Mechanistic insights into maintenance of high p53 acetylation by PTEN

Mol Cell. 2006 Aug;23(4):575-87. doi: 10.1016/j.molcel.2006.06.028.

Abstract

Earlier studies have shown that PTEN regulated p53 protein stability both in a phosphatase-dependent manner through antagonizing Akt-Mdm2 pathway and in a phosphatase-independent manner through interacting with p53. In this study, we report that PTEN forms a complex with p300 in the nucleus and plays a role in maintenance of high p53 acetylation in response to DNA damage. Furthermore, p300 is required for nuclear PTEN-regulated cell cycle arrest. Interestingly, however, p53 acetylation was found to promote PTEN-p53 interaction. To investigate the molecular mechanisms, we show that acetylation promotes p53 tetramerization, which, in turn, is required for the PTEN-p53 interaction and subsequent maintenance of high p53 acetylation. Taken together, our results suggest a physiological role for the PTEN tumor suppressor in the nucleus and provide a molecular explanation for our previous observation that PTEN controls p53 protein levels independent of its phosphatase activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Cell Nucleus / metabolism
  • G1 Phase
  • Humans
  • Models, Biological
  • Multiprotein Complexes / metabolism
  • Nuclear Export Signals
  • Nuclear Localization Signals
  • PTEN Phosphohydrolase / metabolism*
  • Phosphoprotein Phosphatases / metabolism
  • Protein Binding
  • Protein Structure, Quaternary
  • Thermodynamics
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • p300-CBP Transcription Factors / metabolism

Substances

  • Multiprotein Complexes
  • Nuclear Export Signals
  • Nuclear Localization Signals
  • Tumor Suppressor Protein p53
  • p300-CBP Transcription Factors
  • Phosphoprotein Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human