 5 μM, which correlate with plasma concns. in rats under conditions of carcinogenesis, causes sustained mitotic arrest and exit from mitosis without nuclear or cellular division. Mitotic chromosomes were characterized by aberrant condensation and premature sister chromatid sepn. assocd. with altered phosphorylation and acetylation of core histones. To test if OTA directly interferes with histone acetyltransferases (HATs) which regulate lysine acetylation of histones and nonhistone proteins, a cell-free HAT activity assay was conducted using total nuclear exts. of IHKE cells. In this assay, OTA significantly blocked HAT activity in a concn.-dependent manner Overall, results from this study provide further support for a mechanism of OTA carcinogenicity involving interference with the mitotic machinery and suggest HATs as a primary cellular target of OTA.
251. 251
  Ravindra, K. C.; Narayan, V.; Lushington, G. H.; Peterson, B. R.; Prabhu, K. S. Chem. Res. Toxicol. 2012, 25, 337
  There is no corresponding record for this reference.
252. 252
  Reginato, M. J.; Krakow, S. L.; Bailey, S. T.; Lazar, M. A. J. Biol. Chem. 1998, 273, 1855
  There is no corresponding record for this reference.
253. 253
  Ravindra, K. C.; Narayan, V.; Lushington, G. H.; Peterson, B. R.; Prabhu, K. S. Chem. Res. Toxicol. 2012, 25, 337
  There is no corresponding record for this reference.
254. 254
  Stimson, L.; Rowlands, M. G.; Newbatt, Y. M.; Smith, N. F.; Raynaud, F. I.; Rogers, P.; Bavetsias, V.; Gorsuch, S.; Jarman, M.; Bannister, A.; Kouzarides, T.; McDonald, E.; Workman, P.; Aherne, G. W. Mol. Cancer Ther. 2005, 4, 1521
  254
  Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity
  Stimson, Lindsay; Rowlands, Martin G.; Newbatt, Yvette M.; Smith, Nicola F.; Raynaud, Florence I.; Rogers, Paul; Bavetsias, Vassilios; Gorsuch, Stephen; Jarman, Michael; Bannister, Andrew; Kouzarides, Tony; McDonald, Edward; Workman, Paul; Aherne, G. Wynne
  Molecular Cancer Therapeutics (2005), 4 (10), 1521-1532CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
  Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate high-throughput screen, we identified a series of isothiazolone-based HAT inhibitors. Thirty-five N-substituted analogs inhibited both p300/cAMP-responsive element binding protein-binding protein-assocd. factor (PCAF) and p300 (1 to > 50 μmol/L, resp.) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to > 50 μmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2-48 h of exposure) and a concn.-dependent manner (one to five times, 72 h, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of α-tubulin. Four and 24 h of exposure to the compds. produced the same extent of growth inhibition as 72 h of continuous exposure, suggesting that growth arrest was an early event. Chem. reactivity of these compds., as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-mol. inhibitors of HAT activity, further analog synthesis is being pursued to examine the potential scope for reducing chem. reactivity while maintaining HAT inhibition.
255. 255
  Dekker, F. J.; Ghizzoni, M.; van der Meer, N.; Wisastra, R.; Haisma, H. J. Bioorg. Med. Chem. 2009, 17, 460
  There is no corresponding record for this reference.
256. 256
  Gorsuch, S.; Bavetsias, V.; Rowlands, M. G.; Aherne, G. W.; Workman, P.; Jarman, M.; McDonald, E. Bioorg. Med. Chem. 2009, 17, 467
  There is no corresponding record for this reference.
257. 257
  Gorsuch, S.; Bavetsias, V.; Rowlands, M. G.; Aherne, G. W.; Workman, P.; Jarman, M.; McDonald, E. Bioorg. Med. Chem. 2009, 17, 467
  There is no corresponding record for this reference.
258. 258
  Wisastra, R.; Ghizzoni, M.; Maarsingh, H.; Minnaard, A. J.; Haisma, H. J.; Dekker, F. J. Org. Biomol. Chem. 2011, 9, 1817
  There is no corresponding record for this reference.
259. 259
  Dekker, F. J.; Ghizzoni, M.; van der Meer, N.; Wisastra, R.; Haisma, H. J. Bioorg. Med. Chem. 2009, 17, 460
  There is no corresponding record for this reference.
260. 260
  Ornaghi, P.; Rotili, D.; Sbardella, G.; Mai, A.; Filetici, P. Biochem. Pharmacol. 2005, 70, 911
  There is no corresponding record for this reference.
261. 261
  Smith, A. T.; Livingston, M. R.; Mai, A.; Filetici, P.; Queener, S. F.; Sullivan, W. J., Jr. Antimicrob. Agents Chemother. 2007, 51, 1109
  There is no corresponding record for this reference.
262. 262
  Mai, A.; Rotili, D.; Tarantino, D.; Ornaghi, P.; Tosi, F.; Vicidomini, C.; Sbardella, G.; Nebbioso, A.; Miceli, M.; Altucci, L.; Filetici, P. J. Med. Chem. 2006, 49, 6897
  There is no corresponding record for this reference.
263. 263
  Mai, A.; Rotili, D.; Tarantino, D.; Nebbioso, A.; Castellano, S.; Sbardella, G.; Tini, M.; Altucci, L. Bioorg. Med. Chem. Lett. 2009, 19, 1132
  There is no corresponding record for this reference.
264. 264
  Rahim, R.; Strobl, J. S. Anticancer Drugs 2009, 20, 736
  There is no corresponding record for this reference.
265. 265
  Tahan, F.; Jazrawi, E.; Moodley, T.; Rovati, G. E.; Adcock, I. M. Clin. Exp. Allergy 2008, 38, 805
  265
  Montelukast inhibits tumour necrosis factor-α-mediated interleukin-8 expression through inhibition of nuclear factor-κB p65-associated histone acetyltransferase activity
  Tahan, F.; Jazrawi, E.; Moodley, T.; Rovati, G. E.; Adcock, I. M.
  Clinical and Experimental Allergy (2008), 38 (5), 805-811CODEN: CLEAEN; ISSN:0954-7894. (Blackwell Publishing Ltd.)
  Background: Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the mol. mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-κB-assocd. histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. Methods: We examd. the inhibitory effects of montelukast on TNF-α-induced IL-8 prodn. in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-α (10 ng/mL) in the presence or absence of montelukast (0.01-10 μM) for 24 h. After this time, the concn. of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-α-induced IL-8 release was examd. pharmacol. using selective NF-κB/IKK2 (AS602868, 3 μM), (PD98059, 10 μM) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 μM) inhibitors. NF-κB DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-κB-p65-assocd. histone acetyltransferase (HAT) activity was measured by immunopptn. linked to com. fluorescent HAT. Results: TNF-α-induced IL-8 release was suppressed by an NF-κB inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concn.-dependent inhibition of TNF-α-induced IL-8 release and mRNA expression that reached a plateau at 0.1 μM without affecting cell viability. Montelukast did not affect NF-κB p65 activation as measured by DNA binding but suppressed NF-κB p65-assocd. HAT activity. Conclusion: Montelukast inhibits TNF-α-stimulated IL-8 expression through changes in NF-κB p65-assocd. HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast.
266. 266
  Chimenti, F.; Bizzarri, B.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Fioravanti, R.; Granese, A.; Carradori, S.; Tosi, F.; Ballario, P.; Vernarecci, S.; Filetici, P. J. Med. Chem. 2009, 52, 530
  There is no corresponding record for this reference.
267. 267
  Wu, J.; Wang, J.; Li, M.; Yang, Y.; Wang, B.; Zheng, Y. G. Bioorg. Chem. 2011, 39, 53
  267
  Small molecule inhibitors of histone acetyltransferase Tip60
  Wu, Jiang; Wang, Ju-Xian; Li, Min-Yong; Yang, Yu-Tao; Wang, Bing-He; Zheng, Y. George
  Bioorganic Chemistry (2011), 39 (1), 53-58CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)
  Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small mol. inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small mol. inhibitors of Tip60 as mechanistic tools for functional study and as chem. leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small mol. library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compds. with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochem. studies. Further, computer modeling and kinetic assays suggest that these mols. target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chem. hits to develop further potent inhibitors for the MYST HATs.
268. 268
  Whitty, A. Future Med. Chem. 2011, 3, 797
  268
  Growing PAINS in academic drug discovery
  Whitty, Adrian
  Future Medicinal Chemistry (2011), 3 (7), 797-801CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
  In a recent article it was argued that compds. published as drug leads by academic labs. commonly contain functionality that identifies them as nonspecific pan-assay interference compds.'' (PAINS). The article raises broad questions about why best practices for hit and lead qualification that are well known in industry are not more widely employed in academia, as well as about the role of journals in publishing manuscripts that report drug leads of little potential value. Barriers to adoption of best practices for some academic drug-discovery researchers include knowledge gaps and infrastructure deficiencies, but they also arise from fundamental differences in how academic research is structured and how success is measured. Academic drug discovery should not seek to become identical to com. pharmaceutical research, but we can do a better job of assessing and communicating the true potential of the drug leads we publish, thereby reducing the wastage of resources on nonviable compds.
269. 269
  Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010, 53, 2719
  269
  New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
  Baell, Jonathan B.; Holloway, Georgina A.
  Journal of Medicinal Chemistry (2010), 53 (7), 2719-2740CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  This report describes a no. of substructural features which can help to identify compds. that appear as frequent hitters (promiscuous compds.) in many biochem. high throughput screens. The compds. identified by such substructural features are not recognized by filters commonly used to identify reactive compds. Even though these substructural features were identified using only one assay detection technol., such compds. have been reported to be active from many different assays. In fact, these compds. are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.
270. 270
  Mujtaba, S.; Zeng, L.; Zhou, M. M. Oncogene 2007, 26, 5521
  There is no corresponding record for this reference.
271. 271
  Manning, E. T.; Ikehara, T.; Ito, T.; Kadonaga, J. T.; Kraus, W. L. Mol. Cell. Biol. 2001, 21, 3876
  271
  p300 forms a stable, template-committed complex with chromatin: role for the bromodomain
  Manning, E. Tory; Ikehara, Tsuyoshi; Ito, Takashi; Kadonaga, James T.; Kraus, W. Lee
  Molecular and Cellular Biology (2001), 21 (12), 3876-3887CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  The nature of the interaction of coactivator proteins with transcriptionally active promoters in chromatin is a fundamental question in transcriptional regulation by RNA polymerase II. In this study, we used a biochem. approach to examine the functional assocn. of the coactivator p300 with chromatin templates. Using in vitro transcription template competition assays, we obsd. that p300 forms a stable, template-committed complex with chromatin during the transcription process. The template commitment is dependent on the time of incubation of p300 with the chromatin template and occurs independently of the presence of a transcriptional activator protein. In studies examg. interactions between p300 and chromatin, we found that p300 binds directly to chromatin and that the binding requires the p300 bromodomain, a conserved 110-amino-acid sequence found in many chromatin-assocd. proteins. Furthermore, we obsd. that the isolated p300 bromodomain binds directly to histones, preferentially to histone H3. However, the isolated p300 bromodomain does not bind to nucleosomal histones under the same assay conditions, suggesting that free histones and nucleosomal histones are not equiv. as binding substrates. Collectively, our results suggest that the stable assocn. of p300 with chromatin is mediated, at least in part, by the bromodomain and is critically important for p300 function. Furthermore, our results suggest a model for p300 function that involves distinct activator-dependent targeting and activator-independent chromatin binding activities.
272. 272
  Wei, L.; Jamonnak, N.; Choy, J.; Wang, Z.; Zheng, W. Biochem. Biophys. Res. Commun. 2008, 368, 279
  There is no corresponding record for this reference.
273. 273
  Polesskaya, A.; Naguibneva, I.; Duquet, A.; Bengal, E.; Robin, P.; Harel-Bellan, A. Mol. Cell. Biol. 2001, 21, 5312
  273
  Interaction between acetylated MyoD and the bromodomain of CBP and/or p300
  Polesskaya, Anna; Naguibneva, Irina; Duquet, Arnaud; Bengal, Eyal; Robin, Philippe; Harel-Bellan, Annick
  Molecular and Cellular Biology (2001), 21 (16), 5312-5320CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  Acetylation is emerging as a posttranslational modification of nuclear proteins that is essential to the regulation of transcription and that modifies transcription factor affinity for binding sites on DNA, stability, and/or nuclear localization. Here, we present both in vitro and in vivo evidence that acetylation increases the affinity of myogenic factor MyoD for acetyltransferases CBP and p300. In myogenic cells, the fraction of endogenous MyoD that is acetylated was found assocd. with CBP or p300. In vitro, the interaction between MyoD and CBP was more resistant to high salt concns. and was detected with lower doses of MyoD when MyoD was acetylated. Interestingly, an anal. of CBP mutants revealed that the interaction with acetylated MyoD involves the bromodomain of CBP. In live cells, MyoD mutants that cannot be acetylated did not assoc. with CBP or p300 and were strongly impaired in their ability to cooperate with CBP for transcriptional activation of a muscle creatine kinase-luciferase construct. Taken together, our data suggest a new mechanism for activation of protein function by acetylation and demonstrate for the first time an acetylation-dependent interaction between the bromodomain of CBP and a nonhistone protein.
274. 274
  Hou, T.; Ray, S.; Lee, C.; Brasier, A. R. J. Biol. Chem. 2008, 283, 30725
  There is no corresponding record for this reference.
275. 275
  Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O.; Sachchidanand; Sanchez, R.; Zeleznik-Le, N. J.; Ronai, Z.; Zhou, M. M. Mol. Cell 2004, 13, 251
  There is no corresponding record for this reference.
276. 276
  Kim, J. H.; Cho, E. J.; Kim, S. T.; Youn, H. D. Nat. Struct. Mol. Biol. 2005, 12, 423
  276
  CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain
  Kim, Jae-Hwan; Cho, Eun-Jung; Kim, Seong-Tae; Youn, Hong-Duk
  Nature Structural & Molecular Biology (2005), 12 (5), 423-428CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been detd. In this study authors found that CtBP1 directly assocs. with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addn., an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissocn. of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.
277. 277
  Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
  There is no corresponding record for this reference.
278. 278
  Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
  278
  p300/CBP proteins: HATs for transcriptional bridges and scaffolds
  Chan, Ho Man; La Thangue, Nicholas B.
  Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
  A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
279. 279
  Wang, F.; Marshall, C. B.; Ikura, M. Cell. Mol. Life Sci. 2013, 70, 3989
  279
  Transcriptional/epigenetic regulator CBP/p300 in tumorigenesis: structural and functional versatility in target recognition
  Wang, Feng; Marshall, Christopher B.; Ikura, Mitsuhiko
  Cellular and Molecular Life Sciences (2013), 70 (21), 3989-4008CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
  A review. In eukaryotic cells, gene transcription is regulated by sequence-specific DNA-binding transcription factors that recognize promoter and enhancer elements near the transcriptional start site. Some coactivators promote transcription by connecting transcription factors to the basal transcriptional machinery. The highly conserved coactivators CREB-binding protein (CBP) and its paralog, E1A-binding protein (p300), each have four sep. transactivation domains (TADs) that interact with the TADs of a no. of DNA-binding transcription activators as well as general transcription factors (GTFs), thus mediating recruitment of basal transcription machinery to the promoter. Most promoters comprise multiple activator-binding sites, and many activators contain tandem TADs, thus multivalent interactions may stabilize CBP/p300 at the promoter, and intrinsically disordered regions in CBP/p300 and many activators may confer adaptability to these multivalent complexes. CBP/p300 contains a catalytic histone acetyltransferase (HAT) domain, which remodels chromatin to 'relax' its superstructure and enables transcription of proximal genes. The HAT activity of CBP/p300 also acetylates some transcription factors (e.g., p53), hence modulating the function of key transcriptional regulators. Through these numerous interactions, CBP/p300 has been implicated in complex physiol. and pathol. processes, and, in response to different signals, can drive cells towards proliferation or apoptosis. Dysregulation of the transcriptional and epigenetic functions of CBP/p300 is assocd. with leukemia and other types of cancer, thus it has been recognized as a potential anti-cancer drug target. In this review, we focus on recent exciting findings in the structural mechanisms of CBP/p300 involving multivalent and dynamic interactions with binding partners, which may pave new avenues for anti-cancer drug development.
280. 280
  Ragvin, A.; Valvatne, H.; Erdal, S.; Arskog, V.; Tufteland, K. R.; Breen, K.; ØYan, A. M.; Eberharter, A.; Gibson, T. J.; Becker, P. B.; Aasland, R. J. Mol. Biol. 2004, 337, 773
  There is no corresponding record for this reference.
281. 281
  He, J.; Ye, J.; Cai, Y.; Riquelme, C.; Liu, J. O.; Liu, X.; Han, A.; Chen, L. Nucleic Acids Res. 2011, 39, 4464
  There is no corresponding record for this reference.
282. 282
  Zeng, L.; Zhang, Q.; Gerona-Navarro, G.; Moshkina, N.; Zhou, M. M. Structure 2008, 16, 643
  There is no corresponding record for this reference.
283. 283
  Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O.; Sachchidanand; Sanchez, R.; Zeleznik-Le, N. J.; Ronai, Z.; Zhou, M. M. Mol. Cell 2004, 13, 251
  There is no corresponding record for this reference.
284. 284
  Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
  There is no corresponding record for this reference.
285. 285
  Feng, H.; Jenkins, L. M.; Durell, S. R.; Hayashi, R.; Mazur, S. J.; Cherry, S.; Tropea, J. E.; Miller, M.; Wlodawer, A.; Appella, E.; Bai, Y. Structure 2009, 17, 202
  There is no corresponding record for this reference.
286. 286
  Wojciak, J. M.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. EMBO J. 2009, 28, 948
  There is no corresponding record for this reference.
287. 287
  Das, C.; Roy, S.; Namjoshi, S.; Malarkey, C. S.; Jones, D. N.; Kutateladze, T. G.; Churchill, M. E.; Tyler, J. K. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, E1072
  There is no corresponding record for this reference.
288. 288
  Delvecchio, M.; Gaucher, J.; Aguilar-Gurrieri, C.; Ortega, E.; Panne, D. Nat. Struct. Mol. Biol. 2013, 20, 1040
  288
  Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation
  Delvecchio, Manuela; Gaucher, Jonathan; Aguilar-Gurrieri, Carmen; Ortega, Esther; Panne, Daniel
  Nature Structural & Molecular Biology (2013), 20 (9), 1040-1046CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  CBP and p300 are histone acetyltransferases (HATs) that assoc. with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 contg. its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.
289. 289
  He, J.; Ye, J.; Cai, Y.; Riquelme, C.; Liu, J. O.; Liu, X.; Han, A.; Chen, L. Nucleic Acids Res. 2011, 39, 4464
  There is no corresponding record for this reference.
290. 290
  Feng, H.; Jenkins, L. M.; Durell, S. R.; Hayashi, R.; Mazur, S. J.; Cherry, S.; Tropea, J. E.; Miller, M.; Wlodawer, A.; Appella, E.; Bai, Y. Structure 2009, 17, 202
  There is no corresponding record for this reference.
291. 291
  Ferreon, J. C.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 13260
  There is no corresponding record for this reference.
292. 292
  Wojciak, J. M.; Martinez-Yamout, M. A.; Dyson, H. J.; Wright, P. E. EMBO J. 2009, 28, 948
  There is no corresponding record for this reference.
293. 293
