WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.
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.
el-Deiry
W S
WS
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Harper
J W
JW
O'Connor
P M
PM
Velculescu
V E
VE
Canman
C E
CE
Jackman
J
J
Pietenpol
J A
JA
Burrell
M
M
Hill
D E
DE
Wang
Y
Y
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*
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