c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-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 concerted action of c-Myc and a temperature-sensitive (ts) dominant inhibitory 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 could 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 deprivation was accompanied by G1 cell cycle arrest and increased expression of the Bcl-2 antagonist Bar. We concluded that c-Myc could induce apoptosis in epithelial cells by at least two mechanisms that could be distinguished by their p53 requirement, Our results support the possibility that c-Myc-dependent cell death might be exploited for therapeutic ends during carcinoma development, without regard to p53 status of the target cell.