  Chan, H. M.; La Thangue, N. B. J. Cell Sci. 2001, 114, 2363
  293
  p300/CBP proteins: HATs for transcriptional bridges and scaffolds
  Chan, Ho Man; La Thangue, Nicholas B.
  Journal of Cell Science (2001), 114 (13), 2363-2373CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)
  A review with 139 refs. P300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription app., allowing the appropriate level of gene activity to occur in response to diverse physiol. cues that influence, for example, proliferation, differentiation and apoptosis. P300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumor-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription app. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumor suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
294. 294
  Simone, C.; Stiegler, P.; Forcales, S. V.; Bagella, L.; De Luca, A.; Sartorelli, V.; Giordano, A.; Puri, P. L. Oncogene 2004, 23, 2177
  There is no corresponding record for this reference.
295. 295
  Saint Just Ribeiro, M.; Hansson, M. L.; Wallberg, A. E. Biochem. J. 2007, 404, 289
  There is no corresponding record for this reference.
296. 296
  Tax, F. E.; Thomas, J. H.; Ferguson, E. L.; Horvitz, H. R. Genetics 1997, 147, 1675
  There is no corresponding record for this reference.
297. 297
  Petcherski, A. G.; Kimble, J. Nature 2000, 405, 364
  There is no corresponding record for this reference.
298. 298
  Petcherski, A. G.; Kimble, J. Curr. Biol. 2000, 10, R471
  There is no corresponding record for this reference.
299. 299
  Kitagawa, M.; Oyama, T.; Kawashima, T.; Yedvobnick, B.; Kumar, A.; Matsuno, K.; Harigaya, K. Mol. Cell. Biol. 2001, 21, 4337
  299
  A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of Notch and a CSL protein to build a transcriptional activator complex on target promoters
  Kitagawa, Motoo; Oyama, Toshinao; Kawashima, Taichi; Yedvobnick, Barry; Kumar, Anumeha; Matsuno, Kenji; Harigaya, Kenichi
  Molecular and Cellular Biology (2001), 21 (13), 4337-4346CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  Mastermind (Mam) has been implicated as an important pos. regulator of the Notch signaling pathway by genetic studies using Drosophila melanogaster. Here we describe a biochem. mechanism of action of Mam within the Notch signaling pathway. Expression of a human sequence related to Drosophila Mam (hMam-1) in mammalian cells augments induction of Hairy Enhancer of split (HES) promoters by Notch signaling. HMam-1 stabilizes and participates in the DNA binding complex of the intracellular domain of human Notch1 and a CSL protein. Truncated versions of hMam-1 that can maintain an assocn. with the complex behave in a dominant neg. fashion and depress transactivation. Furthermore, Drosophila Mam forms a similar complex with the intracellular domain of Drosophila Notch and Drosophila CSL protein during activation of Enhancer of split, the Drosophila counterpart of HES. These results indicate that Mam is an essential component of the transcriptional app. of Notch signaling.
300. 300
  Wu, L.; Aster, J. C.; Blacklow, S. C.; Lake, R.; Artavanis-Tsakonas, S.; Griffin, J. D. Nat. Genet. 2000, 26, 484
  300
  MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors
  Wu, Lizi; Aster, Jon C.; Blacklow, Stephen C.; Lake, Robert; Artavanis-Tsakonas, Spyros; Griffin, James D.
  Nature Genetics (2000), 26 (4), 484-489CODEN: NGENEC; ISSN:1061-4036. (Nature America Inc.)
  Notch receptors are involved in cell-fate detn. in organisms as diverse as flies, frogs and humans. In Drosophila melanogaster, loss-of-function mutations of Notch produce a "neurogenic" phenotype in which cells destined to become epidermis switch fate and differentiate to neural cells. Upon ligand activation, the intracellular domain of Notch (ICN) translocates to the nucleus, and interacts directly with the DNA-binding protein Suppressor of hairless (Su(H)) in flies, or recombination signal binding protein Jκ (RBP-Jκ) in mammals, to activate gene transcription. But the precise mechanisms of Notch-induced gene expression are not completely understood. The gene mastermind has been identified in multiple genetic screens for modifiers of Notch mutations in Drosophila. Here we clone MAML1, a human homolog of the Drosophila gene Mastermind, and show that it encodes a protein of 130 kD localizing to nuclear bodies. MAML1 binds to the ankyrin repeat domain of all four mammalian NOTCH receptors, forms a DNA-binding complex with ICN and RBP-Jκ, and amplifies NOTCH-induced transcription of HES1. These studies provide a mol. mechanism to explain the genetic links between mastermind and Notch in Drosophila and indicate that MAML1 functions as a transcriptional co-activator for NOTCH signaling.
301. 301
  Wilson, J. J.; Kovall, R. A. Cell 2006, 124, 985
  There is no corresponding record for this reference.
302. 302
  Arnett, K. L.; Hass, M.; McArthur, D. G.; Ilagan, M. X.; Aster, J. C.; Kopan, R.; Blacklow, S. C. Nat. Struct. Mol. Biol. 2010, 17, 1312
  302
  Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes
  Arnett, Kelly L.; Hass, Matthew; McArthur, Debbie G.; Ilagan, Ma Xenia G.; Aster, Jon C.; Kopan, Raphael; Blacklow, Stephen C.
  Nature Structural & Molecular Biology (2010), 17 (11), 1312-1317CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Ligand-induced proteolysis of Notch produces an intracellular effector domain that transduces essential signals by regulating the transcription of target genes. This function relies on the formation of transcriptional activation complexes that include intracellular Notch, a Mastermind co-activator and the transcription factor CSL bound to cognate DNA. These complexes form higher-order assemblies on paired, head-to-head CSL recognition sites. Here we report the X-ray structure of a dimeric human Notch1 transcription complex loaded on the paired site from the human HES1 promoter. The small interface between the Notch ankyrin domains could accommodate DNA bending and untwisting to allow a range of spacer lengths between the two sites. Cooperative dimerization occurred on the human and mouse Hes5 promoters at a sequence that diverged from the CSL-binding consensus at one of the sites. These studies reveal how promoter organizational features control cooperativity and, thus, the responsiveness of different promoters to Notch signaling.
303. 303
  Nam, Y.; Sliz, P.; Song, L.; Aster, J. C.; Blacklow, S. C. Cell 2006, 124, 973
  There is no corresponding record for this reference.
304. 304
  Choi, S. H.; Wales, T. E.; Nam, Y.; O’Donovan, D. J.; Sliz, P.; Engen, J. R.; Blacklow, S. C. Structure 2012, 20, 340
  There is no corresponding record for this reference.
305. 305
  Hansson, M. L.; Popko-Scibor, A. E.; Saint Just Ribeiro, M.; Dancy, B. M.; Lindberg, M. J.; Cole, P. A.; Wallberg, A. E. Nucleic Acids Res. 2009, 37, 2996
  There is no corresponding record for this reference.
306. 306
  Fryer, C. J.; Lamar, E.; Turbachova, I.; Kintner, C.; Jones, K. A. Genes Dev. 2002, 16, 1397
  There is no corresponding record for this reference.
307. 307
  Saint Just Ribeiro, M.; Hansson, M. L.; Wallberg, A. E. Biochem. J. 2007, 404, 289
  There is no corresponding record for this reference.
308. 308
  Black, J. C.; Choi, J. E.; Lombardo, S. R.; Carey, M. Mol. Cell 2006, 23, 809
  There is no corresponding record for this reference.
309. 309
  Kim, J. H.; Cho, E. J.; Kim, S. T.; Youn, H. D. Nat. Struct. Mol. Biol. 2005, 12, 423
  309
  CtBP represses p300-mediated transcriptional activation by direct association with its bromodomain
  Kim, Jae-Hwan; Cho, Eun-Jung; Kim, Seong-Tae; Youn, Hong-Duk
  Nature Structural & Molecular Biology (2005), 12 (5), 423-428CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been detd. In this study authors found that CtBP1 directly assocs. with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addn., an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissocn. of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.
310. 310
  Kraus, W. L.; Manning, E. T.; Kadonaga, J. T. Mol. Cell. Biol. 1999, 19, 8123
  310
  Biochemical analysis of distinct activation functions in p300 that enhance transcription initiation with chromatin templates
  Kraus, W. Lee; Manning, E. Tory; Kadonaga, James T.
  Molecular and Cellular Biology (1999), 19 (12), 8123-8135CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  To investigate the mechanisms of transcriptional enhancement by the p300 coactivator, we analyzed wild-type and mutant versions of p300 with a chromatin transcription system in vitro. Estrogen receptor, NF-κB p65 plus Sp1, and Gal4-VP16 were used as different sequence-specific activators. The CH3 domain (or E1A-binding region) was found to be essential for the function of each of the activators tested. The bromodomain was also obsd. to be generally important for p300 coactivator activity, though to a lesser extent than the CH3 domain/E1A-binding region. The acetyltransferase activity and the C-terminal region (contg. the steroid receptor coactivator/p160-binding region and the glutamine-rich region) were each found to be important for activation by estrogen receptor but not for that by Gal4-VP16. The N-terminal region of p300, which had been previously found to interact with nuclear hormone receptors, was not seen to be required for any of the activators, including estrogen receptor. Single-round transcription expts. revealed that the functionally important subregions of p300 contribute to its ability to promote the assembly of transcription initiation complexes. In addn., the acetyltransferase activity of p300 was obsd. to be distinct from the broadly essential activation function of the CH3 domain/E1A-binding region. These results indicate that specific regions of p300 possess distinct activation functions that are differentially required to enhance the assembly of transcription initiation complexes. Interestingly, with the estrogen receptor, four distinct regions of p300 each have an essential role in the transcription activation process. These data exemplify a situation in which a network of multiple activation functions is required to achieve gene transcription.
311. 311
  Delvecchio, M.; Gaucher, J.; Aguilar-Gurrieri, C.; Ortega, E.; Panne, D. Nat. Struct. Mol. Biol. 2013, 20, 1040
  311
  Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation
  Delvecchio, Manuela; Gaucher, Jonathan; Aguilar-Gurrieri, Carmen; Ortega, Esther; Panne, Daniel
  Nature Structural & Molecular Biology (2013), 20 (9), 1040-1046CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  CBP and p300 are histone acetyltransferases (HATs) that assoc. with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 contg. its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.
312. 312
  Filippakopoulos, P.; Knapp, S. Nat. Rev. Drug Discovery 2014, 13, 337
  312
  Targeting bromodomains: epigenetic readers of lysine acetylation
  Filippakopoulos, Panagis; Knapp, Stefan
  Nature Reviews Drug Discovery (2014), 13 (5), 337-356CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
  A review. Lysine acetylation is a key mechanism that regulates chromatin structure; aberrant acetylation levels have been linked to the development of several diseases. Acetyl-lysine modifications create docking sites for bromodomains, which are small interaction modules found on diverse proteins, some of which have a key role in the acetylation-dependent assembly of transcriptional regulator complexes. These complexes can then initiate transcriptional programs that result in phenotypic changes. The recent discovery of potent and highly specific inhibitors for the BET (bromodomain and extra-terminal) family of bromodomains has stimulated intensive research activity in diverse therapeutic areas, particularly in oncol., where BET proteins regulate the expression of key oncogenes and anti-apoptotic proteins. In addn., targeting BET bromodomains could hold potential for the treatment of inflammation and viral infection. Here, we highlight recent progress in the development of bromodomain inhibitors, and their potential applications in drug discovery.
313. 313
  Nicodeme, E.; Jeffrey, K. L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C. W.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; White, J.; Kirilovsky, J.; Rice, C. M.; Lora, J. M.; Prinjha, R. K.; Lee, K.; Tarakhovsky, A. Nature 2010, 468, 1119
  There is no corresponding record for this reference.
314. 314
  Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V. L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A. B.; Boursier, E.; Martin, S.; Brusq, J. M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. Bioorg. Med. Chem. Lett. 2012, 22, 2963
  There is no corresponding record for this reference.
315. 315
  Dawson, M. A.; Prinjha, R. K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W. I.; Robson, S. C.; Chung, C. W.; Hopf, C.; Savitski, M. M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T. D.; Roberts, E. J.; Soden, P. E.; Auger, K. R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A. K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B. J.; Kouzarides, T. Nature 2011, 478, 529
  There is no corresponding record for this reference.
316. 316
  Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W. B.; Fedorov, O.; Morse, E. M.; Keates, T.; Hickman, T. T.; Felletar, I.; Philpott, M.; Munro, S.; McKeown, M. R.; Wang, Y.; Christie, A. L.; West, N.; Cameron, M. J.; Schwartz, B.; Heightman, T. D.; La Thangue, N.; French, C. A.; Wiest, O.; Kung, A. L.; Knapp, S.; Bradner, J. E. Nature 2010, 468, 1067
  316
  Selective inhibition of BET bromodomains
  Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; Shen, Yao; Smith, William B.; Fedorov, Oleg; Morse, Elizabeth M.; Keates, Tracey; Hickman, Tyler T.; Felletar, Ildiko; Philpott, Martin; Munro, Shongah; McKeown, Michael R.; Wang, Yuchuan; Christie, Amanda L.; West, Nathan; Cameron, Michael J.; Schwartz, Brian; Heightman, Tom D.; La Thangue, Nicholas; French, Christopher; Wiest, Olaf; Kung, Andrew L.; Knapp, Stefan; Bradner, James E.
  Nature (London, United Kingdom) (2010), 468 (7327), 1067-1073CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here the authors report a cell-permeable small mol. (I,JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is obsd. in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chem. scaffold for the development of chem. probes more broadly throughout the bromodomain family.
317. 317
  Fish, P. V.; Filippakopoulos, P.; Bish, G.; Brennan, P. E.; Bunnage, M. E.; Cook, A. S.; Federov, O.; Gerstenberger, B. S.; Jones, H.; Knapp, S.; Marsden, B.; Nocka, K.; Owen, D. R.; Philpott, M.; Picaud, S.; Primiano, M. J.; Ralph, M. J.; Sciammetta, N.; Trzupek, J. D. J. Med. Chem. 2012, 55, 9831
  There is no corresponding record for this reference.
318. 318
  Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P. V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P.; O’Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S. Cancer Res. 2013, 73, 3336
  There is no corresponding record for this reference.
319. 319
  Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. J. Med. Chem. 2011, 54, 6761
  There is no corresponding record for this reference.
320. 320
  Hay, D.; Fedorov, O.; Filippakopoulos, P.; Martin, S.; Philpott, M.; Picaud, S.; Hewings, D. S.; Uttakar, S.; Heightman, T. D.; Conway, S. J.; Knapp, S.; Brennan, P. E. Med. Chem. Commun. 2013, 4, 140
  There is no corresponding record for this reference.
321. 321
  Bamborough, P.; Diallo, H.; Goodacre, J. D.; Gordon, L.; Lewis, A.; Seal, J. T.; Wilson, D. M.; Woodrow, M. D.; Chung, C. W. J. Med. Chem. 2012, 55, 587
  There is no corresponding record for this reference.
322. 322
  Boehm, D.; Calvanese, V.; Dar, R. D.; Xing, S.; Schroeder, S.; Martins, L.; Aull, K.; Li, P. C.; Planelles, V.; Bradner, J. E.; Zhou, M. M.; Siliciano, R. F.; Weinberger, L.; Verdin, E.; Ott, M. Cell Cycle 2013, 12, 452
  There is no corresponding record for this reference.
323. 323
  Li, Z.; Guo, J.; Wu, Y.; Zhou, Q. Nucleic Acids Res. 2013, 41, 277
  There is no corresponding record for this reference.
324. 324
  Zhu, J.; Gaiha, G. D.; John, S. P.; Pertel, T.; Chin, C. R.; Gao, G.; Qu, H.; Walker, B. D.; Elledge, S. J.; Brass, A. L. Cell Rep. 2012, 2, 807
  324
  Reactivation of latent HIV-1 by inhibition of BRD4
  Zhu, Jian; Gaiha, Gaurav D.; John, Sinu P.; Pertel, Thomas; Chin, Christopher R.; Gao, Geng; Qu, Hongjing; Walker, Bruce D.; Elledge, Stephen J.; Brass, Abraham L.
  Cell Reports (2012), 2 (4), 807-816CODEN: CREED8; ISSN:2211-1247. (Cell Press)
  HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the redn. of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain contg. 4 (BRD4) as a neg. regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small mol. inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection.
325. 325
  Banerjee, C.; Archin, N.; Michaels, D.; Belkina, A. C.; Denis, G. V.; Bradner, J.; Sebastiani, P.; Margolis, D. M.; Montano, M. J. Leukocyte Biol. 2012, 92, 1147
  325
  BET bromodomain inhibition as a novel strategy for reactivation of HIV-1
  Banerjee, Camellia; Archin, Nancie; Michaels, Daniel; Belkina, Anna C.; Denis, Gerald V.; Bradner, James; Sebastiani, Paola; Margolis, David M.; Montano, Monty
  Journal of Leukocyte Biology (2012), 92 (6), 1147-1154CODEN: JLBIE7; ISSN:0741-5400. (Society for Leukocyte Biology)
  The persistence of latent HIV-1 remains a major challenge in therapeutic efforts to eradicate infection. We report the capacity for HIV reactivation by a selective small mol. inhibitor of BET family bromodomains, JQ1, a promising therapeutic agent with antioncogenic properties. JQ1 reactivated HIV transcription in models of latent T cell infection and latent monocyte infection. We also tested the effect of exposure to JQ1 to allow recovery of replication-competent HIV from pools of resting CD4+ T cells isolated from HIV-infected, ART-treated patients. In one of three patients, JQ1 allowed recovery of virus at a frequency above unstimulated conditions. JQ1 potently suppressed T cell proliferation with minimal cytotoxic effect. Transcriptional profiling of T cells with JQ1 showed potent down-regulation of T cell activation genes, including CD3, CD28, and CXCR4, similar to HDAC inhibitors, but JQ1 also showed potent up-regulation of chromatin modification genes, including SIRT1, HDAC6, and multiple lysine demethylases (KDMs). Thus, JQ1 reactivates HIV-1 while suppressing T cell activation genes and up-regulating histone modification genes predicted to favor increased Tat activity. Thus, JQ1 may be useful in studies of potentially novel mechanisms for transcriptional control as well as in translational efforts to identify therapeutic mols. to achieve viral eradication.
326. 326
  Wang, X.; Li, J.; Schowalter, R. M.; Jiao, J.; Buck, C. B.; You, J. PLoS Pathog. 2012, 8, e1003021
  There is no corresponding record for this reference.
327. 327
  Goupille, O.; Penglong, T.; Lefèvre, C.; Granger, M.; Kadri, Z.; Fucharoen, S.; Maouche-Chrétien, L.; Leboulch, P.; Chrétien, S. Biochem. Biophys. Res. Commun. 2012, 429, 1
  There is no corresponding record for this reference.
328. 328
  Ott, C. J.; Kopp, N.; Bird, L.; Paranal, R. M.; Qi, J.; Bowman, T.; Rodig, S. J.; Kung, A. L.; Bradner, J. E.; Weinstock, D. M. Blood 2012, 120, 2843
  There is no corresponding record for this reference.
329. 329
  Picaud, S.; Da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P. V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M. E.; Owen, D. R.; Bradner, J. E.; Taniere, P.; O’Sullivan, B.; Müller, S.; Schwaller, J.; Stankovic, T.; Knapp, S. Cancer Res. 2013, 73, 3336
  There is no corresponding record for this reference.
330. 330
  Dawson, M. A.; Prinjha, R. K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W. I.; Robson, S. C.; Chung, C. W.; Hopf, C.; Savitski, M. M.; Huthmacher, C.; Gudgin, E.; Lugo, D.; Beinke, S.; Chapman, T. D.; Roberts, E. J.; Soden, P. E.; Auger, K. R.; Mirguet, O.; Doehner, K.; Delwel, R.; Burnett, A. K.; Jeffrey, P.; Drewes, G.; Lee, K.; Huntly, B. J.; Kouzarides, T. Nature 2011, 478, 529
  There is no corresponding record for this reference.
331. 331
  Zuber, J.; Shi, J.; Wang, E.; Rappaport, A. R.; Herrmann, H.; Sison, E. A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; Taylor, M. J.; Johns, C.; Chicas, A.; Mulloy, J. C.; Kogan, S. C.; Brown, P.; Valent, P.; Bradner, J. E.; Lowe, S. W.; Vakoc, C. R. Nature 2011, 478, 524
  There is no corresponding record for this reference.
332. 332
