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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Cell Death
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Cell Line
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Cell Survival
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DNA Damage
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DNA, Complementary / metabolism
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Dose-Response Relationship, Drug
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Electrophoresis, Polyacrylamide Gel
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Histone Deacetylases / metabolism*
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Humans
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Mice
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Mutagenesis, Site-Directed
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NAD / metabolism
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Neoplasms / metabolism
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Neoplasms / therapy
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Niacinamide / pharmacology
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Oxidative Stress*
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Point Mutation
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Poly(ADP-ribose) Polymerases / metabolism
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Polymerase Chain Reaction
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Protein Binding
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Protein Structure, Tertiary
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Sirtuin 1
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Sirtuins / metabolism*
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Trans-Activators / metabolism*
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Transcriptional Activation
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Tumor Suppressor Protein p53 / biosynthesis*
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fas Receptor / metabolism
Substances
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DNA, Complementary
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Trans-Activators
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Tumor Suppressor Protein p53
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fas Receptor
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NAD
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Niacinamide
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Poly(ADP-ribose) Polymerases
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SIRT1 protein, human
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Sirt1 protein, mouse
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Sirtuin 1
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Sirtuins
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Histone Deacetylases