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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
1997-7-17
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pubmed:abstractText |
CDK inhibitors are thought to prevent cell proliferation by negatively regulating cyclin-CDK complexes. We propose that the opposite is also true, that cyclin-CDK complexes in mammmalian cells can promote cell cycle progression by directly down-regulating CDK inhibitors. We show that expression of cyclin E-CDK2 in murine fibroblasts causes phosphorylation of the CDK inhibitor p27Kip1 on T187, and that cyclin E-CDK2 can directly phosphorylate p27 T187 in vitro. We further show that cyclin E-CDK2-dependent phosphorylation of p27 results in elimination of p27 from the cell, allowing cells to transit from G1 to S phase. Moreover, mutation of T187 in p27 to alanine creates a p27 protein that causes a G1 block resistant to cyclin E and whose level of expression is not modulated by cyclin E. A kinetic analysis of the interaction between p27 and cyclin E-CDK2 explains how p27 can be regulated by the same enzyme it targets for inhibition. We show that p27 interacts with cyclin E-CDK2 in at least two distinct ways: one resulting in p27 phosphorylation and release, the other in tight binding and cyclin E-CDK2 inhibition. The binding of ATP to the CDK governs which state predominates. At low ATP (< 50 microM) p27 is primarily a CDK inhibitor, but at ATP concentrations approaching physiological levels (> 1 mM) p27 is more likely to be a substrate. Thus, we have identified p27 as a biologically relevant cyclin E-CDK2 substrate, demonstrated the physiological consequences of p27 phosphorylation, and developed a kinetic model to explain how p27 can be both an inhibitor and a substrate of cyclin E-CDK2.
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pubmed:grant |
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Adenosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/CDC2-CDC28 Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Cdk2 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1b protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase Inhibitor...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclins,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/Microtubule-Associated Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Threonine,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0890-9369
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
11
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1464-78
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:9192873-3T3 Cells,
pubmed-meshheading:9192873-Adenosine Triphosphate,
pubmed-meshheading:9192873-Animals,
pubmed-meshheading:9192873-CDC2-CDC28 Kinases,
pubmed-meshheading:9192873-Cell Cycle,
pubmed-meshheading:9192873-Cell Cycle Proteins,
pubmed-meshheading:9192873-Cyclin-Dependent Kinase 2,
pubmed-meshheading:9192873-Cyclin-Dependent Kinase Inhibitor p27,
pubmed-meshheading:9192873-Cyclin-Dependent Kinases,
pubmed-meshheading:9192873-Cyclins,
pubmed-meshheading:9192873-Down-Regulation,
pubmed-meshheading:9192873-G1 Phase,
pubmed-meshheading:9192873-Histones,
pubmed-meshheading:9192873-Mice,
pubmed-meshheading:9192873-Microtubule-Associated Proteins,
pubmed-meshheading:9192873-Models, Biological,
pubmed-meshheading:9192873-Mutation,
pubmed-meshheading:9192873-Phosphoproteins,
pubmed-meshheading:9192873-Phosphorylation,
pubmed-meshheading:9192873-Protein-Serine-Threonine Kinases,
pubmed-meshheading:9192873-S Phase,
pubmed-meshheading:9192873-Threonine,
pubmed-meshheading:9192873-Tumor Suppressor Proteins
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pubmed:year |
1997
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pubmed:articleTitle |
Cyclin E-CDK2 is a regulator of p27Kip1.
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pubmed:affiliation |
Division of Basic Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington 98104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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