p53-Dependent apoptosis in the absence of transcriptional activation of p53-target genes

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Abstract
THE tumour suppressor p53 is required to induce programmed cell death (apoptosis) by DNA-damaging agents1,2. As p53 is a transcriptional activator3 that mediates gene induction after DNA damage4, it has been proposed to be a genetic switch that activates apoptosis-mediator genes5. Here we evaluate the role of p53 in DNA-damage-induced apoptosis by establishing derivatives of GHFT1 cells, that are somatotropic progenitors immortalized by expression of SV40 T-antigen6, which express a temperature-sensitive p53 mutant7. In these cells induction of apoptosis by DNA damage depends strictly on p53 function. A shift to 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 propo-sal that p53 is an activator of apoptosis-mediator genes but rather indicate that p53 either represses genes necessary for cell survival8 or is a component of the enzymatic machinery for apoptotic cleav-age or repair of DNA5.