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 Bax. 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.
Sakamuro
D
D
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Eviner
V
V
Elliott
K J
KJ
Showe
L
L
White
E
E
Prendergast
G C
GC
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001769:Blood; D002460:Cell Line; D004848:Epithelium / Q000473:pathology; D016158:Genes, p53; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D013696:Temperature; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051028:bcl-2-Associated X Protein