[Cyclin dependent kinase inhibitors and replicative senescence].
Replicative senescence is defined for human diploid fibroblasts in culture as a cell growth arrest appearing beyond 50 +/- 10 population doublings and associated with telomeres' shortening. This phenomenon shows an increased expression of growth cell inhibitors: p21Waf1 described as an universal CDK inhibitor and p16INK4a as a specific inhibitor for both G1 phase kinases CDK4 and CDK6. The cell proliferation inhibitor p14ARF, product of INK4a/ARF locus is involved in replicative senescence too. Overexpression or homozygotic deletion of these inhibitors demonstrated their role in senescence induction. These proteins are involved in two different metabolic pathways, the first including p53, represented by E2F, ARF, MDM2, p53, p21Waf1, and the second concerning pRb and p16INK4a. These two pathways present numerous interactions and the polymerase (PARP) in relation with p53 and activated by telomere shortening might represent via p21Waf1 a link between this shortening and cell cycle control. An another metabolic pathway involving PTEN and p27KIP1 is discussed in senescent-like phenotype induction, but its activity in replicative senescent is uncertain.
Gerland
L M
LM
Laboratoire de cytologie analytique (Inserm U 453), faculté de médecine, 69373 Lyon, France.
Ffrench
M
M
Magaud
J P
JP
D002455:Cell Division; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts; D006801:Humans; D016160:Retinoblastoma Protein / Q000502:physiology; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C493956:CDKN1A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases
Inhibiteurs des kinases dépendantes des cyclines et sénescence réplicative.