  Mertz, J. A.; Conery, A. R.; Bryant, B. M.; Sandy, P.; Balasubramanian, S.; Mele, D. A.; Bergeron, L.; Sims, R. J., III. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 16669
  There is no corresponding record for this reference.
333. 333
  Delmore, J. E.; Issa, G. C.; Lemieux, M. E.; Rahl, P. B.; Shi, J.; Jacobs, H. M.; Kastritis, E.; Gilpatrick, T.; Paranal, R. M.; Qi, J.; Chesi, M.; Schinzel, A. C.; McKeown, M. R.; Heffernan, T. P.; Vakoc, C. R.; Bergsagel, P. L.; Ghobrial, I. M.; Richardson, P. G.; Young, R. A.; Hahn, W. C.; Anderson, K. C.; Kung, A. L.; Bradner, J. E.; Mitsiades, C. S. Cell 2011, 146, 904
  There is no corresponding record for this reference.
334. 334
  Lockwood, W. W.; Zejnullahu, K.; Bradner, J. E.; Varmus, H. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 19408
  There is no corresponding record for this reference.
335. 335
  Bandukwala, H. S.; Gagnon, J.; Togher, S.; Greenbaum, J. A.; Lamperti, E. D.; Parr, N. J.; Molesworth, A. M.; Smithers, N.; Lee, K.; Witherington, J.; Tough, D. F.; Prinjha, R. K.; Peters, B.; Rao, A. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 14532
  There is no corresponding record for this reference.
336. 336
  Mirguet, O.; Lamotte, Y.; Donche, F.; Toum, J.; Gellibert, F.; Bouillot, A.; Gosmini, R.; Nguyen, V. L.; Delannée, D.; Seal, J.; Blandel, F.; Boullay, A. B.; Boursier, E.; Martin, S.; Brusq, J. M.; Krysa, G.; Riou, A.; Tellier, R.; Costaz, A.; Huet, P.; Dudit, Y.; Trottet, L.; Kirilovsky, J.; Nicodeme, E. Bioorg. Med. Chem. Lett. 2012, 22, 2963
  There is no corresponding record for this reference.
337. 337
  Bamborough, P.; Diallo, H.; Goodacre, J. D.; Gordon, L.; Lewis, A.; Seal, J. T.; Wilson, D. M.; Woodrow, M. D.; Chung, C. W. J. Med. Chem. 2012, 55, 587
  There is no corresponding record for this reference.
338. 338
  Zhang, G.; Liu, R.; Zhong, Y.; Plotnikov, A. N.; Zhang, W.; Zeng, L.; Rusinova, E.; Gerona-Nevarro, G.; Moshkina, N.; Joshua, J.; Chuang, P. Y.; Ohlmeyer, M.; He, J. C.; Zhou, M. M. J. Biol. Chem. 2012, 287, 28840– 51
  There is no corresponding record for this reference.
339. 339
  Matzuk, M. M.; McKeown, M. R.; Filippakopoulos, P.; Li, Q.; Ma, L.; Agno, J. E.; Lemieux, M. E.; Picaud, S.; Yu, R. N.; Qi, J.; Knapp, S.; Bradner, J. E. Cell 2012, 150, 673
  There is no corresponding record for this reference.
340. 340
  Ferguson, F. M.; Fedorov, O.; Chaikuad, A.; Philpott, M.; Muniz, J. R.; Felletar, I.; von Delft, F.; Heightman, T.; Knapp, S.; Abell, C.; Ciulli, A. J. Med. Chem. 2013, 56, 10183
  There is no corresponding record for this reference.
341. 341
  Zhang, W.; Prakash, C.; Sum, C.; Gong, Y.; Li, Y.; Kwok, J. J.; Thiessen, N.; Pettersson, S.; Jones, S. J.; Knapp, S.; Yang, H.; Chin, K. C. J. Biol. Chem. 2012, 287, 43137
  There is no corresponding record for this reference.
342. 342
  Bartholomeeusen, K.; Xiang, Y.; Fujinaga, K.; Peterlin, B. M. J. Biol. Chem. 2012, 287, 36609
  There is no corresponding record for this reference.
343. 343
  Devaiah, B. N.; Lewis, B. A.; Cherman, N.; Hewitt, M. C.; Albrecht, B. K.; Robey, P. G.; Ozato, K.; Sims, R. J., III; Singer, D. S. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 6927
  There is no corresponding record for this reference.
344. 344
  Palermo, R. D.; Webb, H. M.; West, M. J. PLoS Pathog. 2011, 7, e1002334
  There is no corresponding record for this reference.
345. 345
  Delmore, J. E.; Issa, G. C.; Lemieux, M. E.; Rahl, P. B.; Shi, J.; Jacobs, H. M.; Kastritis, E.; Gilpatrick, T.; Paranal, R. M.; Qi, J.; Chesi, M.; Schinzel, A. C.; McKeown, M. R.; Heffernan, T. P.; Vakoc, C. R.; Bergsagel, P. L.; Ghobrial, I. M.; Richardson, P. G.; Young, R. A.; Hahn, W. C.; Anderson, K. C.; Kung, A. L.; Bradner, J. E.; Mitsiades, C. S. Cell 2011, 146, 904
  There is no corresponding record for this reference.
346. 346
  Sachchidanand; Resnick-Silverman, L.; Yan, S.; Mutjaba, S.; Liu, W. J.; Zeng, L.; Manfredi, J. J.; Zhou, M. M. Chem. Biol. 2006, 13, 81
  346
  Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein Association
  Sachchidanand; Resnick-Silverman, Lois; Yan, Sherry; Mutjaba, Shiraz; Liu, Wen-jun; Zeng, Lei; Manfredi, James J.; Zhou, Ming-Ming
  Chemistry & Biology (Cambridge, MA, United States) (2006), 13 (1), 81-90CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small mols. that block lysine 382-acetylated p53 assocn. with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chems. were discovered in target structure-guided NMR spectroscopy screening of a focused chem. library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chems. inhibit CBP/p53 assocn. by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chems. can modulate p53 stability and function in response to doxorubicin-induced DNA damage.
347. 347
  Borah, J. C.; Mujtaba, S.; Karakikes, I.; Zeng, L.; Muller, M.; Patel, J.; Moshkina, N.; Morohashi, K.; Zhang, W.; Gerona-Navarro, G.; Hajjar, R. J.; Zhou, M. M. Chem. Biol. 2011, 18, 531
  347
  A Small Molecule Binding to the Coactivator CREB-Binding Protein Blocks Apoptosis in Cardiomyocytes
  Borah, Jagat C.; Mujtaba, Shiraz; Karakikes, Ioannis; Zeng, Lei; Muller, Michaela; Patel, Jigneshkumar; Moshkina, Natasha; Morohashi, Keita; Zhang, Weijia; Gerona-Navarro, Guillermo; Hajjar, Roger J.; Zhou, Ming-Ming
  Chemistry & Biology (Cambridge, MA, United States) (2011), 18 (4), 531-541CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  Summary: As a master transcription factor in cellular responses to external stress, tumor suppressor p53 is tightly regulated. Excessive p53 activity during myocardial ischemia causes irreversible cellular injury and cardiomyocyte death. P53 activation is dependent on lysine acetylation by the lysine acetyltransferase and transcriptional coactivator CREB-binding protein (CBP) and on acetylation-directed CBP recruitment for p53 target gene expression. Here, we report a small mol. ischemin, developed with a structure-guided approach to inhibit the acetyl-lysine binding activity of the bromodomain of CBP. We show that ischemin alters post-translational modifications on p53 and histones, inhibits p53 interaction with CBP and transcriptional activity in cells, and prevents apoptosis in ischemic cardiomyocytes. Our study suggests small mol. modulation of acetylation-mediated interactions in gene transcription as a new approach to therapeutic interventions of human disorders such as myocardial ischemia.
348. 348
  Gerona-Navarro, G.; Yoel-Rodríguez; Mujtaba, S.; Frasca, A.; Patel, J.; Zeng, L.; Plotnikov, A. N.; Osman, R.; Zhou, M. M. J. Am. Chem. Soc. 2011, 133, 2040
  There is no corresponding record for this reference.
349. 349
  Rooney, T. P.; Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Cortopassi, W. A.; Hay, D. A.; Martin, S.; Tumber, A.; Rogers, C. M.; Philpott, M.; Wang, M.; Thompson, A. L.; Heightman, T. D.; Pryde, D. C.; Cook, A.; Paton, R. S.; Müller, S.; Knapp, S.; Brennan, P. E.; Conway, S. J. Angew. Chem., Int. Ed. 2014, 53, 6126
  There is no corresponding record for this reference.
350. 350
  Fedorov, O.; Lingard, H.; Wells, C.; Monteiro, O. P.; Picaud, S.; Keates, T.; Yapp, C.; Philpott, M.; Martin, S. J.; Felletar, I.; Marsden, B. D.; Filippakopoulos, P.; Müller, S.; Knapp, S.; Brennan, P. E. J. Med. Chem. 2014, 57, 462
  There is no corresponding record for this reference.
351. 351
  Chung, C. W.; Dean, A. W.; Woolven, J. M.; Bamborough, P. J. Med. Chem. 2012, 55, 576
  There is no corresponding record for this reference.
352. 352
  Hewings, D. S.; Wang, M.; Philpott, M.; Fedorov, O.; Uttarkar, S.; Filippakopoulos, P.; Picaud, S.; Vuppusetty, C.; Marsden, B.; Knapp, S.; Conway, S. J.; Heightman, T. D. J. Med. Chem. 2011, 54, 6761
  There is no corresponding record for this reference.
353. 353
  Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Müller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E. J. Am. Chem. Soc. 2014, 136, 9308
  There is no corresponding record for this reference.
354. 354
  Dey, A.; Wong, E. T.; Cheok, C. F.; Tergaonkar, V.; Lane, D. P. Cell Death Differ. 2008, 15, 263
  354
  R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy
  Dey, A.; Wong, E. T.; Cheok, C. F.; Tergaonkar, V.; Lane, D. P.
  Cell Death and Differentiation (2008), 15 (2), 263-273CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)
  Seliciclib (CYC202, R-Roscovitine) is a 2, 6, 9-substituted purine analog that is currently in phase II clin. trials as an anticancer agent. We show in this study that R-Roscovitine can downregulate nuclear factor-kappa B (NF-κB) activation in response to tumor necrosis factor (TNF)α and interleukin 1. Activation of p53-dependent transcription is not compromised when R-Roscovitine is combined with TNFα. We characterize the mol. mechanism governing NF-κB repression and show that R-Roscovitine inhibits the IκB kinase (IKK) kinase activity, which leads to defective IκBα phosphorylation, degrdn. and hence nuclear function of NF-κB. We further show that the downregulation of the NF-κB pathway is also at the level of p65 modification and that the phosphorylation of p65 at Ser 536 is repressed by R-Roscovitine. Consistent with repression of canonical IKK signaling pathway, the induction of NF-κB target genes monocyte chemoattractant protein, intercellular adhesion mol.-1, cyclooxygenase-2 and IL-8 is also inhibited by R-Roscovitine. We further show that treatment of cells with TNFα and R-Roscovitine causes potentiation of cell death. Based on these results, we suggest the potential use of R-Roscovitine as a bitargeted anticancer drug that functions by simultaneously causing p53 activation and NF-κB suppression. This study also provides mechanistic insight into the mol. mechanism of action of R-Roscovitine, thereby possibly explaining its anti-inflammatory properties. Cell Death and Differentiation (2008) 15, 263-273; doi:10.1038/sj.cdd.4402257; published online 2 Nov. 2007.
355. 355
  Li, B. X.; Xiao, X. ChemBioChem 2009, 10, 2721
  There is no corresponding record for this reference.
356. 356
  Best, J. L.; Amezcua, C. A.; Mayr, B.; Flechner, L.; Murawsky, C. M.; Emerson, B.; Zor, T.; Gardner, K. H.; Montminy, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 17622
  There is no corresponding record for this reference.
357. 357
  Minter, A. R.; Brennan, B. B.; Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 10504
  There is no corresponding record for this reference.
358. 358
  Buhrlage, S. J.; Bates, C. A.; Rowe, S. P.; Minter, A. R.; Brennan, B. B.; Majmudar, C. Y.; Wemmer, D. E.; Al-Hashimi, H.; Mapp, A. K. ACS Chem. Biol. 2009, 4, 335
  There is no corresponding record for this reference.
359. 359
  Bates, C. A.; Pomerantz, W. C.; Mapp, A. K. Biopolymers 2011, 95, 17
  There is no corresponding record for this reference.
360. 360
  Rowe, S. P.; Casey, R. J.; Brennan, B. B.; Buhrlage, S. J.; Mapp, A. K. J. Am. Chem. Soc. 2007, 129, 10654
  There is no corresponding record for this reference.
361. 361
  Henderson, W. R., Jr.; Chi, E. Y.; Ye, X.; Nguyen, C.; Tien, Y. T.; Zhou, B.; Borok, Z.; Knight, D. A.; Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 14309
  There is no corresponding record for this reference.
362. 362
  Emami, K. H.; Nguyen, C.; Ma, H.; Kim, D. H.; Jeong, K. W.; Eguchi, M.; Moon, R. T.; Teo, J. L.; Kim, H. Y.; Moon, S. H.; Ha, J. R.; Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12682
  There is no corresponding record for this reference.
363. 363
  Sasaki, T.; Hwang, H.; Nguyen, C.; Kloner, R. A.; Kahn, M. PLoS One 2013, 8, e75010
  There is no corresponding record for this reference.
364. 364
  Hao, S.; He, W.; Li, Y.; Ding, H.; Hou, Y.; Nie, J.; Hou, F. F.; Kahn, M.; Liu, Y. J. Am. Soc. Nephrol. 2011, 22, 1642
  364
  Targeted inhibition of β-catenin/CBP signaling ameliorates renal interstitial fibrosis
  Hao, Sha; He, Weichun; Li, Yingjian; Ding, Hong; Hou, Yayi; Nie, Jing; Hou, Fan Fan; Kahn, Michael; Liu, Youhua
  Journal of the American Society of Nephrology (2011), 22 (9), 1642-1653CODEN: JASNEU; ISSN:1046-6673. (American Society of Nephrology)
  Because fibrotic kidneys exhibit aberrant activation of β-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examd. the effects of β-catenin activation on tubular epithelial-mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small mol. ICG-001, which specifically disrupts β-catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized β-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed β-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-β1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and α-smooth muscle actin (α-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, α-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting β-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases.
365. 365
  Majmudar, C. Y.; Højfeldt, J. W.; Arevang, C. J.; Pomerantz, W. C.; Gagnon, J. K.; Schultz, P. J.; Cesa, L. C.; Doss, C. H.; Rowe, S. P.; Vásquez, V.; Tamayo-Castillo, G.; Cierpicki, T.; Brooks, C. L., III; Sherman, D. H.; Mapp, A. K. Angew. Chem., Int. Ed. 2012, 51, 11258
  There is no corresponding record for this reference.
366. 366
  Kung, A. L.; Zabludoff, S. D.; France, D. S.; Freedman, S. J.; Tanner, E. A.; Vieira, A.; Cornell-Kennon, S.; Lee, J.; Wang, B.; Wang, J.; Memmert, K.; Naegeli, H. U.; Petersen, F.; Eck, M. J.; Bair, K. W.; Wood, A. W.; Livingston, D. M. Cancer Cell 2004, 6, 33
  366
  Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway
  Kung, Andrew L.; Zabludoff, Sonya D.; France, Dennis S.; Freedman, Steven J.; Tanner, Elizabeth A.; Vieira, Annelisa; Cornell-Kennon, Susan; Lee, Jennifer; Wang, Beqing; Wang, Jamin; Memmert, Klaus; Naegeli, Hans-Ulrich; Petersen, Frank; Eck, Michael J.; Bair, Kenneth W.; Wood, Alexander W.; Livingston, David M.
  Cancer Cell (2004), 6 (1), 33-43CODEN: CCAECI; ISSN:1535-6108. (Cell Press)
  Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, the authors identified chetomin as a disrupter of HIF binding to p300. At a mol. level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacol. attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small mol.
367. 367
  Block, K. M.; Wang, H.; Szabó, L. Z.; Polaske, N. W.; Henchey, L. K.; Dubey, R.; Kushal, S.; László, C. F.; Makhoul, J.; Song, Z.; Meuillet, E. J.; Olenyuk, B. Z. J. Am. Chem. Soc. 2009, 131, 18078
  There is no corresponding record for this reference.
368. 368
  Yin, S.; Kaluz, S.; Devi, N. S.; Jabbar, A. A.; de Noronha, R. G.; Mun, J.; Zhang, Z.; Boreddy, P. R.; Wang, W.; Wang, Z.; Abbruscato, T.; Chen, Z.; Olson, J. J.; Zhang, R.; Goodman, M. M.; Nicolaou, K. C.; Van Meir, E. G. Clin. Cancer Res. 2012, 18, 6623
  368
  Arylsulfonamide KCN1 Inhibits In Vivo Glioma Growth and Interferes with HIF Signaling by Disrupting HIF-1α Interaction with Cofactors p300/CBP
  Yin, Shaoman; Kaluz, Stefan; Devi, Narra S.; Jabbar, Adnan A.; de Noronha, Rita G.; Mun, Jiyoung; Zhang, Zhaobin; Boreddy, Purushotham R.; Wang, Wei; Wang, Zhibo; Abbruscato, Thomas; Chen, Zhengjia; Olson, Jeffrey J.; Zhang, Ruiwen; Goodman, Mark M.; Nicolaou, K. C.; Van Meir, Erwin G.
  Clinical Cancer Research (2012), 18 (24), 6623-6633CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  Purpose: The hypoxia-inducible factor-1 (HIF-1) plays a crit. role in tumor adaptation to hypoxia, and its elevated expression correlates with poor prognosis and treatment failure in patients with cancer. In this study, we detd. whether 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1, the lead inhibitor in a novel class of arylsulfonamide inhibitors of the HIF-1 pathway, had antitumorigenic properties in vivo and further defined its mechanism of action. Exptl. Design: We studied the inhibitory effect of systemic KCN1 delivery on the growth of human brain tumors in mice. To define mechanisms of KCN1 anti-HIF activities, we examd. its influence on the assembly of a functional HIF-1α/HIF-1β/p300 transcription complex. Results: KCN1 specifically inhibited HIF reporter gene activity in several glioma cell lines at the nanomolar level. KCN1 also downregulated transcription of endogenous HIF-1 target genes, such as VEGF, Glut-1, and carbonic anhydrase 9, in a hypoxia-responsive element (HRE)-dependent manner. KCN1 potently inhibited the growth of s.c. malignant glioma tumor xenografts with minimal adverse effects on the host. It also induced a temporary survival benefit in an intracranial model of glioma but had no effect in a model of melanoma metastasis to the brain. Mechanistically, KCN1 did not downregulate the levels of HIF-1α or other components of the HIF transcriptional complex; rather, it antagonized hypoxia-inducible transcription by disrupting the interaction of HIF-1α with transcriptional coactivators p300/CBP. Conclusions: Our results suggest that the new HIF pathway inhibitor KCN1 has antitumor activity in mouse models, supporting its further translation for the treatment of human tumors displaying hypoxia or HIF overexpression.
369. 369
  Tanaka, Y.; Naruse, I.; Maekawa, T.; Masuya, H.; Shiroishi, T.; Ishii, S. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 10215
  There is no corresponding record for this reference.
370. 370
  Yao, T. P.; Oh, S. P.; Fuchs, M.; Zhou, N. D.; Ch’ng, L. E.; Newsome, D.; Bronson, R. T.; Li, E.; Livingston, D. M.; Eckner, R. Cell 1998, 93, 361
  There is no corresponding record for this reference.
371. 371
  Roelfsema, J. H.; Peters, D. J. Expert Rev. Mol. Med. 2007, 9, 1
  371
  Rubinstein-Taybi syndrome: clinical and molecular overview
  Roelfsema Jeroen H; Peters Dorien J M
  Expert reviews in molecular medicine (2007), 9 (23), 1-16 ISSN:.
  Rubinstein-Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100,000 newborns. Mutations in two genes - CREBBP and EP300 - have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein-Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein-Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.
372. 372
  Qaksen, H.; Bartsch, O.; Okur, M.; Temel, H.; Açikgoz, M.; Yilmaz, C. Genet. Couns. 2009, 20, 255
  There is no corresponding record for this reference.
373. 373
  Viosca, J.; Lopez-Atalaya, J. P.; Olivares, R.; Eckner, R.; Barco, A. Neurobiol. Dis. 2010, 37, 186
  373
  Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology
  Viosca Jose; Lopez-Atalaya Jose P; Olivares Roman; Eckner Richard; Barco Angel
  Neurobiology of disease (2010), 37 (1), 186-94 ISSN:.
  Rubinstein-Taybi syndrome (RSTS) is a complex autosomal-dominant disease characterized by mental and growth retardation and skeletal abnormalities. A majority of the individuals diagnosed with RSTS carry heterozygous mutation in the gene CREBBP, but a small percentage of cases are caused by mutations in EP300. To investigate the contribution of p300 to RSTS pathoetiology, we carried out a comprehensive and multidisciplinary characterization of p300(+/-) mice. These mice exhibited facial abnormalities and impaired growth, two traits associated to RSTS in humans. We also observed abnormal gait, reduced swimming speed, enhanced anxiety in the elevated plus maze, and mild cognitive impairment during the transfer task in the water maze. These analyses demonstrate that p300(+/-) mice exhibit phenotypes that are reminiscent of neurological traits observed in RSTS patients, but their comparison with previous studies on CBP deficient strains also indicates that, in agreement with the most recent findings in human patients, the activity of p300 in cognition is likely less relevant or more susceptible to compensation than the activity of CBP.
374. 374
  Roelfsema, J. H.; Peters, D. J. Expert Rev. Mol. Med. 2007, 9, 1
  374
  Rubinstein-Taybi syndrome: clinical and molecular overview
  Roelfsema Jeroen H; Peters Dorien J M
  Expert reviews in molecular medicine (2007), 9 (23), 1-16 ISSN:.
  Rubinstein-Taybi syndrome is characterised by mental retardation, growth retardation and a particular dysmorphology. The syndrome is rare, with a frequency of approximately one affected individual in 100,000 newborns. Mutations in two genes - CREBBP and EP300 - have been identified to cause the syndrome. These two genes show strong homology and encode histone acetyltransferases (HATs), which are transcriptional co-activators involved in many signalling pathways. Loss of HAT activity is sufficient to account for the phenomena seen in Rubinstein-Taybi patients. Although some mutations found in CREBBP are translocations, inversions and large deletions, most are point mutations or small deletions and insertions. Mutations in EP300 are comparatively rare. Extensive screening of patients has revealed mutations in CREBBP and EP300 in around 50% of cases. The cause of the syndrome in the remaining patients remains to be identified, but other genes could also be involved. Here, we describe the clinical presentation of Rubinstein-Taybi syndrome, review the mutation spectrum and discuss the current understanding of causative molecular mechanisms.
