THE POLYPROLINE REGION OF P53 IS REQUIRED TO ACTIVATE APOPTOSIS BUT NOT GROWTH ARREST

p53 is a pivotal regulator of apoptosis but its mechanism of action is obscure. We report that the polyproline (PP) region located between p 53's transactivation and DNA binding domains is necessary to induce ap optosis but not cell growth arrest. The PP region was dispensable for DNA binding, inhibition of SAOS-2 tumor cell growth, suppression of E1 A+RAS cell transformation, and cell cycle inhibition. A temperature-se nsitive dominant inhibitory p53 mutant lacking PP (p53ts Delta PP) ret ained its ability to cooperate with adenovirus E1A in transformation o f primary BRK cells. However, while activation of wt p53 induced apopt osis in E1A+p53ts-transformed cells, activation of p53 Delta PP induce d cell cycle arrest but not apoptosis in E1A+p53ts Delta PP-transforme d cells. Similarly, PP deletion abolished apoptosis in LoVo colon carc inoma cells, which are killed by wt p53 overexpression. Transactivatio n was largely unaffected by PP deletion, Significantly, BAX induction was intact, indicating that additional events are required for p53 to induce apoptosis. As a recently described site for familial mutation i n at least one breast cancer family, the PP region represents a domain that may be altered in human tumors. We concluded that p53's ability to induce apoptosis is dispensable for inhibiting cell growth and tran sformation and that the PP region plays a crucial role in apoptotic si gnaling.