WAF1/CIP1 Is Induced in /?53-mediated G! Arrest and Apoptosis1

The tumor growth suppressor WAF1/C1PÌ 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 WAFIICIPI and endogenous regulation of p53 function. WAF1/CIP1 protein was first localized to the nucleus of cells containing wild-type p53 and undergoing G| arrest. WAFIICIPI was induced in wild-type p53-containing cells by exposure to DNA damaging agents, but not in mutant p5.?-containing cells. The induction of WAF1/CIP1 protein occurred in cells undergoing either p5.!-associated G¡ arrest or apoptosis but not in cells induced to arrest in GÌ or to undergo apoptosis through p5J-independent mechanisms. DNA damage led to increased levels of WAF1/CIP1 in cyclin E-containing complexes and to an associated de crease in cyclin-dependent kinase activity. These results support the idea that WAF1/CIP1 is a critical downstream effector in the p5J-specific path way of growth control in mammalian cells.