P53-INDEPENDENT DEATH AND P53-INDUCED PROTECTION AGAINST APOPTOSIS INFIBROBLASTS TREATED WITH CHEMOTHERAPEUTIC DRUGS

Many recent studies have implicated p53 in the cellular response to in jury and induction of cell death by apoptosis. In a rat embryonal fibr oblast cell line transformed with c-Ha-ras and a mutant temperature-se nsitive p53 (val135), cells were G(1) arrested at the permissive tempe rature of 32 degrees C when overexpressed p53 was in wild-type conform ation. In this state cells were resistant to apoptosis induced by etop oside (at up to 50 mu M) or bleomycin (15 mu U ml(-1)). Cells at 37 de grees C with overexpressed p53 in mutant conformation were freed from this growth arrest, continued proliferating and showed dose-dependent increases in apoptosis. This death is independent of wild-type p53 fun ction. Control cells containing a non-temperature-sensitive mutant p53 (phe132) were sensitive to both etoposide and bleomycin after 24 h at 32 degrees C and 37 degrees C, indicating that the results are not si mply due to temperature effects on pharmacokinetics or DNA damage. Our data show that induction of a stable p53-mediated growth arrest rende rs these cells much less likely to undergo apoptosis in response to ce rtain anti-cancer drugs, and we conclude that the regulatory role of p 53 in apoptosis is influenced by the particular cellular context in wh ich this gene is expressed.