1. Mammalian SIRT1 represses forkhead transcription factors.
- Author
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Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, and Guarente L
- Subjects
- Acetylation, Animals, Apoptosis, Blotting, Northern, Blotting, Western, Cell Line, Dose-Response Relationship, Drug, Down-Regulation, Embryo, Mammalian cytology, Forkhead Box Protein O1, Forkhead Transcription Factors, Gene Expression Regulation, Genes, Reporter, HeLa Cells, Histone Acetyltransferases, Histone Deacetylases metabolism, Humans, Mice, Mice, Knockout, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases metabolism, Plasmids metabolism, Precipitin Tests, Protein Binding, Sirtuin 1, Sirtuins metabolism, Stem Cells metabolism, Transcription, Genetic, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins metabolism, Up-Regulation, p300-CBP Transcription Factors, Acetyltransferases metabolism, Cell Cycle Proteins metabolism, DNA-Binding Proteins metabolism, Histone Deacetylases physiology, Sirtuins physiology, Transcription Factors metabolism
- Abstract
The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
- Published
- 2004
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