PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

Mark Pearson, Roberta Carbone, Carla Sebastiani, Mario Cioce, Marta Fagioli, Shin’ichi Saito, Yuichiro Higashimoto, Ettore Appella, Saverio Minucci, Pier Paolo Pandolfi and Pier Giuseppe Pelicci ()
Additional contact information
Mark Pearson: European Institute of Oncology Department of Experimental Oncology
Roberta Carbone: European Institute of Oncology Department of Experimental Oncology
Carla Sebastiani: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Mario Cioce: European Institute of Oncology Department of Experimental Oncology
Marta Fagioli: Istituto di Medicina Interna e Scienze Oncologiche, Perugia University
Shin’ichi Saito: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health
Yuichiro Higashimoto: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health
Ettore Appella: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health
Saverio Minucci: European Institute of Oncology Department of Experimental Oncology
Pier Paolo Pandolfi: Memorial Sloan-Kettering Cancer Center, Cornell University
Pier Giuseppe Pelicci: European Institute of Oncology Department of Experimental Oncology

Nature, 2000, vol. 406, issue 6792, 207-210

Abstract: 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.

Date: 2000
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DOI: 10.1038/35018127

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