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PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

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  • 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
    Istituto di Medicina Interna e Scienze Oncologiche, Perugia University)

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.

Suggested Citation

  • Mark Pearson & Roberta Carbone & Carla Sebastiani & Mario Cioce & Marta Fagioli & Shin’ichi Saito & Yuichiro Higashimoto & Ettore Appella & Saverio Minucci & Pier Paolo Pandolfi & Pier Giuseppe Pelicc, 2000. "PML regulates p53 acetylation and premature senescence induced by oncogenic Ras," Nature, Nature, vol. 406(6792), pages 207-210, July.
    • Handle: RePEc:nat:nature:v:406:y:2000:i:6792:d:10.1038_35018127
    DOI: 10.1038/35018127
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    Cited by:

    1. Blasi, Monica Francesca & Casorelli, Ida & Colosimo, Alfredo & Blasi, Francesco Simone & Bignami, Margherita & Giuliani, Alessandro, 2005. "A recursive network approach can identify constitutive regulatory circuits in gene expression data," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 348(C), pages 349-370.
    2. Xiaoyu Ma & Yingyi Zhang & Yuanyuan Zhang & Xu Zhang & Yan Huang & Kai He & Chuan Chen & Jielu Hao & Debiao Zhao & Nathan K. LeBrasseur & James L. Kirkland & Eduardo N. Chini & Qing Wei & Kun Ling & J, 2023. "A stress-induced cilium-to-PML-NB route drives senescence initiation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Sascha Schäuble & Karolin Klement & Shiva Marthandan & Sandra Münch & Ines Heiland & Stefan Schuster & Peter Hemmerich & Stephan Diekmann, 2012. "Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-14, August.

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