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Negative control of p53 by Sir2alpha promotes cell survival under stress

J Luo1, A Y Nikolaev, S Imai

  • 1Institute of Cancer Genetics and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.

Cell
|October 24, 2001
PubMed

Insights

Mammalian Sir2alpha interacts with p53, inhibiting its function and repressing apoptosis. Nicotinamide (Vitamin B3) blocks this deacetylation, impacting cellular stress response and cancer therapy.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Sir2 proteins are NAD-dependent deacetylases linking metabolism to gene silencing and aging.
  • Mammalian Sir2 homologs, including Sir2alpha, are implicated in various cellular processes.

Purpose of the Study:

  • To investigate the interaction between mammalian Sir2alpha and the tumor suppressor p53.
  • To elucidate the role of Sir2alpha in regulating p53-mediated functions, including apoptosis and cellular stress responses.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate physical interaction between Sir2alpha and p53.
  • In vivo and in vitro experiments to assess the effect of Sir2alpha on p53 acetylation and deacetylation.
  • Cellular assays measuring apoptosis and stress response in the presence of Sir2alpha or its mutant.

Main Results:

  • Mammalian Sir2alpha physically interacts with p53.
  • Sir2alpha attenuates p53-mediated transcriptional activity and DNA binding.
  • Nicotinamide (Vitamin B3) inhibits Sir2alpha-induced p53 deacetylation and enhances p53 acetylation in vivo.
  • Sir2alpha represses p53-dependent apoptosis induced by DNA damage and oxidative stress.
  • Expression of a Sir2alpha point mutant sensitizes cells to stress-induced apoptosis.

Conclusions:

  • Mammalian Sir2alpha plays a critical role in a p53 regulatory pathway.
  • Sir2alpha modulates cellular sensitivity to p53-dependent apoptosis.
  • Targeting the Sir2alpha-p53 interaction may offer novel therapeutic strategies for cancer.

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