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SIRT1 negatively regulates the mammalian target of rapamycin.

Ghosh HS, McBurney M, Robbins PD - PLoS ONE (2010)

Bottom Line: 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.These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

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.

Show MeSH
mTOR signaling in response to SIRT1 activator (resveratrol) and inhibitor (nicotinamide).(A) HeLa cells were either mock-treated (vehicle alone) or treated with –leucine media or 200nM insulin, with or without 50 µM resveratrol as indicated. (B) SIRT1-depleted and control HeLa cells were either mock-treated or treated with 10mM nicotinamide.
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pone-0009199-g002: mTOR signaling in response to SIRT1 activator (resveratrol) and inhibitor (nicotinamide).(A) HeLa cells were either mock-treated (vehicle alone) or treated with –leucine media or 200nM insulin, with or without 50 µM resveratrol as indicated. (B) SIRT1-depleted and control HeLa cells were either mock-treated or treated with 10mM nicotinamide.

Mentions: SIRT1 is a NAD+ dependent deacetylase whose catalytic activity is important for most of its known functions. To determine if the catalytic activity of SIRT1 is important for regulation of mTOR signaling, HeLa cells were treated with the SIRT1 activator resveratrol (RES), under stress (-leucine) or growth (insulin) conditions and mTOR signaling measured by examining phosphorylation levels of S6 and 4EBP1 (Figure 2A). Resveratrol suppressed mTOR signaling regardless of stress or growth conditions, suggesting that inducing the catalytic activity of SIRT1 negatively regulates mTOR signaling. To further confirm this observation, matched-control and SIRT1-depleted HeLa cells were treated with the SIRT1 inhibitor nicotinamide (NAM). Consistent with the resveratrol results, the NAM treated control cells showed upregulation of S6 and 4EBP1 phophorylation (Figure 2B). This result further demonstrates that the catalytic activity of SIRT1 is important for mTOR regulation and inhibition of the catalytic activity results in elevated mTOR signaling in normal cells.


SIRT1 negatively regulates the mammalian target of rapamycin.

Ghosh HS, McBurney M, Robbins PD - PLoS ONE (2010)

mTOR signaling in response to SIRT1 activator (resveratrol) and inhibitor (nicotinamide).(A) HeLa cells were either mock-treated (vehicle alone) or treated with –leucine media or 200nM insulin, with or without 50 µM resveratrol as indicated. (B) SIRT1-depleted and control HeLa cells were either mock-treated or treated with 10mM nicotinamide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821410&req=5

pone-0009199-g002: mTOR signaling in response to SIRT1 activator (resveratrol) and inhibitor (nicotinamide).(A) HeLa cells were either mock-treated (vehicle alone) or treated with –leucine media or 200nM insulin, with or without 50 µM resveratrol as indicated. (B) SIRT1-depleted and control HeLa cells were either mock-treated or treated with 10mM nicotinamide.
Mentions: SIRT1 is a NAD+ dependent deacetylase whose catalytic activity is important for most of its known functions. To determine if the catalytic activity of SIRT1 is important for regulation of mTOR signaling, HeLa cells were treated with the SIRT1 activator resveratrol (RES), under stress (-leucine) or growth (insulin) conditions and mTOR signaling measured by examining phosphorylation levels of S6 and 4EBP1 (Figure 2A). Resveratrol suppressed mTOR signaling regardless of stress or growth conditions, suggesting that inducing the catalytic activity of SIRT1 negatively regulates mTOR signaling. To further confirm this observation, matched-control and SIRT1-depleted HeLa cells were treated with the SIRT1 inhibitor nicotinamide (NAM). Consistent with the resveratrol results, the NAM treated control cells showed upregulation of S6 and 4EBP1 phophorylation (Figure 2B). This result further demonstrates that the catalytic activity of SIRT1 is important for mTOR regulation and inhibition of the catalytic activity results in elevated mTOR signaling in normal cells.

Bottom Line: 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.These results demonstrate that SIRT1 negatively regulates mTOR signaling potentially through the TSC1/2 complex.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

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.

Show MeSH