title: WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
abstract: The tumor growth suppressor WAF1/CIP1 was recently shown to be induced by p53 and to be a potent inhibitor of cyclin-dependent kinases. In the present studies, we sought to determine the relationship between the expression of WAF1/CIP1 and endogenous regulation of p53 function. WAF1/CIP1 protein was first localized to the nucleus of cells containing wild-type p53 and undergoing G1 arrest. WAF1/CIP1 was induced in wild-type p53-containing cells by exposure to DNA damaging agents, but not in mutant p53-containing cells. The induction of WAF1/CIP1 protein occurred in cells undergoing either p53-associated G1 arrest or apoptosis but not in cells induced to arrest in G1 or to undergo apoptosis through p53-independent mechanisms. DNA damage led to increased levels of WAF1/CIP1 in cyclin E-containing complexes and to an associated decrease in cyclin-dependent kinase activity. These results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-specific pathway of growth control in mammalian cells.
authors.affiliation: Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
authors.forename: W S
authors.initials: WS
authors.lastname: el-Deiry
authors.forename: J W
authors.initials: JW
authors.lastname: Harper
authors.forename: P M
authors.initials: PM
authors.lastname: O'Connor
authors.forename: V E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: C E
authors.initials: CE
authors.lastname: Canman
authors.forename: J
authors.initials: J
authors.lastname: Jackman
authors.forename: J A
authors.initials: JA
authors.lastname: Pietenpol
authors.forename: M
authors.initials: M
authors.lastname: Burrell
authors.forename: D E
authors.initials: DE
authors.lastname: Hill
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D016193:G1 Phase / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases