PMID:11672522

Citation	Luo, J, Nikolaev, AY, Imai, S, Chen, D, Su, F, Shiloh, A, Guarente, L and Gu, W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107:137-48
Abstract	The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
Links	PubMed
Keywords	Animals; Antigens, CD95/metabolism; Apoptosis; Blotting, Western; Cell Death; Cell Line; Cell Survival; DNA Damage; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Histone Deacetylases/metabolism; Humans; Mice; Mutagenesis, Site-Directed; NAD/metabolism; Neoplasms/metabolism; Neoplasms/therapy; Niacinamide/pharmacology; Oxidative Stress; Point Mutation; Poly(ADP-ribose) Polymerases/metabolism; Polymerase Chain Reaction; Protein Binding; Protein Structure, Tertiary; Sirtuin 1; Sirtuins/metabolism; Trans-Activators/metabolism; Transcriptional Activation; Tumor Suppressor Protein p53/biosynthesis
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