sirt1 negatively regulates the mammalian target of rapamycinsirt1的负调节哺乳动物雷帕霉素靶.pdfVIP

SIRT1 Negatively Regulates the Mammalian Target of Rapamycin 1¤ 2 1 Hiyaa Singhee Ghosh , Michael McBurney , Paul D. Robbins * 1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 2 Ottawa Health Research Institute and Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada 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. Citation: Ghosh HS, McBurney M, Robbins PD (2010) SIRT1 Negatively Regulates the Mammalian Target of Rapamycin. PLoS ONE 5(2): e9199. doi:10.1371/ journal.pone.0009199 Editor: Mikhail V. Blagosklonny, Roswell Park Cancer Institute, United States of America Received August 29, 2009; Accepted Janu