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PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

Nature volume 406, pages 207–210 (2000)Cite this article

Abstract

The tumour suppressor p53 induces cellular senescence in response to oncogenic signals1. p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation2. The mechanism of p53 activation by oncogenes remains largely unknown. Here we report that the tumour suppressor PML regulates the p53 response to oncogenic signals. We found that oncogenic Ras upregulates PML expression, and overexpression of PML induces senescence in a p53-dependent manner. p53 is acetylated at lysine 382 upon Ras expression, an event that is essential for its biological function. Ras induces re-localization of p53 and the CBP acetyltransferase within the PML nuclear bodies and induces the formation of a trimeric p53–PML–CBP complex. Lastly, Ras-induced p53 acetylation, p53–CBP complex stabilization and senescence are lost in PML-/-fibroblasts. Our data establish a link between PML and p53 and indicate that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression.

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Figure 1: PML is required for Ras-induced senescence in primary cells.
Figure 2: PML-induced senescence is dependent on p53.
Figure 3: p53 acetylation accompanies sensenance and is downregulated in PML —/- fibroblasts
Figure 4: RasV12 induces complex formation between p53, PML and CBP.
Figure 5: Colocalization of PML, CBP and p53 after expression of PML or RasV12.

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Acknowledgements

We thank Y. Nakatani, M. Sciurpi and A. Ariesi for reagents, discussion and technical help. This work was supported by grants from MURST, AIRC and the EC.

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Authors and Affiliations

  1. European Institute of Oncology Department of Experimental Oncology, Milan, 20141, Italy

    Mark Pearson, Roberta Carbone, Mario Cioce, Saverio Minucci & Pier Giuseppe Pelicci

  2. Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, Perugia, 06100, Italy

    Carla Sebastiani, Marta Fagioli & Pier Giuseppe Pelicci

  3. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Shin’ichi Saito, Yuichiro Higashimoto & Ettore Appella

  4. Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, 10021, USA

    Pier Paolo Pandolfi

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Correspondence to Pier Giuseppe Pelicci.

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Pearson, M., Carbone, R., Sebastiani, C. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000). https://doi.org/10.1038/35018127

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