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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2010-4-1
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pubmed:abstractText |
Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:AnnanRoland SRS,
pubmed-author:BelmontLisa DLD,
pubmed-author:BergnesGustaveG,
pubmed-author:BrejcKatjusaK,
pubmed-author:ChuaPenelope RPR,
pubmed-author:CopelandRobert ARA,
pubmed-author:CornwellWilliam DWD,
pubmed-author:DesaiRadhikaR,
pubmed-author:DhanakDashyantD,
pubmed-author:DiamondMelody AMA,
pubmed-author:FaucetteLeo FLF,
pubmed-author:FinerJeffrey TJT,
pubmed-author:GarciaCarlosC,
pubmed-author:GiardiniereMicheleM,
pubmed-author:GilmartinAidan GAG,
pubmed-author:GreshockJoel DJD,
pubmed-author:HuangPearl SPS,
pubmed-author:JacksonJeffrey RJR,
pubmed-author:KnightSteven DSD,
pubmed-author:LadLateshL,
pubmed-author:LeeYanY,
pubmed-author:LichtsteinerSergeS,
pubmed-author:LuoLusongL,
pubmed-author:McNultyDean EDE,
pubmed-author:MorgansDavid JDJJr,
pubmed-author:NevinsNeysaN,
pubmed-author:QianXiangpingX,
pubmed-author:SakowiczRomanR,
pubmed-author:SchauerStephen PSP,
pubmed-author:SunChiu-MeiCM,
pubmed-author:SuttonDavidD,
pubmed-author:VidalJustin DJD,
pubmed-author:WoodKenneth WKW,
pubmed-author:WoosterRichard FRF,
pubmed-author:ZhangShuyunS
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pubmed:issnType |
Electronic
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pubmed:day |
30
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pubmed:volume |
107
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
5839-44
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pubmed:dateRevised |
2010-10-1
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pubmed:meshHeading |
pubmed-meshheading:20167803-Allosteric Site,
pubmed-meshheading:20167803-Animals,
pubmed-meshheading:20167803-Antineoplastic Agents,
pubmed-meshheading:20167803-Binding Sites,
pubmed-meshheading:20167803-Cell Line, Tumor,
pubmed-meshheading:20167803-Chromosomal Proteins, Non-Histone,
pubmed-meshheading:20167803-Dogs,
pubmed-meshheading:20167803-Drug Screening Assays, Antitumor,
pubmed-meshheading:20167803-Humans,
pubmed-meshheading:20167803-Kinesin,
pubmed-meshheading:20167803-Mice,
pubmed-meshheading:20167803-Microtubules,
pubmed-meshheading:20167803-Mitosis,
pubmed-meshheading:20167803-Models, Molecular,
pubmed-meshheading:20167803-Molecular Structure,
pubmed-meshheading:20167803-Xenograft Model Antitumor Assays
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pubmed:year |
2010
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pubmed:articleTitle |
Antitumor activity of an allosteric inhibitor of centromere-associated protein-E.
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pubmed:affiliation |
Cytokinetics Inc, South San Francisco, CA 94080, USA. kwood@cytokinetics.com
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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