P53-DEPENDENT APOPTOSIS IN THE ABSENCE OF TRANSCRIPTIONAL ACTIVATION OF P53-TARGET GENES

THE tumour suppressor p53 is required to induce programmed cell death (apoptosis) by DNA-damaging agents(1,2). As p53 is a transcriptional a ctivator(3) that mediates gene induction after DNA damage(4), it has b een proposed to be a genetic switch that activates apoptosis-mediator genes(5). Here we evaluate the role of p53 in DNA-damage-induced apopt osis by establishing derivatives of GHFT1 cells, that are somatotropic progenitors immortalized by expression of SV40 T-antigen(6), which ex press a temperature-sensitive p53 mutant(7). In these cells induction of apoptosis by DNA damage depends strictly on p53 function. A shift t o the permissive temperature triggers apoptosis following DNA damage, but this is independent of new RNA or protein synthesis. The extent of apoptotic DNA cleavage is directly proportional to the period during which p53 is functional. These results do not support the proposal tha t p53 is an activator of apoptosis-mediator genes but rather indicate that p53 either represses genes necessary for cell survival(8) or is a component of the enzymatic machinery for apoptotic cleavage or repair of DNA(5).