375. 375
  Gervasini, C.; Mottadelli, F.; Ciccone, R.; Castronovo, P.; Milani, D.; Scarano, G.; Bedeschi, M. F.; Belli, S.; Pilotta, A.; Selicorni, A.; Zuffardi, O.; Larizza, L. Eur. J. Hum. Genet. 2010, 18, 768
  375
  High frequency of copy number imbalances in Rubinstein-Taybi patients negative to CREBBP mutational analysis
  Gervasini, Cristina; Mottadelli, Federica; Ciccone, Roberto; Castronovo, Paola; Milani, Donatella; Scarano, Gioacchino; Bedeschi, Maria Francesca; Belli, Serena; Pilotta, Alba; Selicorni, Angelo; Zuffardi, Orsetta; Larizza, Lidia
  European Journal of Human Genetics (2010), 18 (7), 768-775CODEN: EJHGEU; ISSN:1018-4813. (Nature Publishing Group)
  Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder characterized by facial dysmorphisms, growth and psychomotor development delay, and skeletal defects. The known genetic causes are point mutations or deletions of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal rearrangements indicating novel positional candidate RSTS genes, we used a-CGH to study 26 patients fulfilling the diagnostic criteria for RSTS who were neg. at fluorescence in situ hybridization analyses of the CREBBP and EP300 regions, and direct sequencing analyses of the CREBBP gene. We found seven imbalances (27%): Four de novo and three inherited rearrangements not reported among the copy no. variants. A de novo 7p21.1 deletion of 500 kb included the TWIST1 gene, a suggested candidate for RSTS that is responsible for the Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate genes could not be sought in the remaining pathogenetic imbalances, because of the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the inherited rearrangements, the 17q11.2 379Kb duplication, represents the reciprocal event of the deletion underlying an overgrowth syndrome, both being mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this and the other detected CNVs to the clin. RSTS phenotype is difficult to assess.
376. 376
  Foley, P.; Bunyan, D.; Stratton, J.; Dillon, M.; Lynch, S. A. Am. J. Med. Genet., Part A 2009, 149A, 997
  376
  Further case of Rubinstein-Taybi syndrome due to a deletion in EP300
  Foley, Patricia; Bunyan, David; Stratton, John; Dillon, Michelle; Lynch, Sally Ann
  American Journal of Medical Genetics, Part A (2009), 149A (5), 997-1000CODEN: AJMGB8; ISSN:1552-4825. (Wiley-Liss, Inc.)
  Rubinstein-Taybi syndrome (RSTS) is a heterogeneous disorder with approx. 45-55% of patients showing mutations in the CREB binding protein and a further 3% of patients having mutations in EP300. We report a male child with a deletion of exons 3-8 of the EP300 gene who has RSTS. He has a milder skeletal phenotype, a finding that has been described in other cases with EP300 mutations. The mother suffered from preeclampsia and HELLP syndrome in the pregnancy. She subsequently developed a mullerian tumor of her cervix 6 years after the birth of her son.
377. 377
  Bartholdi, D.; Roelfsema, J. H.; Papadia, F.; Breuning, M. H.; Niedrist, D.; Hennekam, R. C.; Schinzel, A.; Peters, D. J. J. Med. Genet. 2007, 44, 327
  377
  Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300
  Bartholdi, Deborah; Roelfsema, Jeroen H.; Papadia, Francesco; Breuning, Martijn H.; Niedrist, Dunja; Hennekam, Raoul C.; Schinzel, Albert; Peters, Dorien J. M.
  Journal of Medical Genetics (2007), 44 (5), 327-333CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
  Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is assocd. with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically obsd. in patients with RSTS. Part of the clin. variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.
378. 378
  Tsai, A. C.; Dossett, C. J.; Walton, C. S.; Cramer, A. E.; Eng, P. A.; Nowakowska, B. A.; Pursley, A. N.; Stankiewicz, P.; Wiszniewska, J.; Cheung, S. W. Eur. J. Hum. Genet. 2011, 19, 43
  378
  Exon deletions of the EP300 and CREBBP genes in two children with Rubinstein-Taybi syndrome detected by aCGH
  Tsai Anne Chun-Hui; Dossett Cherilyn J; Walton Carol S; Cramer Andrea E; Eng Patti A; Nowakowska Beata A; Pursley Amber N; Stankiewicz Pawel; Wiszniewska Joanna; Cheung Sau Wai
  European journal of human genetics : EJHG (2011), 19 (1), 43-9 ISSN:.
  We demonstrate the utility of an exon coverage microarray platform in detecting intragenic deletions: one in exons 24-27 of the EP300 gene and another in exons 27 and 28 of the CREBBP gene in two patients with Rubinstein-Taybi syndrome (RSTS). RSTS is a heterogeneous disorder in which approximately 45-55% of cases result from deletion or mutations in the CREBBP gene and an unknown portion of cases result from gene changes in EP300. The first case is a 3-year-old female with an exonic deletion of the EP300 gene who has classic facial features of RSTS without the thumb and great toe anomalies, consistent with the milder skeletal phenotype that has been described in other RSTS cases with EP300 mutations. In addition, the mother of this patient also had preeclampsia during pregnancy, which has been infrequently reported. The second case is a newborn male who has the classical features of RSTS. Our results illustrate that exon-targeted array comparative genomic hybridization (aCGH) is a powerful tool for detecting clinically significant intragenic rearrangements that would be otherwise missed by aCGH platforms lacking sufficient exonic coverage or sequencing of the gene of interest.
379. 379
  Zimmermann, N.; Acosta, A. M.; Kohlhase, J.; Bartsch, O. Eur. J. Hum. Genet. 2007, 15, 837
  379
  Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome
  Zimmermann, Nicole; Acosta, Ana Maria Bravo Ferrer; Kohlhase, Juergen; Bartsch, Oliver
  European Journal of Human Genetics (2007), 15 (8), 837-842CODEN: EJHGEU; ISSN:1018-4813. (Nature Publishing Group)
  The Rubinstein-Taybi syndrome (RSTS, MIM 180849), a dominant Mendelian disorder with typical face, short stature, skeletal abnormalities, and mental retardation, is usually caused by heterozygous mutations of the CREBBP gene, but recently, EP300 gene mutations were reported in three individuals. Using quant. PCR (for the CREBBP and EP300 genes) and genomic sequencing (for the EP300 gene), we studied here 13 patients who had shown no mutation after genomic sequencing of the CREBBP gene in a previous investigation. Two new disease-causing mutations were identified, including a partial deletion of CREBBP and a 1-bp deletion in EP300, c.7100delC (p.P2366fsX2401). The 1-bp deletion represents the fourth EP300 mutation reported to date and was identified in a patient with non-classical RSTS. Based on the very similar structure of the CREBBP and EP300 genes and the higher rate of single-nucleotide polymorphisms in EP300 (2.23 per individual) as compared to CREBBP (0.71 per individual) (P>0.001, Wilcoxon test), it may be assumed that EP300 gene mutations should be as frequent as CREBBP gene mutations. Based on the location of the EP300 gene mutations identified so far (outside the histone acetyl transferase domain) and the obsd. (although not very striking) phenotypical differences with the EP300 mutations, we propose that most EP300 mutations could be assocd. with other phenotypes, not classical RSTS.
380. 380
  Bartholdi, D.; Roelfsema, J. H.; Papadia, F.; Breuning, M. H.; Niedrist, D.; Hennekam, R. C.; Schinzel, A.; Peters, D. J. J. Med. Genet. 2007, 44, 327
  380
  Genetic heterogeneity in Rubinstein-Taybi syndrome: delineation of the phenotype of the first patients carrying mutations in EP300
  Bartholdi, Deborah; Roelfsema, Jeroen H.; Papadia, Francesco; Breuning, Martijn H.; Niedrist, Dunja; Hennekam, Raoul C.; Schinzel, Albert; Peters, Dorien J. M.
  Journal of Medical Genetics (2007), 44 (5), 327-333CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
  Rubinstein-Taybi syndrome (RSTS) is a congenital disorder characterised by growth retardation, facial dysmorphisms, skeletal abnormalities and mental retardation. Broad thumbs and halluces are the hallmarks of the syndrome. RSTS is assocd. with chromosomal rearrangements and mutations in the CREB-binding protein gene (CREBBP), also termed CBP, encoding the CREB-binding protein. Recently, it was shown that mutations in EP300, coding for the p300 protein, also cause RSTS. CBP and EP300 are highly homologous genes, which play important roles as global transcriptional coactivators. To report the phenotype of the presently known patients with RSTS (n = 4) carrying germline mutations of EP300. The patients with EP300 mutations displayed the typical facial gestalt and malformation pattern compatible with the diagnosis of RSTS. However, three patients exhibited much milder skeletal findings on the hands and feet than typically obsd. in patients with RSTS. Part of the clin. variability in RSTS is explained by genetic heterogeneity. The diagnosis of RSTS must be expanded to include patients without broad thumbs or halluces.
381. 381
  Lopez-Atalaya, J. P.; Gervasini, C.; Mottadelli, F.; Spena, S.; Piccione, M.; Scarano, G.; Selicorni, A.; Barco, A.; Larizza, L. J. Med. Genet. 2012, 49, 66
  381
  Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome
  Lopez-Atalaya, J. P.; Gervasini, C.; Mottadelli, F.; Spena, S.; Piccione, M.; Scarano, G.; Selicorni, A.; Barco, A.; Larizza, L.
  Journal of Medical Genetics (2012), 49 (1), 66-74CODEN: JMDGAE; ISSN:0022-2593. (BMJ Publishing Group)
  Background: Rubinstein-Taybi syndrome (RSTS) is a congenital neurodevelopmental disorder defined by postnatal growth deficiency, characteristic skeletal abnormalities and mental retardation and caused by mutations in the genes encoding for the transcriptional co-activators with intrinsic lysine acetyltransferase (KAT) activity CBP and p300. Previous studies have shown that neuronal histone acetylation is reduced in mouse models of RSTS. Methods: The authors identified different mutations at the CREBBP locus and generated lymphoblastoid cell lines derived from nine patients with RSTS carrying distinct CREBBP mutations that illustrate different grades of the clin. severity in the spectrum of the syndrome. They next assessed whether histone acetylation levels were altered in these cell lines. Results: The comparison of CREBBP-mutated RSTS cell lines with cell lines derived from patients with an unrelated mental retardation syndrome or healthy controls revealed significant deficits in histone acetylation, affecting primarily histone H2B and histone H2A. The most severe defects were obsd. in the lines carrying the whole deletion of the CREBBP gene and the truncating mutation, both leading to a haploinsufficiency state. Interestingly, this deficit was rescued by treatment with an inhibitor of histone deacetylases (HDACi). Conclusions: The authors' results extend to humans the seminal observations in RSTS mouse models and point to histone acetylation defects, mainly involving H2B and H2A, as relevant mol. markers of the disease.
382. 382
  Miller, R. W.; Rubinstein, J. H. Am. J. Med. Genet. 1995, 56, 112
  382
  Tumors in Rubinstein-Taybi syndrome
  Miller R W; Rubinstein J H
  American journal of medical genetics (1995), 56 (1), 112-5 ISSN:0148-7299.
  The 14 tumors reported in Rubinstein-Taybi syndrome since 1989, when added to the 22 previously reported, are beginning to show a pattern of neural and developmental tumors, especially of the head, which is malformed in the syndrome. Among the neoplasms were 12 of the nervous system: 2 each of oligodendroglioma, medulloblastoma, neuroblastoma, and benign meningioma, a pheochromocytoma, and 3 other benign tumors; 2 of nasopharyngeal rhabdomyosarcoma; and 1 each of leiomyosarcoma, seminoma, and embryonal carcinoma. Among the other benign tumors were an odontoma, a choristoma, a dermoid cyst, and 2 pilomatrixomas.
383. 383
  Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
  383
  p300/CBP and cancer
  Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
  Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
  A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
384. 384
  Tillinghast, G. W.; Partee, J.; Albert, P.; Kelley, J. M.; Burtow, K. H.; Kelly, K. Genes, Chromosomes Cancer 2003, 37, 121
  384
  Analysis of genetic stability at the EP300 and CREBBP loci in a panel of cancer cell lines
  Tillinghast, Guy W.; Partee, Jason; Albert, Paul; Kelley, Jenny M.; Burtow, Kenneth H.; Kelly, Kathleen
  Genes, Chromosomes & Cancer (2003), 37 (2), 121-131CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
  EP300 (p300) and CREBBP (CBP) are highly related transcriptional co-activators possessing histone acetyltransferase activity. These proteins have been implicated in coordinating numerous transcriptional responses that are important in the processes of proliferation and differentiation. A role for EP300 and CREBBP as tumor suppressors in cancer has been suggested by the fact that they are targeted by viral oncogenes; there is an increased incidence of hematol. malignancies in mice monoallelic for CREBBP; and loss, albeit at a low frequency, of both EP300 alleles in epithelial cancers has been obsd. Because the level of EP300/CREBBP appears to have a crit. effect on integrating certain transcriptional processes, we sought to det. whether a loss in the combined gene dosage of EP300 and CREBBP might play a role in cancer. Accordingly, we screened a panel of 103 cell lines for loss of heterozygosity and found 35 and 51% LOH for the CREBBP and EP300 loci, resp. Concordant loss of CREBBP and EP300 was not assocd. with mutations in important regions of the remaining EP300 or CREBBP genes. In addn., there did not appear to be a statistically significant selection in cancer cells, stratified by various criteria, for the concordant loss of EP300 and CREBBP. We conclude that EP300 and CREBBP rarely act as classical tumor suppressors in human cancer.
385. 385
  Bryan, E. J.; Jokubaitis, V. J.; Chamberlain, N. L.; Baxter, S. W.; Dawson, E.; Choong, D. Y.; Campbell, I. G. Int. J. Cancer 2002, 102, 137
  385
  Mutation analysis of EP300 in colon, breast and ovarian carcinomas
  Bryan, Emma J.; Jokubaitis, Venta J.; Chamberlain, Narelle L.; Baxter, Simon W.; Dawson, Elisabeth; Choong, David Y. H.; Campbell, Ian G.
  International Journal of Cancer (2002), 102 (2), 137-141CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
  The putative tumor suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. The authors analyzed 203 human breast, colon and ovarian primary tumors and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumors but no somatic mutations in EP300 were identified in any primary tumor. Anal. of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). The authors confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbors an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot anal. confirmed the presence of an apparently wild-type protein. The authors' study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harboring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumor types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.
386. 386
  Muraoka, M.; Konishi, M.; Kikuchi-Yanoshita, R.; Tanaka, K.; Shitara, N.; Chong, J. M.; Iwama, T.; Miyaki, M. Oncogene 1996, 12, 1565
  There is no corresponding record for this reference.
387. 387
  Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
  387
  p300/CBP and cancer
  Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
  Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
  A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
388. 388
  Pasqualucci, L.; Dominguez-Sola, D.; Chiarenza, A.; Fabbri, G.; Grunn, A.; Trifonov, V.; Kasper, L. H.; Lerach, S.; Tang, H.; Ma, J.; Rossi, D.; Chadburn, A.; Murty, V. V.; Mullighan, C. G.; Gaidano, G.; Rabadan, R. Nature 2011, 471, 189
  There is no corresponding record for this reference.
389. 389
  Kishimoto, M.; Kohno, T.; Okudela, K.; Otsuka, A.; Sasaki, H.; Tanabe, C.; Sakiyama, T.; Hirama, C.; Kitabayashi, I.; Minna, J. D.; Takenoshita, S.; Yokota, J. Clin. Cancer Res. 2005, 11, 512
  389
  Mutations and deletions of the CBP gene in human lung cancer
  Kishimoto, Masahiro; Kohno, Takashi; Okudela, Koji; Otsuka, Ayaka; Sasaki, Hiroki; Tanabe, Chikako; Sakiyama, Tokuki; Hirama, Chie; Kitabayashi, Issay; Minna, John D.; Takenoshita, Seiichi; Yokota, Jun
  Clinical Cancer Research (2005), 11 (2, Pt. 1), 512-519CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
  Microarray-based comparative genomic hybridization anal. led us to detect a homozygous deletion at the cAMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive anal. of genetic CBP alterations in human lung cancer. Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene. Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examd. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant redn. in transcription activation activity of CBP protein in vivo. A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.
390. 390
  Suganuma, T.; Kawabata, M.; Ohshima, T.; Ikeda, M. A. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13073
  There is no corresponding record for this reference.
391. 391
  Mullighan, C. G.; Zhang, J.; Kasper, L. H.; Lerach, S.; Payne-Turner, D.; Phillips, L. A.; Heatley, S. L.; Holmfeldt, L.; Collins-Underwood, J. R.; Ma, J.; Buetow, K. H.; Pui, C. H.; Baker, S. D. Nature 2011, 471, 235
  There is no corresponding record for this reference.
392. 392
  Sánchez-Molina, S.; Oliva, J. L.; García-Vargas, S.; Valls, E.; Rojas, J. M.; Martínez-Balbás, M. A. Biochem. J. 2006, 398, 215
  There is no corresponding record for this reference.
393. 393
  Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
  393
  p300/CBP and cancer
  Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
  Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
  A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
394. 394
  Fan, S.; Ma, Y. X.; Wang, C.; Yuan, R. Q.; Meng, Q.; Wang, J. A.; Erdos, M.; Goldberg, I. D.; Webb, P.; Kushner, P. J.; Pestell, R. G.; Rosen, E. M. Cancer Res. 2002, 62, 141
  There is no corresponding record for this reference.
395. 395
  Liang, J.; Prouty, L.; Williams, B. J.; Dayton, M. A.; Blanchard, K. L. Blood 1998, 92, 2118
  There is no corresponding record for this reference.
396. 396
  Carapeti, M.; Aguiar, R. C.; Goldman, J. M.; Cross, N. C. Blood 1998, 91, 3127
  There is no corresponding record for this reference.
397. 397
  Kindle, K. B.; Troke, P. J.; Collins, H. M.; Matsuda, S.; Bossi, D.; Bellodi, C.; Kalkhoven, E.; Salomoni, P.; Pelicci, P. G.; Minucci, S.; Heery, D. M. Mol. Cell. Biol. 2005, 25, 988
  397
  MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function
  Kindle, Karin B.; Troke, Philip J. F.; Collins, Hilary M.; Matsuda, Sachiko; Bossi, Daniela; Bellodi, Cristian; Kalkhoven, Eric; Salomoni, Paolo; Pelicci, Pier Giuseppe; Minucci, Saverio; Heery, David M.
  Molecular and Cellular Biology (2005), 25 (3), 988-1002CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  Chromosomal rearrangements assocd. with acute myeloid leukemia (AML) include fusions of the genes encoding the acetyltransferase MOZ or MORF with genes encoding the nuclear receptor coactivator TIF2, p300, or CBP. Here we show that MOZ-TIF2 acts as a dominant inhibitor of the transcriptional activities of CBP-dependent activators such as nuclear receptors and p53. The dominant neg. property of MOZ-TIF2 requires the CBP-binding domain (activation domain 1 [AD1]), and coimmunopptn. and fluorescent resonance energy transfer expts. show that MOZ-TIF2 interacts with CBP directly in vivo. The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-neg. cells in vitro. We show that MOZ-TIF2 displays an aberrant nuclear distribution and that cells expressing this protein have reduced levels of cellular CBP, leading to depletion of CBP from PML bodies. In summary, our results indicate that disruption of the normal function of CBP and CBP-dependent activators is an important feature of MOZ-TIF2 action in AML.
398. 398
  Ito, Y.; Miyazono, K. Curr. Opin. Genet. Dev. 2003, 13, 43
  There is no corresponding record for this reference.
399. 399
  Grossman, S. R. Eur. J. Biochem. 2001, 268, 2773
  399
  p300/CBP/p53 interaction and regulation of the p53 response
