WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis.

TLDR

WAF1/CIP1 is a tumor‑suppressor protein that is induced by p53 and potently inhibits cyclin‑dependent kinases. The study aimed to elucidate how WAF1/CIP1 expression is regulated by endogenous p53 activity. WAF1/CIP1 localizes to the nucleus of wild‑type p53 cells undergoing G1 arrest, is induced by DNA damage only in these cells, associates with cyclin E complexes, reduces CDK activity, and is absent in mutant p53 or p53‑independent arrest/apoptosis, confirming it as a critical downstream effector of p53‑mediated growth control.

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.