C-MYC INDUCES APOPTOSIS IN EPITHELIAL-CELLS BY BOTH P53-DEPENDENT ANDP53-INDEPENDENT MECHANISMS

We tested the hypothesis that wild-type p53 activity is required for c -Myc-dependent apoptosis in epithelial cells, Primary baby rat kidney epithelial cell lines were generated by immortalization through the co ncerted action of c-Myc and a temperature-sensitive (ts) dominant inhi bitory mutant allele of p53 (BRK myc/p53ts cells), When shifted to the permissive temperature for wild-type p53 activity, the BRK myc/p53ts cells underwent growth arrest and apoptosis, However, apoptosis also c ould be induced by serum deprivation at the nonpermissive temperature, when p53 was in the mutant state, Bcl-2 suppressed both modes of cell death, Apoptosis induced by wild-type p53 but not by serum deprivatio n was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bar. We concluded that c-Myc could induce apoptos is in epithelial cells by at least two mechanisms that could be distin guished by their p53 requirement, Our results support the possibility that c-Myc-dependent cell death might be exploited for therapeutic end s during carcinoma development, without regard to p53 status of the ta rget cell.