  Grossman, Steven R.
  European Journal of Biochemistry (2001), 268 (10), 2773-2778CODEN: EJBCAI; ISSN:0014-2956. (Blackwell Science Ltd.)
  A review with 50 refs. Substantial evidence points to a crit. role for the p300/CREB binding protein (CBP) co-activators in p53 responses to DNA damage. The p300/CBP and the assocd. protein P/CAF bind to and acetylate p53 during the DNA damage response, and are needed for full p53 transactivation as well as downstream p53 effects of growth arrest and/or apoptosis. Beyond this simplistic model, p300/CBP appear to be complex integrators of signals that regulate p53, and biochem., the multipartite p53/p300/CBP interaction is equally complex. Through phys. interaction with p53, p300/CBP can both pos. and neg. regulate p53 transactivation, as well as p53 protein turnover depending on cellular context and environmental stimuli, such as DNA damage.
400. 400
  Iyer, N. G.; Xian, J.; Chin, S. F.; Bannister, A. J.; Daigo, Y.; Aparicio, S.; Kouzarides, T.; Caldas, C. Oncogene 2007, 26, 21
  There is no corresponding record for this reference.
401. 401
  Galbiati, L.; Mendoza-Maldonado, R.; Gutierrez, M. I.; Giacca, M. Cell Cycle 2005, 4, 930
  There is no corresponding record for this reference.
402. 402
  Oike, Y.; Hata, A.; Mamiya, T.; Kaname, T.; Noda, Y.; Suzuki, M.; Yasue, H.; Nabeshima, T.; Araki, K.; Yamamura, K. Hum. Mol. Genet. 1999, 8, 387
  402
  Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism
  Oike, Yuichi; Hata, Akira; Mamiya, Takayoshi; Kaname, Tadashi; Noda, Yukihiro; Suzuki, Misao; Yasue, Hirofumi; Nabeshima, Toshitaka; Araki, Kimi; Yamamura, Ken-Ichi
  Human Molecular Genetics (1999), 8 (3), 387-396CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
  A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cAMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) contg. the CREB-binding domain (residues 462-661), showed clin. features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-neg. inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP+/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.
403. 403
  Viosca, J.; Lopez-Atalaya, J. P.; Olivares, R.; Eckner, R.; Barco, A. Neurobiol. Dis. 2010, 37, 186
  403
  Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology
  Viosca Jose; Lopez-Atalaya Jose P; Olivares Roman; Eckner Richard; Barco Angel
  Neurobiology of disease (2010), 37 (1), 186-94 ISSN:.
  Rubinstein-Taybi syndrome (RSTS) is a complex autosomal-dominant disease characterized by mental and growth retardation and skeletal abnormalities. A majority of the individuals diagnosed with RSTS carry heterozygous mutation in the gene CREBBP, but a small percentage of cases are caused by mutations in EP300. To investigate the contribution of p300 to RSTS pathoetiology, we carried out a comprehensive and multidisciplinary characterization of p300(+/-) mice. These mice exhibited facial abnormalities and impaired growth, two traits associated to RSTS in humans. We also observed abnormal gait, reduced swimming speed, enhanced anxiety in the elevated plus maze, and mild cognitive impairment during the transfer task in the water maze. These analyses demonstrate that p300(+/-) mice exhibit phenotypes that are reminiscent of neurological traits observed in RSTS patients, but their comparison with previous studies on CBP deficient strains also indicates that, in agreement with the most recent findings in human patients, the activity of p300 in cognition is likely less relevant or more susceptible to compensation than the activity of CBP.
404. 404
  Kung, A. L.; Rebel, V. I.; Bronson, R. T.; Ch’ng, L. E.; Sieff, C. A.; Livingston, D. M.; Yao, T. P. Genes Dev. 2000, 14, 272
  There is no corresponding record for this reference.
405. 405
  Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
  405
  Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
  Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
  Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
406. 406
  Rebel, V. I.; Kung, A. L.; Tanner, E. A.; Yang, H.; Bronson, R. T.; Livingston, D. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14789
  There is no corresponding record for this reference.
407. 407
  Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
  407
  Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
  Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
  Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
408. 408
  Qiao, Y.; Molina, H.; Pandey, A.; Zhang, J.; Cole, P. A. Science 2006, 311, 1293
  There is no corresponding record for this reference.
409. 409
  Liao, Z. W.; Zhou, T. C.; Tan, X. J.; Song, X. L.; Liu, Y.; Shi, X. Y.; Huang, W. J.; Du, L. L.; Tu, B. J.; Lin, X. D. J. Transl. Med. 2012, 10, 110
  409
  High expression of p300 is linked to aggressive features and poor prognosis of nasopharyngeal carcinoma
  Liao, Zhi-Wei; Zhou, Tong-Chong; Tan, Xiao-Jun; Song, Xian-Lu; Liu, Yuan; Shi, Xing-Yuan; Huang, Wen-Jin; Du, Li-Li; Tu, Bo-Jun; Lin, Xiao-Dan
  Journal of Translational Medicine (2012), 10 (), 110CODEN: JTMOBV; ISSN:1479-5876. (BioMed Central Ltd.)
  Background: Increased expression of transcriptional coactivator p300 has been obsd. in a variety of human cancers. However, the expression status of p300 protein/mRNA in nasopharyngeal carcinoma (NPC) tissues and its clinicopathol./prognostic implication are poorly understood. Methods: In our study, mRNA and protein expression levels of p300 was explored by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting (WB) and immunohistochem. (IHC) in nasopharyngeal mucosal and NPC tissues. The data were analyzed by receiver operating characteristic (ROC) curve anal., spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model. Results: Up-regulated expression of p300 mRNA/p300 protein was detected in NPC tissues by RT-PCR and WB, when compared to nasopharyngeal mucosal tissues. Based on ROC curve anal., the cutoff score for p300 high expression was defined when more than 35% of the tumor cells were pos. stained. High expression of p300 was obsd. in 127/209 (60.7%) of NPCs. In NPCs, high expression of p300 was pos. assocd. with later T classification, later N classification, distant metastasis and later clin. stage (P < 0.05). In univariate survival anal., overexpression of p300 was found to be an indicator of progression-free (P = 0.002) and overall survival (P = 0.001) in NPCs. More importantly, p300 expression was evaluated as an independent prognostic factor for NPC in multivariate anal. (P = 0.036). Conclusions: Our findings support that high expression of p300 protein might be important in conferring a more aggressive behavior, and is an independent mol. marker for shortened survival time of patients with NPC.
410. 410
  Li, M.; Luo, R. Z.; Chen, J. W.; Cao, Y.; Lu, J. B.; He, J. H.; Wu, Q. L.; Cai, M. Y. J. Transl. Med. 2011, 9, 5
  410
  High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma
  Li, Mei; Luo, Rong-Zhen; Chen, Jie-Wei; Cao, Yun; Lu, Jia-Bin; He, Jie-Hua; Wu, Qiu-Liang; Cai, Mu-Yan
  Journal of Translational Medicine (2011), 9 (), 5CODEN: JTMOBV; ISSN:1479-5876. (BioMed Central Ltd.)
  Background: It has been suggested that p300 participates in the regulation of a wide range of cell biol. processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clin./prognostic significance are unclear. Methods: In this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochem. (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve anal., spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results: Up-regulated expression of p300 mRNA and protein was obsd. in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were pos. stained. High expression of p300 was examd. in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival anal., a significant assocn. between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate anal. (P = 0.021). Consequently, a new clinicopathol. prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001). Conclusions: Our findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examd. by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathol. prognostic model may become a useful tool for identifying HCC patients with different clin. outcomes.
411. 411
  Vleugel, M. M.; Shvarts, D.; van der Wall, E.; van Diest, P. J. Hum. Pathol. 2006, 37, 1085
  411
  p300 and p53 levels determine activation of HIF-1 downstream targets in invasive breast cancer
  Vleugel, Marije M.; Shvarts, David; van der Wall, Elsken; van Diest, Paul J.
  Human Pathology (2006), 37 (8), 1085-1092CODEN: HPCQA4; ISSN:0046-8177. (Elsevier Inc.)
  In previous studies, we noted that overexpression of hypoxia-inducible factor (HIF)-1α in breast cancer, esp. the diffuse form, does not always lead to functional activation of its downstream genes. Transcriptional activity of HIF-1 may be repressed by p53 through competition for transcriptional coactivators such as p300. The aim of this study was therefore to explore the role of p53 and p300 in relation to overexpression of HIF-1α and activation of HIF-1 downstream genes in invasive breast cancer. p300 immunohistochem. was performed in a group of 183 early-stage invasive breast cancers, and related to p53 accumulation, overexpression of HIF-1α, and several HIF-1 downstream genes. p300 was expressed in varying degrees in 84% of invasive breast cancers. p300 staining intensity correlated pos. with HIF-1α expression (P = .04), p53 accumulation (P = .001), and overexpression of glucose transporter 1 (GLUT-1) (P < .001), a glucose transporter downstream target gene of HIF-1. GLUT-1 levels were significantly assocd. with p300 in HIF-1α pos. patients (P = .02). p53 accumulation significantly pos. correlated with carbonic anhydrase IX (CAIX)/GLUT-1 coexpression in HIF-1α-pos. patients (P = .007). p53 accumulation/high p300 levels, the most favorable situation for HIF-1 downstream activation, were significantly assocd. with GLUT-1 overexpression (P = .01) and coexpression of CAIX/GLUT-1 (P = .03), compared with low p53/low p300 levels, the most unfavorable situation for HIF-1 downstream activation. p300 is a cofactor highly assocd. with p53 accumulation and HIF-1α levels in invasive breast cancer. Furthermore, low levels of p300 may explain absence of downstream effects in HIF-1α-overexpressing cancers, an effect that seems to be enhanced by wild-type levels of p53. This underlines the importance of p300 levels and p53 accumulation in the HIF-1-regulated response toward hypoxia.
412. 412
  Hudelist, G.; Czerwenka, K.; Kubista, E.; Marton, E.; Pischinger, K.; Singer, C. F. Breast Cancer Res. Treat. 2003, 78, 193
  412
  Expression of Sex Steroid Receptors and their Co-Factors in Normal and Malignant Breast Tissue: AIB1 is a Carcinoma-Specific Co-Activator
  Hudelist, Gernot; Czerwenka, Klaus; Kubista, Ernst; Marton, Erika; Pischinger, Kerstin; Singer, Christian F.
  Breast Cancer Research and Treatment (2003), 78 (2), 193-204CODEN: BCTRD6; ISSN:0167-6806. (Kluwer Academic Publishers)
  The differential expression pattern of estrogen receptor alpha (ER-α), estrogen receptor beta (ER-β) and their co-activator/co-repressor proteins is thought to modulate estrogenic action and to be present already during the early stages of tumorigenesis. It has therefore been postulated that certain co-activator and co-repressor proteins contribute to the development of breast cancer. There are some reports providing information on gene amplification and mRNA over-expression of certain co-factors in breast cancer, but to date there is only limited knowledge about their resp. protein expressions. The aim of this study was to examine the expression of four steroid receptor co-activators (steroid receptor co-activator 1 (SRC-1), transcription intermediary factor 2 (TIF 2), protein 300 kDa/CREB binding protein (p300/CBP), amplified in breast cancer 1 (AIB1)), and of the co-repressor nuclear receptor co-repressor (NCoR), in malignant breast tissues and in matching normal breast biopsies of the same individuals. Protein expression was analyzed by immunohistochem. and was compared to prognostic parameters such as lymph node involvement, tumor grading and receptor status. All members of the co-regulatory protein family were detected in both, benign and matching malignant tissue samples, except for AIB1, which was found to be expressed exclusively in malignant epithelium. AIB1 was preferentially present in carcinomas with high tumor grade (r = 0.48, p = 0.014), and was co-expressed with p300/CBP (r = 0.54, p = 0.006). TIF 2 correlated significantly to nodal status (r = 0.46, p = 0.025). Furthermore, protein levels of ER-β, p300/CBP and AIB1 were higher in invasive ductal carcinomas than in normal mammary tissue. The tumoral ER-α protein expression was significantly correlated with that of PgR (r = 0.61, p = 0.001) and NCoR (r = 0.4, p = 0.043), whereas ER-β expression was assocd. with SRC-1 (r = 0.68, p ≤ 0.001), TIF 2 (r = 0.64, p = 0.001) and NCoR (r = 0.48, p = 0.014) protein levels in malignant specimens. In our hands, 20% of ER-β pos. tumors did not express ER-α protein, thereby suggesting that a substantial fraction of ER-beta pos. tumors is falsely considered to be estrogen receptor neg.' if only ER-α specific antibodies are employed in the histol. assessment of the ER status.
413. 413
  Debes, J. D.; Sebo, T. J.; Lohse, C. M.; Murphy, L. M.; Haugen, D. A.; Tindall, D. J. Cancer Res. 2003, 63, 7638
  There is no corresponding record for this reference.
414. 414
  Isharwal, S.; Miller, M. C.; Marlow, C.; Makarov, D. V.; Partin, A. W.; Veltri, R. W. Prostate 2008, 68, 1097
  There is no corresponding record for this reference.
415. 415
  Heery, D. M.; Fischer, P. M. Drug Discovery Today 2007, 12, 88
  There is no corresponding record for this reference.
416. 416
  Lin, W. M.; Baker, A. C.; Beroukhim, R.; Winckler, W.; Feng, W.; Marmion, J. M.; Laine, E.; Greulich, H.; Tseng, H.; Gates, C.; Hodi, F. S.; Dranoff, G.; Sellers, W. R.; Thomas, R. K.; Meyerson, M.; Golub, T. R.; Dummer, R.; Herlyn, M.; Getz, G.; Garraway, L. A. Cancer Res. 2008, 68, 664
  There is no corresponding record for this reference.
417. 417
  Rotte, A.; Bhandaru, M.; Cheng, Y.; Sjoestroem, C.; Martinka, M.; Li, G. PLoS One 2013, 8, e75405
  There is no corresponding record for this reference.
418. 418
  Bhandaru, M.; Ardekani, G. S.; Zhang, G.; Martinka, M.; McElwee, K. J.; Li, G.; Rotte, A. BMC Cancer 2014, 14– 398
  There is no corresponding record for this reference.
419. 419
  Bandyopadhyay, D.; Okan, N. A.; Bales, E.; Nascimento, L.; Cole, P. A.; Medrano, E. E. Cancer Res. 2002, 62, 6231
  There is no corresponding record for this reference.
420. 420
  Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
  There is no corresponding record for this reference.
421. 421
  Iyer, N. G.; Chin, S. F.; Ozdag, H.; Daigo, Y.; Hu, D. E.; Cariati, M.; Brindle, K.; Aparicio, S.; Caldas, C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 7386
  There is no corresponding record for this reference.
422. 422
  Giles, R. H.; Petrij, F.; Dauwerse, H. G.; den Hollander, A. I.; Lushnikova, T.; van Ommen, G. J.; Goodman, R. H.; Deaven, L. L.; Doggett, N. A.; Peters, D. J.; Breuning, M. H. Genomics 1997, 42, 96
  There is no corresponding record for this reference.
423. 423
  Rozman, M.; Camós, M.; Colomer, D.; Villamor, N.; Esteve, J.; Costa, D.; Carrió, A.; Aymerich, M.; Aguilar, J. L.; Domingo, A.; Solé, F.; Gomis, F.; Florensa, L.; Montserrat, E.; Campo, E. Genes, Chromosomes Cancer 2004, 40, 140
  423
  Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation
  Rozman, Maria; Camos, Mireia; Colomer, Dolors; Villamor, Neus; Esteve, Jordi; Costa, Dolors; Carrio, Ana; Aymerich, Marta; Aguilar, Josep Lluis; Domingo, Alicia; Sole, Francesc; Gomis, Federico; Florensa, Lourdes; Montserrat, Emili; Campo, Elias
  Genes, Chromosomes & Cancer (2004), 40 (2), 140-145CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
  The t(8;16)(p11;p13) fuses the MOZ (MYST3) gene at 8p11 with CBP (CREBBP) at 16p13 and is assocd. with an infrequent but well-defined type of acute myeloid leukemia (AML) that has unique morphocytochem. findings (monocytoid blast morphol. with erythrophagocytosis and simultaneously pos. for myeloperoxidase and nonspecific esterases). RT-PCR amplification of MOZ/CBP (MYST3/CREBBP) chimera has proved difficult, with four different transcripts found in four reported cases. The authors studied 7 AML-t(8;16) patients, 5 with cytogenetically demonstrated t(8;16) and 2 with similar morphocytochem. and immunophenotypical characteristics. Clin., 3 cases presented as therapy-related leukemia. Extramedullar involvement was obsd. at presentation in 2 patients and coagulopathy in 4. The clinicobiol. findings confirmed the distinctiveness of this entity. Of note is the erythrophagocytosis in 5 of 7 cases and the immunol. negativity for CD34 and CD117 and positivity for CD56. Using a new RT-PCR strategy, the authors were able to amplify a specific band of 212 bp in six cases in which sequence anal. confirmed the presence of the previously described MOZ/CBP fusion transcript type 1. This is the largest molecularly studied AML-t(8;16) series, which demonstrates that MOZ/CBP breakpoints are usually clustered in intron 16 of MOZ and intron 2 of CBP. The newly designed single-round PCR provides a simple tool for the mol. confirmation of MOZ/CBP rearrangement.
424. 424
  Borrow, J.; Stanton, V. P., Jr.; Andresen, J. M.; Becher, R.; Behm, F. G.; Chaganti, R. S.; Civin, C. I.; Disteche, C.; Dubé, I.; Frischauf, A. M.; Horsman, D.; Mitelman, F.; Volinia, S.; Watmore, A. E.; Housman, D. E. Nat. Genet. 1996, 14, 33
  424
  The translocation t(8;16)(p11;p13) of acute myeloid leukemia fuses a putative acetyltransferase to the CREB-binding protein
  Borrow, Julian; Stanton, Vincent P., Jr.; Andresen, J. Michael; Becher, Reinhard; Behm, Frederick G.; Chagaanti, Raju S. K.; Civin, Curt I.; Disteche, Christine; Dube, Ian; et al.
  Nature Genetics (1996), 14 (1), 33-41CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Co.)
  The recurrent translocation t(8;16)(p11;p13) is a cytogenetic hallmark for the M4/M5 subtype of acute myeloid leukemia. Here the authors identify the breakpoint-assocd. genes. Positional cloning on chromosome 16 implicates the CREB-binding protein (CBP), a transcriptional adaptor/co-activator protein. At the chromosome 8 breakpoint the authors identify a novel gene, MOZ, which encodes a 2,004-amino-acid protein characterized by two C4HC3 zinc fingers and a single C2HC zinc finger in conjunction with a putative acetyltransferase signature. In-frame MOZ-CBP fusion transcripts combine the MOZ finger motifs and putative acetyltransferase domain with a largely intact CBP. The authors suggest that MOZ may represent a chromatin-assocd. acetyltransferase, and raise the possibility that a dominant MOZ-CBP fusion protein could mediate leukemogenesis via aberrant chromatin acetylation.
425. 425
  Chaffanet, M.; Gressin, L.; Preudhomme, C.; Soenen-Cornu, V.; Birnbaum, D.; Pébusque, M. J. Genes, Chromosomes Cancer 2000, 28, 138
  425
  MOZ is fused to p300 in an acute monocytic leukemia with t(8;22)
  Chaffanet, Max; Gressin, Laetitia; Preudhomme, Claude; Soenen-Cornu, Valerie; Birnbaum, Daniel; Pebusque, Marie-Josephe
  Genes, Chromosomes & Cancer (2000), 28 (2), 138-144CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
  The authors report on the fusion of the monocytic leukemia zinc finger protein (MOZ) gene to the adenoviral EIA-assocd. protein p300 gene in acute monocytic leukemia MS assocd. with a t(8;22)(p11;q13) translocation. The authors studied two patients with double-color fluorescence in situ hybridization (FISH) using the yeast artificial chromosome 176C9 and the bacterial artificial chromosome clone H59D10 specific to the MOZ and p300 genes, resp. Both probes were split in the patients' chromosome metaphase cells, and the two deriv. chromosomes were each labeled with both probes. The authors showed by Southern blot the rearrangement of the MOZ gene, and cloned the fusion transcripts in one patient carrying the t(8;22) by reverse transcription-polymerase chain reaction using MOZ- and p300-specific primers. Both fusion transcripts were expressed. This result defines a novel reciprocal translocation involving two acetyltransferases, MOZ and p300, resulting in an abnormal transcriptional co-activator that could play a crit. role in leukemogenesis.
426. 426
