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SIRT1 Negatively Regulates the Mammalian Target of Rapamycin
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Journal Article
SIRT1 Negatively Regulates the Mammalian Target of Rapamycin
2010
Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Analysis
/ Animals
/ Cell Biology/Cellular Death and Stress Responses
/ Humans
/ Insects
/ Insulin
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Kinases
/ Mice
/ Mutation
/ NAD
/ Protein-Serine-Threonine Kinases - metabolism
/ Proteins
/ Rodents
/ Signal Transduction - drug effects
/ Signal Transduction - physiology
/ Stress
/ Stresses
/ TOR Serine-Threonine Kinases
/ Tuberous Sclerosis Complex 1
/ Tuberous Sclerosis Complex 2
/ Tumor Suppressor Proteins - genetics
/ Tumor Suppressor Proteins - metabolism
/ Yeast
