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Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-β

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Chem. Biol. 2011, 6, 7, 700-708
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    Importazole, a Small Molecule Inhibitor of the Transport Receptor Importin-β
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    † The Department of Molecular and Cell Biology, University of California, Berkeley, MC 3200 LSA, Berkeley, California 94720-3200, United States
    ‡ National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-4256, United States
    § The Small Molecule Discovery Center, University of California, San Francisco, MC2552 Byers Hall S504, 1700 fourth Street, San Francisco, California 94158-2330, United States
    E-mail: [email protected]; [email protected]
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2011, 6, 7, 700–708
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    https://doi.org/10.1021/cb2000296
    Published April 6, 2011
    Copyright © 2011 American Chemical Society
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    During interphase, the transport receptor importin-β carries cargoes into the nucleus, where RanGTP releases them. A similar mechanism operates in mitosis to generate a gradient of active spindle assembly factors around mitotic chromosomes. Importin-β and RanGTP have been implicated in additional cellular processes, but the precise roles of the Ran/importin-β pathway throughout the cell cycle remain poorly understood. We implemented a FRET-based, high-throughput small molecule screen for compounds that interfere with the interaction between RanGTP and importin-β and identified importazole, a 2,4-diaminoquinazoline. Importazole specifically blocks importin-β-mediated nuclear import both in Xenopus egg extracts and cultured cells, without disrupting transportin-mediated nuclear import or CRM1-mediated nuclear export. When added during mitosis, importazole impairs the release of an importin-β cargo FRET probe and causes both predicted and novel defects in spindle assembly. Together, these results indicate that importazole specifically inhibits the function of importin-β, likely by altering its interaction with RanGTP. Importazole is a valuable tool to evaluate the function of the importin-β/RanGTP pathway at specific stages during the cell cycle.

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    This article is cited by 187 publications.

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