title: SIRT1 negatively regulates the mammalian target of rapamycin.
abstract: The IGF/mTOR pathway, which is modulated by nutrients, growth factors, energy status and cellular stress regulates aging in various organisms. SIRT1 is a NAD+ dependent deacetylase that is known to regulate caloric restriction mediated longevity in model organisms, and has also been linked to the insulin/IGF signaling pathway. Here we investigated the potential regulation of mTOR signaling by SIRT1 in response to nutrients and cellular stress. We demonstrate that SIRT1 deficiency results in elevated mTOR signaling, which is not abolished by stress conditions. The SIRT1 activator resveratrol reduces, whereas SIRT1 inhibitor nicotinamide enhances mTOR activity in a SIRT1 dependent manner. Furthermore, we demonstrate that SIRT1 interacts with TSC2, a component of the mTOR inhibitory-complex upstream to mTORC1, and regulates mTOR signaling in a TSC2 dependent manner. These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Hiyaa Singhee
authors.initials: HS
authors.lastname: Ghosh
authors.forename: Michael
authors.initials: M
authors.lastname: McBurney
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009536:Niacinamide / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D013267:Stilbenes; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D009536:Niacinamide; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol