WAF1 CIP1 IS INDUCED IN P53-MEDIATED G(1) ARREST AND APOPTOSIS/

The tumor growth suppressor WAF1/CIP1 was recently shown to be induced p53 and to be a potent inhibitor of cyclin-dependent kinases. In the present studies, we sought to determine the relationship between the e xpression of WAF1/CIP1 and endogenous regulation of p53 function. WAF1 /CIP1 protein was first localized to the nucleus of cells containing m ild-type p53 and undergoing G(1) 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 oc curred in cells undergoing either p53-associated G(1) arrest or apopto sis but not in cells induced to arrest in G(1) or to undergo apoptosis through p53-independent mechanisms. DNA damage Led to increased level s of WAF1/CIP1 in cyclin E-containing complexes and to an associated d ecrease in cyclin-dependent kinase activity. These results support the idea that WAF1/CIP1 is a critical downstream effector in the p53-spec ific pathway of growth control in mammalian cells.