  Kitabayashi, I.; Aikawa, Y.; Yokoyama, A.; Hosoda, F.; Nagai, M.; Kakazu, N.; Abe, T.; Ohki, M. Leukemia 2001, 15, 89
  There is no corresponding record for this reference.
427. 427
  Panagopoulos, I.; Fioretos, T.; Isaksson, M.; Samuelsson, U.; Billström, R.; Strömbeck, B.; Mitelman, F.; Johansson, B. Hum. Mol. Genet. 2001, 10, 395
  427
  Fusion of the MORF and CBP genes in acute myeloid leukemia with the t(10;16)(q22;p13)
  Panagopoulos, Ioannis; Fioretos, Thoas; Isaksson, Margareth; Samuelsson, Ulf; Billstrom, Rolf; Strombeck, Bodil; Mitelman, Felix; Johansson, Bertil
  Human Molecular Genetics (2001), 10 (4), 395-404CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
  The CBP gene at 16p13 fuses to MOZ and MLL as a result of the t(8;16)(p11;p13) in acute (myelo)monocytic leukemias (AML M4/M5) and the t(11;16)(q23;p13) in treatment-related AML, resp. Here the authors show that a novel t(10;16)(q22;p13) in a childhood AML M5a leads to a MORF-CBP chimera. RT-PCR using MORF forward and CBP reverse primers amplified a MORF-CBP fusion in which nucleotide 3103 of MORF was fused in-frame with nucleotide 284 of CBP. Nested RT-PCR with CBP forward and MORF reverse primers generated a CBP-MORF transcript in which nucleotide 283 of CBP was fused in-frame with nucleotide 3104 of MORF. Genomic analyses revealed that the breaks were close to Alu elements in intron 16 of MORF and intron 2 of CBP and that duplications had occurred near the breakpoints. A database search using MORF cDNA enabled us to construct an exon-intron map of the MORF gene. The MORF-CBP protein retains the zinc fingers, two nuclear localization signals, the histone acetyltransferase (HAT) domain, a portion of the acidic domain of MORF and the CBP protein downstream of codon 29. Thus, the part of CBP encoding the RARA-binding domain, the CREB-binding domain, the three Cys/His-rich regions, the bromodomain, the HAT domain and the Glu-rich domains is present. In the reciprocal CBP-MORF, part of the acidic domain and the C-terminal Ser- and Met-rich regions of MORF are likely to be driven by the CBP promoter. Since both fusion transcripts were present, their exact role in the leukemogenic process remains to be elucidated.
428. 428
  Vizmanos, J. L.; Larráyoz, M. J.; Lahortiga, I.; Floristán, F.; Alvarez, C.; Odero, M. D.; Novo, F. J.; Calasanz, M. J. Genes, Chromosomes Cancer 2003, 36, 402
  428
  t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia
  Vizmanos, Jose L.; Larrayoz, Maria J.; Lahortiga, Idoya; Floristan, Filomena; Alvarez, Carmen; Odero, Maria D.; Novo, Francisco J.; Calasanz, Maria J.
  Genes, Chromosomes & Cancer (2003), 36 (4), 402-405CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss, Inc.)
  Recently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in a case of childhood acute myeloid leukemia (AML) M5a, with a complex karyotype contg. other rearrangements. Here, we report a new case with the MORF-CREBBP fusion in an 84-yr-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration. This supports that this is a recurrent pathogenic translocation in AML.
429. 429
  Uppal, G. K.; Leighton, J.; Da Costa, D.; Czulewicz, A.; Palazzo, I. E. Hematol. Rep. 2011, 3, e23
  There is no corresponding record for this reference.
430. 430
  Kojima, K.; Kaneda, K.; Yoshida, C.; Dansako, H.; Fujii, N.; Yano, T.; Shinagawa, K.; Yasukawa, M.; Fujita, S.; Tanimoto, M. Br. J. Haematol. 2003, 120, 271
  430
  A novel fusion variant of the MORF and CBP genes detected in therapy-related myelodysplastic syndrome with t(10;16)(q22;p13)
  Kojima, Kensuke; Kaneda, Kinuyo; Yoshida, Chikamasa; Dansako, Hirokata; Fujii, Nobuharu; Yano, Tomofumi; Shinagawa, Katsuji; Yasukawa, Masaki; Fujita, Shigeru; Tanimoto, Mitsune
  British Journal of Haematology (2003), 120 (2), 271-273CODEN: BJHEAL; ISSN:0007-1048. (Blackwell Publishing Ltd.)
  We report a case of therapy-related myelodysplastic syndrome (t-MDS) with t(10;16)(q22;p13), in which novel fusion transcripts of the MORF and CBP genes were detected. In one MORF-CBP fusion transcript, exon 15 of the MORF gene was fused in frame with exon 5 of the CBP gene. In a reciprocal CBP-MORF transcript, exon 4 of the CBP gene was fused in frame with exon 16 of the MORF gene. This is the first reported case of t-MDS assocd. with t(10;16), and provides mol. evidence that the novel MORF-CBP and/or CBP-MORF fusion protein(s) might play an important role in the development of t-MDS.
431. 431
  Taki, T.; Sako, M.; Tsuchida, M.; Hayashi, Y. Blood 1997, 89, 3945
  There is no corresponding record for this reference.
432. 432
  Sobulo, O. M.; Borrow, J.; Tomek, R.; Reshmi, S.; Harden, A.; Schlegelberger, B.; Housman, D.; Doggett, N. A.; Rowley, J. D.; Zeleznik-Le, N. J. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 8732
  There is no corresponding record for this reference.
433. 433
  Satake, N.; Ishida, Y.; Otoh, Y.; Hinohara, S.; Kobayashi, H.; Sakashita, A.; Maseki, N.; Kaneko, Y. Genes, Chromosomes Cancer 1997, 20, 60
  433
  Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation
  Satake, Noriko; Ishida, Yasushi; Otoh, Yoshiko; Hinohara, Shin-Ichi; Kobayashi, Hirofumi; Sakashita, Akiko; Maseki, Nobuo; Kaneko, Yasuhiko
  Genes, Chromosomes & Cancer (1997), 20 (1), 60-63CODEN: GCCAES; ISSN:1045-2257. (Wiley-Liss)
  CBP, which is located on 16p13 and encodes a transcriptional adaptor/coactivator protein, has been shown to fuse by the t(8;16)(p11;p13) translocation to MOZ on 8p11 in acute myeloid leukemia. The authors found a t(11;16)(q23;p13) in a child with therapy-related chronic myelomonocytic leukemia. Subsequent reverse transcriptase-polymerase chain reaction and direct sequencing analyses revealed the MLL-CBP fusion transcript in CMML cells. Because 11q23 translocations involving MLL and t(8;16) involving MOZ and CBP have been reported in therapy-related leukemias, both the MLL and CBP genes may be targets for topoisomerase II inhibitors. Accordingly, the authors believe that most t(11;16)-assocd. leukemias may develop in patients who have been treated with cytotoxic chemotherapy for primary malignant diseases.
434. 434
  Ida, K.; Kitabayashi, I.; Taki, T.; Taniwaki, M.; Noro, K.; Yamamoto, M.; Ohki, M.; Hayashi, Y. Blood 1997, 90, 4699
  There is no corresponding record for this reference.
435. 435
  Wang, J.; Iwasaki, H.; Krivtsov, A.; Febbo, P. G.; Thorner, A. R.; Ernst, P.; Anastasiadou, E.; Kutok, J. L.; Kogan, S. C.; Zinkel, S. S.; Fisher, J. K.; Hess, J. L.; Golub, T. R.; Armstrong, S. A.; Akashi, K.; Korsmeyer, S. J. EMBO J. 2005, 24, 368
  There is no corresponding record for this reference.
436. 436
  Wang, L.; Gural, A.; Sun, X. J.; Zhao, X.; Perna, F.; Huang, G.; Hatlen, M. A.; Vu, L.; Liu, F.; Xu, H.; Asai, T.; Xu, H.; Deblasio, T.; Menendez, S.; Voza, F.; Jiang, Y.; Cole, P. A.; Zhang, J.; Melnick, A.; Roeder, R. G.; Nimer, S. D. Science 2011, 333, 765
  There is no corresponding record for this reference.
437. 437
  Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
  There is no corresponding record for this reference.
438. 438
  Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
  There is no corresponding record for this reference.
439. 439
  Pattabiraman, D. R.; Sun, J.; Dowhan, D. H.; Ishii, S.; Gonda, T. J. Mol. Cancer Res. 2009, 7, 1477
  439
  Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability
  Pattabiraman, Diwakar R.; Sun, Jane; Dowhan, Dennis H.; Ishii, Shunsuke; Gonda, Thomas J.
  Molecular Cancer Research (2009), 7 (9), 1477-1486CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)
  The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the neg. regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for mol. targeting of Myb in leukemia. (Mol Cancer Res 2009;7(9):1477-86).
440. 440
  Iyer, N. G.; Ozdag, H.; Caldas, C. Oncogene 2004, 23, 4225
  440
  p300/CBP and cancer
  Iyer, Narayanan Gopalakrishna; Oezdag, Hilal; Caldas, Carlos
  Oncogene (2004), 23 (24), 4225-4231CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)
  A review. P300 and cAMP response element-binding protein (CBP) are adenoviral E1A-binding proteins involved in multiple cellular processes, and function as transcriptional co-factors and histone acetyltransferases. Germline mutation of CBP results in Rubinstein-Taybi syndrome, which is characterized by an increased predisposition to childhood malignancies. Furthermore, somatic mutations of p300 and CBP occur in a no. of malignancies. Chromosome translocations target CBP and, less commonly, p300 in acute myeloid leukemia and treatment-related hematol. disorders. P300 mutations in solid tumors result in truncated p300 protein products or amino-acid substitutions in crit. protein domains, and these are often assocd. with inactivation of the second allele. A mouse model confirms that p300 and CBP function as suppressors of hematol. tumor formation. The involvement of these proteins in crit. tumorigenic pathways (including TGF-β, p53 and Rb) provides a mechanistic route as to how their inactivation could result in cancer.
441. 441
  Varier, R. A.; Kundu, T. K. Curr. Pharm. Des. 2006, 12, 1975
  441
  Chromatin modifications (acetylation/ deacetylation/ methylation) as new targets for HIV therapy
  Varier, Radhika A.; Kundu, Tapas K.
  Current Pharmaceutical Design (2006), 12 (16), 1975-1993CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
  A review. Human immunodeficiency virus (HIV) is one of the most deadly threats to the human race. Though the developed countries have been able to control the epidemic by utilizing the discovery of very expensive diagnostics, the situation is dangerously alarming in developing and underdeveloped countries. The development of highly active antiretroviral drugs has improved the survival and quality of life, but prolonged treatment results in viral load rebound to pretherapy levels. Recent advances in the understanding of eukaryotic and genome-integrated viral gene expression showed that regulation of chromatin function is closely linked to the multiplication of HIV. Therefore, a new therapeutic approach has been initiated targeting the chromatin-modifying enzymes mainly histone acetyltransferases and deacetylases which may lead to a better and economical anti- HIV combinatorial therapeutics. In this review, the authors have discussed the mechanisms of HIV gene expression in the chromatin context and its potentiality to be exploited as a new therapeutic target.
442. 442
  Mujtaba, S.; Zhou, M. M. Methods 2011, 53, 97
  There is no corresponding record for this reference.
443. 443
  Sakane, N.; Kwon, H. S.; Pagans, S.; Kaehlcke, K.; Mizusawa, Y.; Kamada, M.; Lassen, K. G.; Chan, J.; Greene, W. C.; Schnoelzer, M.; Ott, M. PLoS Pathog. 2011, 7, e1002184
  There is no corresponding record for this reference.
444. 444
  Mujtaba, S.; Zhou, M. M. Methods 2011, 53, 97
  There is no corresponding record for this reference.
445. 445
  Allouch, A.; Di Primio, C.; Alpi, E.; Lusic, M.; Arosio, D.; Giacca, M.; Cereseto, A. Cell Host Microbe 2011, 9, 484
  445
  The TRIM Family Protein KAP1 Inhibits HIV-1 Integration
  Allouch, Awatef; Di Primio, Cristina; Alpi, Emanuele; Lusic, Marina; Arosio, Daniele; Giacca, Mauro; Cereseto, Anna
  Cell Host & Microbe (2011), 9 (6), 484-495CODEN: CHMECB; ISSN:1931-3128. (Cell Press)
  Summary: The integration of viral cDNA into the host genome is a crit. step in the life cycle of HIV-1. This step is catalyzed by integrase (IN), a viral enzyme that is pos. regulated by acetylation via the cellular histone acetyl transferase (HAT) p300. To investigate the relevance of IN acetylation, we searched for cellular proteins that selectively bind acetylated IN and identified KAP1, a protein belonging to the TRIM family of antiviral proteins. KAP1 binds acetylated IN and induces its deacetylation through the formation of a protein complex which includes the deacetylase HDAC1. Modulation of intracellular KAP1 levels in different cell types including T cells, the primary HIV-1 target, revealed that KAP1 curtails viral infectivity by selectively affecting HIV-1 integration. This study identifies KAP1 as a cellular factor restricting HIV-1 infection and underscores the relevance of IN acetylation as a crucial step in the viral infectious cycle.
446. 446
  Terreni, M.; Valentini, P.; Liverani, V.; Gutierrez, M. I.; Di Primio, C.; Di Fenza, A.; Tozzini, V.; Allouch, A.; Albanese, A.; Giacca, M.; Cereseto, A. Retrovirology 2010, 7, 18
  There is no corresponding record for this reference.
447. 447
  Zou, W.; Wang, Z.; Liu, Y.; Fan, Y.; Zhou, B. Y.; Yang, X. F.; He, J. J. Glia 2010, 58, 1640
  There is no corresponding record for this reference.
448. 448
  Kauppi, M.; Murphy, J. M.; de Graaf, C. A.; Hyland, C. D.; Greig, K. T.; Metcalf, D.; Hilton, A. A.; Nicola, N. A.; Kile, B. T.; Hilton, D. J.; Alexander, W. S. Blood 2008, 112, 3148
  There is no corresponding record for this reference.
449. 449
  Hilton, D. J.; Kile, B. T.; Alexander, W. S. Blood 2009, 113, 5599
  There is no corresponding record for this reference.
450. 450
  Yanazume, T.; Morimoto, T.; Wada, H.; Kawamura, T.; Hasegawa, K. Mol. Cell. Biochem. 2003, 248, 115
  There is no corresponding record for this reference.
451. 451
  Gusterson, R. J.; Jazrawi, E.; Adcock, I. M.; Latchman, D. S. J. Biol. Chem. 2003, 278, 6838
  There is no corresponding record for this reference.
452. 452
  Zhou, X. Y.; Shibusawa, N.; Naik, K.; Porras, D.; Temple, K.; Ou, H.; Kaihara, K.; Roe, M. W.; Brady, M. J.; Wondisford, F. E. Nat. Med. 2004, 10, 633
  452
  Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein
  Zhou, Xiao Yan; Shibusawa, Nobuyuki; Naik, Karuna; Porras, Delia; Temple, Karla; Ou, Hesheng; Kaihara, Kelly; Roe, Michael W.; Brady, Matthew J.; Wondisford, Fredric E.
  Nature Medicine (New York, NY, United States) (2004), 10 (6), 633-637CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
  Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concns. and is regulated by opposing stimulatory (cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, the authors show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose prodn. The authors propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.
453. 453
  Cha-Molstad, H.; Saxena, G.; Chen, J.; Shalev, A. J. Biol. Chem. 2009, 284, 16898
  There is no corresponding record for this reference.
454. 454
  Bricambert, J.; Miranda, J.; Benhamed, F.; Girard, J.; Postic, C.; Dentin, R. J. Clin. Invest. 2010, 120, 4316
  There is no corresponding record for this reference.
455. 455
  Schnell, U.; Dijk, F.; Sjollema, K. A.; Giepmans, B. N. Nat. Methods 2012, 9, 152
  455
  Immunolabeling artifacts and the need for live-cell imaging
  Schnell, Ulrike; Dijk, Freark; Sjollema, Klaas A.; Giepmans, Ben N. G.
  Nature Methods (2012), 9 (2), 152-158CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
  A review. Fluorescent fusion proteins have revolutionized examn. of proteins in living cells. Still, studies using these proteins are met with criticism because proteins are modified and ectopically expressed, in contrast to immunofluorescence studies. However, introducing immunoreagents inside cells can cause protein extn. or relocalization, not reflecting the in vivo situation. Here we discuss pitfalls of immunofluorescence labeling that often receive little attention and argue that immunostaining expts. in dead, permeabilized cells should be complemented with live-cell imaging when scrutinizing protein localization.
456. 456
  McNeil, P. L. J. Cell Sci. 1987, 88, 669
  456
  Glass beads load macromolecules into living cells
  McNeil P L; Warder E
  Journal of cell science (1987), 88 ( Pt 5) (), 669-78 ISSN:0021-9533.
  We describe and characterize an exceptionally rapid and simple new technique for loading large numbers of cultured cells with large macromolecules. The culture medium of the cell monolayer is replaced by a small volume of the macromolecule to be loaded. Glass beads (75-500 micron diameter) are then sprinkled onto the cells, the cells are washed free of beads and exogenous macromolecules, and 'bead-loading' is completed. The conditions for bead-loading can readily be modified to accommodate cell type and loading objectives: for example, the amount of loading per cell increases if bead size is increased or if beads are agitated after sprinkling onto the monolayer, but at the expense of increased cell loss. As many as 97% of a population of bovine aortic endothelial (BAE) cells were loaded with a 10,000 Mr dextran; and 79% with a 150,000 Mr dextran using bead-loading. Various cell lines have been loaded using glass beads. Moreover, bead-loading has the advantage of producing loaded cells that remain adherent and well-spread, thus minimizing recovery time and permitting immediate microscopic examination.
457. 457
  Hayashi-Takanaka, Y.; Yamagata, K.; Wakayama, T.; Stasevich, T. J.; Kainuma, T.; Tsurimoto, T.; Tachibana, M.; Shinkai, Y.; Kurumizaka, H.; Nozaki, N.; Kimura, H. Nucleic Acids Res. 2011, 39, 6475
  There is no corresponding record for this reference.
458. 458
  Hayashi-Takanaka, Y.; Yamagata, K.; Nozaki, N.; Kimura, H. J. Cell Biol. 2009, 187, 781
  There is no corresponding record for this reference.
459. 459
  Johansen, K. M.; Johansen, J. Chromosome Res. 2006, 14, 393
  459
  Regulation of chromatin structure by histone H3S10 phosphorylation
  Johansen, Kristen M.; Johansen, Jorgen
  Chromosome Research (2006), 14 (4), 393-404CODEN: CRRSEE; ISSN:0967-3849. (Springer)
  A review. The epigenetic phospho-serine 10 modification of histone H3 has been a puzzle due to its assocn. with two apparently opposed chromatin states. It is found at elevated levels on the highly condensed, transcriptionally inactive mitotic chromosomes yet is also correlated with the more extended chromatin configuration of active genes, euchromatic interband regions, and activated heat shock puffs of Drosophila polytene chromosomes. In addn., phosphorylation of histone H3S10 is up-regulated on the hypertranscribed male X chromosome. Here we review the cellular effects of histone H3S10 phosphorylation and discuss a model for its involvement in regulating chromatin organization and heterochromatization that would be applicable to both interphase and mitotic chromosomes.
460. 460
  Stasevich, T. J.; Hayashi-Takanaka, Y.; Sato, Y.; Maehara, K.; Ohkawa, Y.; Sakata-Sogawa, K.; Tokunaga, M.; Nagase, T.; Nozaki, N.; McNally, J. G.; Kimura, H. Nature 2014, 516, 272
  There is no corresponding record for this reference.
461. 461
  Rothbauer, U.; Zolghadr, K.; Tillib, S.; Nowak, D.; Schermelleh, L.; Gahl, A.; Backmann, N.; Conrath, K.; Muyldermans, S.; Cardoso, M. C.; Leonhardt, H. Nat. Methods. 2006, 3, 887
  461
  Targeting and tracing antigens in live cells with fluorescent nanobodies
  Rothbauer, Ulrich; Zolghadr, Kourosh; Tillib, Sergei; Nowak, Danny; Schermelleh, Lothar; Gahl, Anja; Backmann, Natalija; Conrath, Katja; Muyldermans, Serge; Cardoso, M. Cristina; Leonhardt, Heinrich
  Nature Methods (2006), 3 (11), 887-889CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
  The authors fused the epitope-recognizing fragment of heavy-chain antibodies from Camelidae sp. with fluorescent proteins to generate fluorescent, antigen-binding nanobodies (chromobodies) that can be expressed in living cells. The authors demonstrate that chromobodies can recognize and trace antigens in different subcellular compartments throughout S phase and mitosis. Chromobodies should enable new functional studies, as potentially any antigenic structure can be targeted and traced in living cells in this fashion.
462. 462
  Sato, Y.; Mukai, M.; Ueda, J.; Muraki, M.; Stasevich, T. J.; Horikoshi, N.; Kujirai, T.; Kita, H.; Kimura, T.; Hira, S.; Okada, Y.; Hayashi-Takanaka, Y.; Obuse, C.; Kurumizaka, H.; Kawahara, A.; Yamagata, K.; Nozaki, N.; Kimura, H. Sci. Rep. 2013, 3, 2436
  462
  Genetically encoded system to track histone modification in vivo
  Sato Yuko; Mukai Masanori; Ueda Jun; Muraki Michiko; Stasevich Timothy J; Horikoshi Naoki; Kujirai Tomoya; Kita Hiroaki; Kimura Taisuke; Hira Seiji; Okada Yasushi; Hayashi-Takanaka Yoko; Obuse Chikashi; Kurumizaka Hitoshi; Kawahara Atsuo; Yamagata Kazuo; Nozaki Naohito; Kimura Hiroshi
  Scientific reports (2013), 3 (), 2436 ISSN:.
