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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
29
pubmed:dateCreated
2000-8-24
pubmed:abstractText
A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/2-(4-morpholinyl)-8-phenyl-4H-1-benz..., http://linkedlifedata.com/resource/pubmed/chemical/Cdkn1b protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Chromones, 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/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Microtubule-Associated Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Morpholines, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
275
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
21960-8
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:10791951-Animals, pubmed-meshheading:10791951-Cell Aging, pubmed-meshheading:10791951-Cell Cycle Proteins, pubmed-meshheading:10791951-Cell Division, pubmed-meshheading:10791951-Cells, Cultured, pubmed-meshheading:10791951-Chromones, pubmed-meshheading:10791951-Cyclin-Dependent Kinase Inhibitor p27, pubmed-meshheading:10791951-Cyclin-Dependent Kinases, pubmed-meshheading:10791951-Down-Regulation, pubmed-meshheading:10791951-Enzyme Inhibitors, pubmed-meshheading:10791951-Fibroblasts, pubmed-meshheading:10791951-Mice, pubmed-meshheading:10791951-Microtubule-Associated Proteins, pubmed-meshheading:10791951-Morpholines, pubmed-meshheading:10791951-Phosphatidylinositol 3-Kinases, pubmed-meshheading:10791951-Signal Transduction, pubmed-meshheading:10791951-Tumor Suppressor Proteins
pubmed:year
2000
pubmed:articleTitle
Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1.
pubmed:affiliation
Ludwig Institute for Cancer Research and Section of Virology and Cell Biology, Imperial College School of Medicine at St. Mary's Campus, London, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't