p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs.
Many recent studies have implicated p53 in the cellular response to injury and induction of cell death by apoptosis. In a rat embryonal fibroblast cell line transformed with c-Ha-ras and a mutant temperature-sensitive p53 (val135), cells were G1 arrested at the permissive temperature of 32 degrees C when overexpressed p53 was in wild-type conformation. In this state cells were resistant to apoptosis induced by etoposide (at up to 50 microM) or bleomycin (15 microU ml-1). Cells at 37 degrees 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 function. 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 simply due to temperature effects on pharmacokinetics or DNA damage. Our data show that induction of a stable p53-mediated growth arrest renders these cells much less likely to undergo apoptosis in response to certain anti-cancer drugs, and we conclude that the regulatory role of p53 in apoptosis is influenced by the particular cellular context in which this gene is expressed.
Malcomson
R D
RD
Department of Pathology, University of Edinburgh Medical School, UK.
Oren
M
M
Wyllie
A H
AH
Harrison
D J
DJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001761:Bleomycin / Q000494:pharmacology*; D002478:Cells, Cultured; D005047:Etoposide / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D016158:Genes, p53 / Q000502:physiology*; D051381:Rats; D013696:Temperature
D000970:Antineoplastic Agents; D001761:Bleomycin; D005047:Etoposide