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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

M Pearson1, R Carbone, C Sebastiani

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

Nature
|July 26, 2000
PubMed

Insights

The promyelocytic leukemia (PML) protein regulates the p53 tumor suppressor

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tumor suppressor p53 induces cellular senescence in response to oncogenic signals.
  • p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation.
  • The mechanism of p53 activation by oncogenes remains largely unknown.

Purpose of the Study:

  • To investigate the role of the tumor suppressor PML in regulating the p53 response to oncogenic signals.
  • To elucidate the mechanism by which oncogenic Ras activates p53.
  • To determine the requirement of PML nuclear bodies for p53 acetylation and senescence.

Main Methods:

  • Overexpression of PML and oncogenic Ras in fibroblasts.
  • Analysis of p53 acetylation at lysine 382.
  • Immunofluorescence to study the re-localization of p53 and CBP.
  • Co-immunoprecipitation to detect p53-PML-CBP complex formation.
  • Studies in PML-/- fibroblasts to assess the necessity of PML.

Main Results:

  • Oncogenic Ras upregulates PML expression.
  • Overexpression of PML induces p53-dependent senescence.
  • Ras induces p53 acetylation at lysine 382, essential for its function.
  • Ras promotes re-localization of p53 and CBP into PML nuclear bodies, forming a p53-PML-CBP complex.
  • Ras-induced p53 acetylation, complex stabilization, and senescence are abolished in PML-/- fibroblasts.

Conclusions:

  • The tumor suppressor PML regulates the p53 response to oncogenic signals.
  • PML nuclear bodies are essential for p53 acetylation and subsequent senescence induction upon oncogene expression.
  • A direct link between PML and p53 acetylation and senescence is established.

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