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Specific Inhibition of the Transcription Factor Ci by a Cobalt(III) Schiff Base–DNA Conjugate

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† ‡ § ∥ Department of Molecular Biosciences, Department of Chemistry, §Department of Radiology, and Department of Neurobiology, Northwestern University, Evanston, Illinois 60208, United States
*T.J.M.: 2175 Campus Drive, Silverman Hall 2504, Evanston, Illinois 60208, United States; fax, 847-467-3832; e-mail, [email protected]. R.A.H.: 2220 Campus Drive, Cook Hall 3117, Evanston, Illinois 60208, United States; fax, 847-467-1380; e-mail, [email protected]
Cite this: Mol. Pharmaceutics 2012, 9, 2, 325–333
Publication Date (Web):January 3, 2012
https://doi.org/10.1021/mp2005577
Copyright © 2012 American Chemical Society

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    Abstract

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    We describe the use of Co(III) Schiff base–DNA conjugates, a versatile class of research tools that target C2H2 transcription factors, to inhibit the Hedgehog (Hh) pathway. In developing mammalian embryos, Hh signaling is critical for the formation and development of many tissues and organs. Inappropriate activation of the Hedgehog (Hh) pathway has been implicated in a variety of cancers including medulloblastomas and basal cell carcinomas. It is well-known that Hh regulates the activity of the Gli family of C2H2 zinc finger transcription factors in mammals. In Drosophila the function of the Gli proteins is performed by a single transcription factor with an identical DNA binding consensus sequence, Cubitus Interruptus (Ci). We have demonstrated previously that conjugation of a specific 17 base-pair oligonucleotide to a Co(III) Schiff base complex results in a targeted inhibitor of the Snail family C2H2 zinc finger transcription factors. Modification of the oligonucleotide sequence in the Co(III) Schiff base–DNA conjugate to that of Ci’s consensus sequence (Co(III)-Ci) generates an equally selective inhibitor of Ci. Co(III)-Ci irreversibly binds the Ci zinc finger domain and prevents it from binding DNA in vitro. In a Ci responsive tissue culture reporter gene assay, Co(III)-Ci reduces the transcriptional activity of Ci in a concentration dependent manner. In addition, injection of wild-type Drosophila embryos with Co(III)-Ci phenocopies a Ci loss of function phenotype, demonstrating effectiveness in vivo. This study provides evidence that Co(III) Schiff base–DNA conjugates are a versatile class of specific and potent tools for studying zinc finger domain proteins and have potential applications as customizable anticancer therapeutics.

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    Detailed synthesis information for Co(III)-Ci and Co(III)-CiMut. Control experiments verifying the identity of EMSA shifted bands CiZn and KrZn. Verification experiments that PtcΔ136mut-Fluc is a Ci dependent luciferase readout of Ci activity. This material is available free of charge via the Internet at http://pubs.acs.org.

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