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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
Expression and signaling in mTOR pathway in response to stress stimuli and rapamycin.(A) Western blot analysis of extracts from matched-control and SIRT1 depleted HeLa cells after stress treatments as indicated. (B) SIRT1-depleted and matched-control HeLa cells, and (C) Wild-type, SIRT1  and TSC2  MEFs were either mock-treated (vehicle alone) or treated with 25nM rapamycin for 1 hr followed by Western blot analysis for mTOR activity. S+: SIRT1+/+, S-: SIRT1−/−, T+: TSC2+/+, T-: TSC2−/−.
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pone-0009199-g003: Expression and signaling in mTOR pathway in response to stress stimuli and rapamycin.(A) Western blot analysis of extracts from matched-control and SIRT1 depleted HeLa cells after stress treatments as indicated. (B) SIRT1-depleted and matched-control HeLa cells, and (C) Wild-type, SIRT1 and TSC2 MEFs were either mock-treated (vehicle alone) or treated with 25nM rapamycin for 1 hr followed by Western blot analysis for mTOR activity. S+: SIRT1+/+, S-: SIRT1−/−, T+: TSC2+/+, T-: TSC2−/−.

Mentions: To determine if SIRT1 modulates the expression of the critical proteins involved in regulation of the mTOR pathway, protein expression analysis of TSC1, TSC2, Raptor and Rheb in SIRT1 depleted cells under various stress conditions was performed. As shown in figure 3A, SIRT1 deficiency does not affect the expression of the mTOR regulatory proteins.


SIRT1 negatively regulates the mammalian target of rapamycin.

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

Expression and signaling in mTOR pathway in response to stress stimuli and rapamycin.(A) Western blot analysis of extracts from matched-control and SIRT1 depleted HeLa cells after stress treatments as indicated. (B) SIRT1-depleted and matched-control HeLa cells, and (C) Wild-type, SIRT1  and TSC2  MEFs were either mock-treated (vehicle alone) or treated with 25nM rapamycin for 1 hr followed by Western blot analysis for mTOR activity. S+: SIRT1+/+, S-: SIRT1−/−, T+: TSC2+/+, T-: TSC2−/−.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0009199-g003: Expression and signaling in mTOR pathway in response to stress stimuli and rapamycin.(A) Western blot analysis of extracts from matched-control and SIRT1 depleted HeLa cells after stress treatments as indicated. (B) SIRT1-depleted and matched-control HeLa cells, and (C) Wild-type, SIRT1 and TSC2 MEFs were either mock-treated (vehicle alone) or treated with 25nM rapamycin for 1 hr followed by Western blot analysis for mTOR activity. S+: SIRT1+/+, S-: SIRT1−/−, T+: TSC2+/+, T-: TSC2−/−.
Mentions: To determine if SIRT1 modulates the expression of the critical proteins involved in regulation of the mTOR pathway, protein expression analysis of TSC1, TSC2, Raptor and Rheb in SIRT1 depleted cells under various stress conditions was performed. As shown in figure 3A, SIRT1 deficiency does not affect the expression of the mTOR regulatory proteins.

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