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SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 Apr 22; Vol. 280 (16), pp. 16456-60. Date of Electronic Publication: 2005 Feb 16. - Publication Year :
- 2005
-
Abstract
- In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha. In addition, SIRT1 and PGC-1alpha directly interact and can be co-immunoprecipitated as a molecular complex. A single amino acid mutation in the putative ADP-ribosyltransferase domain of SIRT1 inhibits the interaction of SIRT1 with PGC-1alpha but does not effect the interaction of SIRT1 with either p53 or Foxo3a. We further show that PGC-1alpha is acetylated in vivo. This acetylation is augmented by treatment with the SIRT1 inhibitor nicotinamide or by expression of the transcriptional coactivator p300. Finally we demonstrate that SIRT1 catalyzes PGC-1alpha deacetylation both in vitro and in vivo. These results provide a direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular metabolism.
- Subjects :
- Acetylation
Animals
DNA-Binding Proteins metabolism
E1A-Associated p300 Protein
Forkhead Box Protein O1
Forkhead Transcription Factors
HeLa Cells
Humans
NAD metabolism
Nerve Tissue Proteins
Niacinamide metabolism
Nuclear Proteins metabolism
Oxygen Consumption physiology
PC12 Cells
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
RNA-Binding Proteins genetics
Rats
Sirtuin 1
Sirtuins genetics
Trans-Activators metabolism
Transcription Factors genetics
Tumor Suppressor Protein p53 metabolism
RNA-Binding Proteins metabolism
Sirtuins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15716268
- Full Text :
- https://doi.org/10.1074/jbc.M501485200