title: p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53.
abstract: We have shown previously that wild type p53 can rapidly induce replicative senescence in EJ human bladder carcinoma cells lacking functional p53. A major effector of p53 functions is p21Waf1/Cip1/Sdi1, a potent cyclin-dependent kinase inhibitor. p21Waf1/Cip1/Sdi1 has been shown to be involved in both p53 dependent and independent control of cell proliferation, differentiation and death. To directly investigate the effects of p21Waf1/Cip1/Sdi1 in the p53 response observed in EJ tumor cells, we established p21Waf1/Cip1/Sdi1 inducible lines using the tetracycline-regulatable vector system. p21Waf1/Cip1/Sdi1 induction caused irreversible cell cycle arrest in both G1 and G2/M, and diminished Cdk2 kinase activity. In addition, p21Waf1/Cip1/Sdi1 induction led to morphological alterations characteristic of cells undergoing replicative senescence with morphological, biochemical and ultrastructural markers of the senescent phenotype. Furthermore, sustained p21Waf1/Cip1/Sdi1 induction sensitized EJ cells to apoptotic cell death induced by mitomycin C, a cross-linking DNA damaging agent. These findings support the function of p21Waf1/Cip1/Sdi1 as an inducer of replicative senescence and a major mediator of this phenomenon in response to p53. Moreover, our results imply that therapeutic intervention in human cancers might be aimed at sustained elevation of p21Waf1/Cip1/Sdi1 expression.
authors.affiliation: Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fang
authors.forename: M
authors.initials: M
authors.lastname: Igarashi
authors.forename: J
authors.initials: J
authors.lastname: Leung
authors.forename: M M
authors.initials: MM
authors.lastname: Sugrue
authors.forename: S W
authors.initials: SW
authors.lastname: Lee
authors.forename: S A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D042846:CDC2-CDC28 Kinases; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C493956:CDKN1A protein, human; D003432:Cross-Linking Reagents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D001616:beta-Galactosidase; D013752:Tetracycline