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Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress

Oncogene volume 25, pages 940–953 (2006)Cite this article

Abstract

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.

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Acknowledgements

We thank H Lother for invaluable support, J Milner, AJ Levine, F Fackelmayer, E Kim, I Dornreiter and A Hermannstädter for providing cell lines and reagents, C Stocking and F Fackelmayer for critically reading the manuscript, E Kim for insightful discussions and M Hintz-Malchow for her competent help in editing this manuscript. This work was supported by Deutsche Krebshilfe/Förderungsschwerpunkt ‘Apoptosedefizienz und ihre Modulation bei malignen Erkrankungen’, by the Fonds der Chemischen Industrie, and by EC FP6 funding. This publication reflects the author's views and not necessarily those of the EC. The community is not liable for any use that may be made of the information contained herein. The Heinrich-Pette-Institut is financially supported by Freie und Hansestadt Hamburg, and by Bundesministerium für Gesundheit und Soziales.

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  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Hamburg, Germany

    D Speidel, H Helmbold & W Deppert

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  1. D Speidel
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  2. H Helmbold
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Correspondence to W Deppert.

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Supplementary information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Speidel, D., Helmbold, H. & Deppert, W. Dissection of transcriptional and non-transcriptional p53 activities in the response to genotoxic stress. Oncogene 25, 940–953 (2006). https://doi.org/10.1038/sj.onc.1209126

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