  Post-translational histone modifications play key roles in gene regulation, development, and differentiation, but their dynamics in living organisms remain almost completely unknown. To address this problem, we developed a genetically encoded system for tracking histone modifications by generating fluorescent modification-specific intracellular antibodies (mintbodies) that can be expressed in vivo. To demonstrate, an H3 lysine 9 acetylation specific mintbody (H3K9ac-mintbody) was engineered and stably expressed in human cells. In good agreement with the localization of its target acetylation, H3K9ac-mintbody was enriched in euchromatin, and its kinetics measurably changed upon treatment with a histone deacetylase inhibitor. We also generated transgenic fruit fly and zebrafish stably expressing H3K9ac-mintbody for in vivo tracking. Dramatic changes in H3K9ac-mintbody localization during Drosophila embryogenesis could highlight enhanced acetylation at the start of zygotic transcription around mitotic cycle 7. Together, this work demonstrates the broad potential of mintbody and lays the foundation for epigenetic analysis in vivo.
463. 463
  Vincenz, C.; Kerppola, T. K. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 16572
  There is no corresponding record for this reference.
464. 464
  Forster, T. H. Ann. Phys. 1948, 437, 55
  There is no corresponding record for this reference.
465. 465
  Helms, V. Fluorescence Resonance Energy Transfer. Principles of Computational Cell Biology; Wiley-VCH: Weinheim, 2008; p 202, ISBN 978-3-527-31555-0.
  There is no corresponding record for this reference.
466. 466
  Kanno, T.; Kanno, Y.; Siegel, R. M.; Jang, M. K.; Lenardo, M. J.; Ozato, K. Mol. Cell 2004, 13, 33
  There is no corresponding record for this reference.
467. 467
  Sasaki, K.; Ito, T.; Nishino, N.; Khochbin, S.; Yoshida, M. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 16257
  There is no corresponding record for this reference.
468. 468
  Ito, T.; Umehara, T.; Sasaki, K.; Nakamura, Y.; Nishino, N.; Terada, T.; Shirouzu, M.; Padmanabhan, B.; Yokoyama, S.; Ito, A.; Yoshida, M. Chem. Biol. 2011, 18, 495
  468
  Real-Time Imaging of Histone H4K12-Specific Acetylation Determines the Modes of Action of Histone Deacetylase and Bromodomain Inhibitors
  Ito, Tamaki; Umehara, Takashi; Sasaki, Kazuki; Nakamura, Yoshihiro; Nishino, Norikazu; Terada, Takaho; Shirouzu, Mikako; Padmanabhan, Balasundaram; Yokoyama, Shigeyuki; Ito, Akihiro; Yoshida, Minoru
  Chemistry & Biology (Cambridge, MA, United States) (2011), 18 (4), 495-507CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)
  Histone acetylation constitutes an epigenetic mark for transcriptional regulation. Here we developed a fluorescent probe to visualize acetylation of histone H4 Lys12 (H4K12) in living cells using fluorescence resonance energy transfer (FRET) and the binding of the BRD2 bromodomain to acetylated H4K12. Using this probe designated as Histac-K12, we demonstrated that histone H4K12 acetylation is retained in mitosis and that some histone deacetylase (HDAC) inhibitors continue to inhibit cellular HDAC activity even after their removal from the culture. In addn., a small mol. that interferes with ability of the bromodomain to bind to acetylated H4K12 could be assessed using Histac-K12 in cells. Thus, Histac-K12 will serve as a powerful tool not only to understand the dynamics of H4K12-specific acetylation but also to characterize small mols. that modulate the acetylation or interaction status of histones.
469. 469
  Carrillo, L. D.; Krishnamoorthy, L.; Mahal, L. K. J. Am. Chem. Soc. 2006, 128, 14768
  There is no corresponding record for this reference.
470. 470
  Newman, R. H.; Zhang, J. Mol. BioSyst. 2008, 4, 496
  470
  Visualization of phosphatase activity in living cells with a FRET-based calcineurin activity sensor
  Newman, Robert H.; Zhang, Jin
  Molecular BioSystems (2008), 4 (6), 496-501CODEN: MBOIBW; ISSN:1742-206X. (Royal Society of Chemistry)
  Protein kinases and phosphatases are organized into complex intracellular signaling networks designed to coordinate their activities in both space and time. In order to better understand the mol. mechanisms underlying the regulation of signal transduction networks, it is important to define the spatiotemporal dynamics of both protein kinases and phosphatases within their endogenous environment. Herein, we report the development of a genetically-encoded protein biosensor designed to specifically probe the activity of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. Our reporter design utilizes a phosphatase activity-dependent mol. switch based on the N-terminal regulatory domain of the nuclear factor of activated T-cells as a specific substrate of calcineurin, sandwiched between cyan fluorescent protein and yellow fluorescent protein. Using this reporter, calcineurin activity can be monitored as dephosphorylation-induced increases in fluorescence resonance energy transfer and can be simultaneously imaged with intracellular calcium dynamics. The successful design of a prototype phosphatase activity sensor lays a foundation for studying targeting and compartmentation of phosphatases.
471. 471
  Nagai, Y.; Miyazaki, M.; Aoki, R.; Zama, T.; Inouye, S.; Hirose, K.; Iino, M.; Hagiwara, M. Nat. Biotechnol. 2000, 18, 313
  There is no corresponding record for this reference.
472. 472
  Ting, A. Y.; Kain, K. H.; Klemke, R. L.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 15003
  There is no corresponding record for this reference.
473. 473
  Kurokawa, K.; Mochizuki, N.; Ohba, Y.; Mizuno, H.; Miyawaki, A.; Matsuda, M. J. Biol. Chem. 2001, 276, 31305
  There is no corresponding record for this reference.
474. 474
  Lin, C. W.; Jao, C. Y.; Ting, A. Y. J. Am. Chem. Soc. 2004, 126, 5982
  There is no corresponding record for this reference.
475. 475
  Lin, C. W.; Ting, A. Y. Angew. Chem., Int. Ed. 2004, 43, 2940
  There is no corresponding record for this reference.
476. 476
  Yoshida, M.; Kijima, M.; Akita, M.; Beppu, T. J. Biol. Chem. 1990, 265, 17174
  There is no corresponding record for this reference.
477. 477
  Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57
  477
  The hallmarks of cancer
  Hanahan, Douglas; Weinberg, Robert A.
  Cell (Cambridge, Massachusetts) (2000), 100 (1), 57-70CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  A review is given with many refs. on principles governing the transformation of normal human cells into malignant cancers. The authors suggest that research over the past decades has revealed a small no. of mol., biochem., and cellular traits (acquired capabilities) shared by most and perhaps all types of cancer. Topics included are the acquired capabilities self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis followed by genome instability as an enabling characteristic and alternative pathways to cancer.
478. 478
  Hanahan, D.; Weinberg, R. A. Cell 2011, 144, 646
  478
  Hallmarks of cancer: the next generation
  Hanahan, Douglas; Weinberg, Robert A.
  Cell (Cambridge, MA, United States) (2011), 144 (5), 646-674CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
  A review. The hallmarks of cancer comprise six biol. capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metab. and evading immune destruction. In addn. to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment.". Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
479. 479
  Reynoird, N.; Schwartz, B. E.; Delvecchio, M.; Sadoul, K.; Meyers, D.; Mukherjee, C.; Caron, C.; Kimura, H.; Rousseaux, S.; Cole, P. A.; Panne, D.; French, C. A.; Khochbin, S. EMBO J. 2010, 29, 2943
  There is no corresponding record for this reference.
480. 480
  Crump, N. T.; Hazzalin, C. A.; Bowers, E. M.; Alani, R. M.; Cole, P. A.; Mahadevan, L. C. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 7814
  There is no corresponding record for this reference.
481. 481
  Santer, F. R.; Höschele, P. P.; Oh, S. J.; Erb, H. H.; Bouchal, J.; Cavarretta, I. T.; Parson, W.; Meyers, D. J.; Cole, P. A.; Culig, Z. Mol. Cancer Ther. 2011, 10, 1644
  481
  Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines
  Santer, Frederic R.; Hoeschele, Philipp P. S.; Oh, Su Jung; Erb, Holger H. H.; Bouchal, Jan; Cavarretta, Ilaria T.; Parson, Walther; Meyers, David J.; Cole, Philip A.; Culig, Zoran
  Molecular Cancer Therapeutics (2011), 10 (9), 1644-1655CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
  Inhibitors of histone deacetylases have been approved for clin. application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chem. inhibition of the acetyltransferase activity by a newly developed small mol., C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-κB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. Mol Cancer Ther; 10(9); 1644-55.
482. 482
  Wang, Y.; Toh, H. C.; Chow, P.; Chung, A. Y.; Meyers, D. J.; Cole, P. A.; Ooi, L. L.; Lee, C. G. FASEB J. 2012, 26, 3032
  There is no corresponding record for this reference.
483. 483
  Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
  There is no corresponding record for this reference.
484. 484
  Santer, F. R.; Höschele, P. P.; Oh, S. J.; Erb, H. H.; Bouchal, J.; Cavarretta, I. T.; Parson, W.; Meyers, D. J.; Cole, P. A.; Culig, Z. Mol. Cancer Ther. 2011, 10, 1644
  484
  Inhibition of the Acetyltransferases p300 and CBP Reveals a Targetable Function for p300 in the Survival and Invasion Pathways of Prostate Cancer Cell Lines
  Santer, Frederic R.; Hoeschele, Philipp P. S.; Oh, Su Jung; Erb, Holger H. H.; Bouchal, Jan; Cavarretta, Ilaria T.; Parson, Walther; Meyers, David J.; Cole, Philip A.; Culig, Zoran
  Molecular Cancer Therapeutics (2011), 10 (9), 1644-1655CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)
  Inhibitors of histone deacetylases have been approved for clin. application in cancer treatment. On the other hand, histone acetyltransferase (HAT) inhibitors have been less extensively investigated for their potential use in cancer therapy. In prostate cancer, the HATs and coactivators p300 and CBP are upregulated and may induce transcription of androgen receptor (AR)-responsive genes, even in the absence or presence of low levels of AR. To discover a potential anticancer effect of p300/CBP inhibition, we used two different approaches: (i) downregulation of p300 and CBP by specific short interfering RNA (siRNA) and (ii) chem. inhibition of the acetyltransferase activity by a newly developed small mol., C646. Knockdown of p300 by specific siRNA, but surprisingly not of CBP, led to an increase of caspase-dependent apoptosis involving both extrinsic and intrinsic cell death pathways in androgen-dependent and castration-resistant prostate cancer cells. Induction of apoptosis was mediated by several pathways including inhibition of AR function and decrease of the nuclear factor kappa B (NF-κB) subunit p65. Furthermore, cell invasion was decreased upon p300, but not CBP, depletion and was accompanied by lower matrix metalloproteinase (MMP)-2 and MMP-9 transcriptions. Thus, p300 and CBP have differential roles in the processes of survival and invasion of prostate cancer cells. Induction of apoptosis in prostate cancer cells was confirmed by the use of C646. This was substantiated by a decrease of AR function and downregulation of p65 impairing several NF-κB target genes. Taken together, these results suggest that p300 inhibition may be a promising approach for the development of new anticancer therapies. Mol Cancer Ther; 10(9); 1644-55.
485. 485
  Wang, L.; Gural, A.; Sun, X. J.; Zhao, X.; Perna, F.; Huang, G.; Hatlen, M. A.; Vu, L.; Liu, F.; Xu, H.; Asai, T.; Xu, H.; Deblasio, T.; Menendez, S.; Voza, F.; Jiang, Y.; Cole, P. A.; Zhang, J.; Melnick, A.; Roeder, R. G.; Nimer, S. D. Science 2011, 333, 765
  There is no corresponding record for this reference.
486. 486
  Liu, Y.; Wang, L.; Predina, J.; Han, R.; Beier, U. H.; Wang, L. C.; Kapoor, V.; Bhatti, T. R.; Akimova, T.; Singhal, S.; SBrindle, P. K.; Cole, P. A.; Albelda, S. M.; Hancock, W. W. Nat. Med. 2013, 19, 1173
  486
  Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity
  Liu, Yujie; Wang, Liqing; Predina, Jarrod; Han, Rongxiang; Beier, Ulf H.; Wang, Liang-Chuan S.; Kapoor, Veena; Bhatti, Tricia R.; Akimova, Tatiana; Singhal, Sunil; Brindle, Paul K.; Cole, Philip A.; Albelda, Steven M.; Hancock, Wayne W.
  Nature Medicine (New York, NY, United States) (2013), 19 (9), 1173-1177CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)
  Forkhead box P3 (Foxp3)+ T regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3+ Treg cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that exptl. depleting Foxp3+ Treg cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacol. inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3+ Treg cells increased T cell receptor-induced apoptosis in Treg cells, impaired Treg cell suppressive function and peripheral Treg cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3+ Treg cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-mol. inhibitors can diminish Treg cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.
487. 487
  Min, S. W.; Cho, S. H.; Zhou, Y.; Schroeder, S.; Haroutunian, V.; Seeley, W. W.; Huang, E. J.; Shen, Y.; Masliah, E.; Mukherjee, C.; Meyers, D.; Cole, P. A.; Ott, M.; Gan, L. Neuron 2010, 67, 953
  Erratum in: Neuron2010, 68, 801
  There is no corresponding record for this reference.
488. 488
  Mali, P.; Chou, B. K.; Yen, J.; Ye, Z.; Zou, J.; Dowey, S.; Brodsky, R. A.; Ohm, J. E.; Yu, W.; Baylin, S. B.; Yusa, K.; Bradley, A.; Meyers, D. J.; Mukherjee, C.; Cole, P. A.; Cheng, L. Stem Cells 2010, 28, 713
  There is no corresponding record for this reference.
489. 489
  Xu, C. R.; Cole, P. A.; Meyers, D. J.; Kormish, J.; Dent, S.; Zaret, K. S. Science 2011, 332, 963
  There is no corresponding record for this reference.
490. 490
  Marek, R.; Coelho, C. M.; Sullivan, R. K.; Baker-Andresen, D.; Li, X.; Ratnu, V.; Dudley, K. J.; Meyers, D.; Mukherjee, C.; Cole, P. A.; Sah, P.; Bredy, T. W. J. Neurosci. 2011, 31, 7486
  490
  Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300
  Marek, Roger; Coelho, Carlos M.; Sullivan, Robert K. P.; Baker-Andresen, Danay; Li, Xiang; Ratnu, Vikram; Dudley, Kevin J.; Meyers, David; Mukherjee, Chandrani; Cole, Philip A.; Sah, Pankaj; Bredy, Timothy W.
  Journal of Neuroscience (2011), 31 (20), 7486-7491CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
  It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examd. the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here, the authors report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. These results also demonstrated that the HAT p300 was highly expressed within pyramidal neurons of the ILPFC and that the small-mol. p300-specific inhibitor (C 646) infused into the ILPFC immediately after weak extinction training enhanced the consolidation of fear extinction memory. C 646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that did not evoke long-lasting LTP. These data suggested that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a redn. in the function of this HAT is required for the formation of fear extinction memory.
491. 491
  Knight, Z. A.; Shokat, K. M. Cell 2007, 128, 425
  There is no corresponding record for this reference.
492. 492
  Kasper, L. H.; Fukuyama, T.; Biesen, M. A.; Boussouar, F.; Tong, C.; de Pauw, A.; Murray, P. J.; van Deursen, J. M.; Brindle, P. K. Mol. Cell. Biol. 2006, 26, 789
  492
  Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development
  Kasper, Lawryn H.; Fukuyama, Tomofusa; Biesen, Michelle A.; Boussouar, Faycal; Tong, Caili; de Pauw, Antoine; Murray, Peter J.; van Deursen, Jan M. A.; Brindle, Paul K.
  Molecular and Cellular Biology (2006), 26 (3), 789-809CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)
  The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300flox) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300flax and a CBP conditional knockout allele (CBPflax) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-neg. thymocyte stage of T-cell development. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-pos. thymocytes, but an increase in the percentage of CD8+ single-pos. thymocytes seen in CBP mutant mice was not obsd. in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
493. 493
  Kasper, L. H.; Lerach, S.; Wang, J.; Wu, S.; Jeevan, T.; Brindle, P. K. EMBO J. 2010, 29, 3660
  There is no corresponding record for this reference.
494. 494
  Phan, H. M.; Xu, A. W.; Coco, C.; Srajer, G.; Wyszomierski, S.; Evrard, Y. A.; Eckner, R.; Dent, S. Y. Dev. Dyn. 2005, 233, 1337
  There is no corresponding record for this reference.
495. 495
  Huang, Y.; Vasilatos, S. N.; Boric, L.; Shaw, P. G.; Davidson, N. E. Breast Cancer Res. Treat. 2012, 131, 777– 89
  495
  Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells
  Huang, Yi; Vasilatos, Shauna N.; Boric, Lamia; Shaw, Patrick G.; Davidson, Nancy E.
  Breast Cancer Research and Treatment (2012), 131 (3), 777-789CODEN: BCTRD6; ISSN:0167-6806. (Springer)
  Abnormal activities of histone lysine demethylases (KDMs) and lysine deacetylases (HDACs) are assocd. with aberrant gene expression in breast cancer development. However, the precise mol. mechanisms underlying the crosstalk between KDMs and HDACs in chromatin remodeling and regulation of gene transcription are still elusive. In this study, we showed that treatment of human breast cancer cells with inhibitors targeting the zinc cofactor dependent class I/II HDAC, but not NAD+ dependent class III HDAC, led to significant increase of H3K4me2 which is a specific substrate of histone lysine-specific demethylase 1 (LSD1) and a key chromatin mark promoting transcriptional activation. We also demonstrated that inhibition of LSD1 activity by a pharmacol. inhibitor, pargyline, or siRNA resulted in increased acetylation of H3K9 (AcH3K9). However, siRNA knockdown of LSD2, a homolog of LSD1, failed to alter the level of AcH3K9, suggesting that LSD2 activity may not be functionally connected with HDAC activity. Combined treatment with LSD1 and HDAC inhibitors resulted in enhanced levels of H3K4me2 and AcH3K9, and exhibited synergistic growth inhibition of breast cancer cells. Finally, microarray screening identified a unique subset of genes whose expression was significantly changed by combination treatment with inhibitors of LSD1 and HDAC. Our study suggests that LSD1 intimately interacts with histone deacetylases in human breast cancer cells. Inhibition of histone demethylation and deacetylation exhibits cooperation and synergy in regulating gene expression and growth inhibition, and may represent a promising and novel approach for epigenetic therapy of breast cancer.
496. 496
  Han, H.; Yang, X.; Pandiyan, K.; Liang, G. PLoS One 2013, 8, e75136
  There is no corresponding record for this reference.
497. 497
  Prusevich, P.; Kalin, J. H.; Ming, S. A.; Basso, M.; Givens, J.; Li, X.; Hu, J.; Taylor, M. S.; Cieniewicz, A. M.; Hsiao, P. Y.; Huang, R.; Roberson, H.; Adejola, N.; Avery, L. B.; Casero, R. A., Jr.; Taverna, S. D.; Qian, J.; Tackett, A. J.; Ratan, R. R.; McDonald, O. G.; Feinberg, A. P.; Cole, P. A. ACS Chem. Biol. 2014, 9, 1284
  There is no corresponding record for this reference.
498. 498
  Yan, G.; Eller, M. S.; Elm, C.; Larocca, C. A.; Ryu, B.; Panova, I. P.; Dancy, B. M.; Bowers, E. M.; Meyers, D.; Lareau, L.; Cole, P. A.; Taverna, S. D.; Alani, R. M. J. Invest. Dermatol. 2013, 133, 2444
  There is no corresponding record for this reference.
499. 499
  Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K. Eur. J. Pharm. Sci. 2010, 41, 571
  499
  Codrug: An efficient approach for drug optimization
  Das, N.; Dhanawat, M.; Dash, B.; Nagarwal, R. C.; Shrivastava, S. K.
  European Journal of Pharmaceutical Sciences (2010), 41 (5), 571-588CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
  A review. Codrug or mutual prodrug is an approach where various effective drugs, which are assocd. with some drawbacks, can be modified by attaching with other drugs of same or different categories directly or via a linkage. More appropriately one can say combining two different pharmacophores with similar or different pharmacol. activities elicit synergistic action or help to target the parent drug to specific site/organ/cells resp. This approach is commonly used to improve physicochem., biopharmaceutical and drug delivery properties of therapeutic agents.
Supporting Information
Supporting Information
Table of 98 protein acetylation substrates of p300/CBP and table of 411 protein binding partners of p300/CBP. This material is available free of charge via the Internet at http://pubs.acs.org.
- cr500452k_si_001.pdf (254.15 kb)
Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Protein Lysine Acetylation by p300/CBPClick to copy article linkArticle link copied!

