Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress.
Following genotoxic stress, p53 either rescues a damaged cell or promotes its elimination. The parameters determining a specific outcome of the p53 response are largely unknown. In mouse fibroblasts treated with different irradiation schemes, we monitored transcriptional and non-transcriptional p53 activities and identified determinants that initiate an anti- or a pro-apoptotic p53 response within the context of p53-independent stress signaling. The primary, transcription-mediated p53 response in these cells is anti-apoptotic, while induction of p53-dependent apoptosis requires an additional, transcription-independent p53 activity, provided by high intracellular levels of activated p53. High intracellular levels of p53 were selectively generated after apoptosis-inducing high-dose UV-irradiation, and correlated with a strongly delayed upregulation of Mdm2. Following high-dose UV-irradiation, p53 accumulated in the cytoplasm and led to activation of the pro-apoptotic protein Bax. As p53-dependent Bax-activation is transcription-independent, we postulated that certain transcription-deficient mutant p53 proteins might also exert this activity. Indeed we found an endogenous, transcription-inactive mutant p53 that upon genotoxic stress induced Bax-activation in vivo. Our results demonstrate the impact and in vivo relevance of non-transcriptional mechanisms for wild-type and mutant p53-mediated apoptosis.
Speidel
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Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, D-20251 Hamburg, Germany.
Helmbold
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H
Deppert
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D016475:3T3 Cells / Q000528:radiation effects; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000528:radiation effects; D003600:Cytosol / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009152:Mutagenicity Tests; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism / Q000528:radiation effects; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D014466:Ultraviolet Rays; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000528:radiation effects
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C411296:TP53I3 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2