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Inhibition of the G2 DNA damage checkpoint and of protein kinases Chk1 and Chk2 by the marine sponge alkaloid debromohymenialdisine

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dc.contributor.author Curman, D. en_US
dc.contributor.author Cinel, B. en_US
dc.contributor.author Williams, D. E. en_US
dc.contributor.author Rundle, N. en_US
dc.contributor.author Block, W. D. en_US
dc.contributor.author Goodarzi, A. A. en_US
dc.contributor.author Hutchins, J. R. en_US
dc.contributor.author Clarke, P. R. en_US
dc.contributor.author Zhou, B. B. en_US
dc.contributor.author Lees-Miller, S. P. en_US
dc.contributor.author Andersen, R. J. en_US
dc.contributor.author Roberge, M. en_US
dc.date.accessioned 2006-06-19T17:41:03Z
dc.date.available 2006-06-19T17:41:03Z
dc.date.issued 2001-05 en_US
dc.identifier.citation J Biol Chem 276, 17914-9 (2001) en_US
dc.identifier.uri http://hdl.handle.net/1807.1/62
dc.description This article is hosted on a website external to the CBCRA Open Access Archive. Selecting “View/Open” below will launch the full-text article in another browser window.
dc.description.abstract Cells can respond to DNA damage by activating checkpoints that delay cell cycle progression and allow time for DNA repair. Chemical inhibitors of the G(2) phase DNA damage checkpoint may be used as tools to understand better how the checkpoint is regulated and may be used to sensitize cancer cells to DNA-damaging therapies. However, few inhibitors are known. We used a cell-based assay to screen natural extracts for G(2) checkpoint inhibitors and identified debromohymenialdisine (DBH) from a marine sponge. DBH is distinct structurally from previously known G(2) checkpoint inhibitors. It inhibited the G(2) checkpoint with an IC(50) of 8 micrometer and showed moderate cytotoxicity (IC(50) = 25 micrometer) toward MCF-7 cells. DBH inhibited the checkpoint kinases Chk1 (IC(50) = 3 micrometer) and Chk2 (IC(50) = 3.5 micrometer) but not ataxia-telangiectasia mutated (ATM), ATM-Rad3-related protein, or DNA-dependent protein kinase in vitro, indicating that it blocks two major branches of the checkpoint pathway downstream of ATM. It did not cause the activation or inhibition of different signal transduction proteins, as determined by mobility shift analysis in Western blots, suggesting that it inhibits a narrow range of protein kinases in vivo. en_US
dc.description.provenance Made available in DSpace on 2006-06-19T17:41:03Z (GMT). No. of bitstreams: 1 Curman.2001.17914.html: 415 bytes, checksum: 6816cde45862bb8c69afcfa91e45f96c (MD5) Previous issue date: 2001-05 en
dc.format.extent 415 bytes
dc.format.mimetype text/html
dc.language.iso en en_US
dc.publisher American Society for Biochemistry and Molecular Biology en_US
dc.relation.uri http://www.asbmb.org/ en_US
dc.title Inhibition of the G2 DNA damage checkpoint and of protein kinases Chk1 and Chk2 by the marine sponge alkaloid debromohymenialdisine en_US
dc.type Article en_US

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