Chemical Reviews

SPECIAL ISSUE

1 Introduction

2 Background Information

2.1 Epigenetics and Chromatin

2.2 Post-Translational Modifications of Proteins

Figure 1

Figure 2

2.3 Case Study: Histone H4 Tail

2.4 Discovery of p300/CBP

Figure 3

2.5 p300/CBP Function in Signaling Pathways

Figure 4

Figure 5

3 p300 Acetyltransferase Activity

3.1 p300 Acetyltransferase Domain Structure

Figure 6

3.2 p300 Acetyltransferase Reaction Chemistry

Figure 7

4 Inhibitors of p300 Acetyltransferase Activity

4.1 Bisubstrate Acetyltransferase Inhibitors

Figure 8

4.2 Natural Product Acetyltransferase Inhibitors

Figure 9

4.3 Synthetic Acetyltransferase Inhibitors

Figure 10

Figure 11

5 Protein Ligands of p300/CBP

5.1 Structures of p300/CBP with Bound Protein Ligands

Figure 12

Figure 13

5.2 Flanking Domains on p300/CBP Acetyltransferase Activity

Figure 14

Figure 15

Figure 16

5.3 Compounds That Block or Mimic p300/CBP Ligand Binding

Figure 17

Figure 18

6 Potential Applications for Inhibitors and Activators of p300/CBP

6.1 Loss of p300/CBP Activity in Human Disease

6.2 Overexpression, Inappropriate Activation, or Mistargeting of p300/CBP

Figure 19

6.3 Cell-Based Assays of p300/CBP Activity and Inhibition

6.4 Overlap between Genetic and Pharmacologic Disruption of p300/CBP

7 Future Directions

8 Conclusion

Supporting Information

Terms & Conditions

Author Information

Biographies

Beverley M. Dancy

Philip A. Cole

Acknowledgment

Abbreviations

References

Cited By

Chemical Reviews

Article Views

Altmetric

Citations

Recommended Articles

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Protein Lysine Acetylation by p300/CBP
Click to copy article linkArticle link copied!