Abstract
Resveratrol (RSV) is a naturally occurring polyphenol that has been found to exert antioxidant, anti-inflammatory, and neuroprotective properties. However, how RSV exerts its beneficial health effects remains largely unknown. Here, we show that RSV inhibits insulin- and leucine-stimulated mTOR signaling in C2C12 fibroblasts via a Sirt1-independent mechanism. Treating C2C12 cells with RSV dramatically inhibited insulin-stimulated Akt, S6 kinase, and 4E-BP1 phosphorylation but had little effect on tyrosine phosphorylation of the insulin receptor and activation of the p44/42 MAPK signaling pathway. RSV treatment also partially blocked mTOR and S6 kinase phosphorylation in TSC1/2-deficient mouse embryonic fibroblasts, suggesting the presence of an inhibitory site downstream of TSC1/2. Knocking out PDK1 or suppressing AMP-activated protein kinase had little effect on leucine-stimulated mTOR signaling. On the other hand, RSV significantly increased the association between mTOR and its inhibitor, DEPTOR. Furthermore, the inhibitory effect of RSV on leucine-stimulated mTOR signaling was greatly reduced in cells in which the expression levels of DEPTOR were suppressed by RNAi. Taken together, our studies reveal that RSV inhibits leucine-stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Blotting, Western
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Cells, Cultured
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins
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Leucine / pharmacology
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Mice
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Mice, Knockout
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Myoblasts / cytology
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Myoblasts / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / physiology
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Resveratrol
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Signal Transduction / drug effects*
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Sirtuin 1 / physiology
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Stilbenes / pharmacology*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / physiology
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Vasodilator Agents / pharmacology*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Intracellular Signaling Peptides and Proteins
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PDK1 protein, human
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Pdk1 protein, mouse
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Stilbenes
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TSC1 protein, human
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Tsc1 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Vasodilator Agents
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DEPTOR protein, human
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Sirt1 protein, mouse
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Sirtuin 1
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Leucine
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Resveratrol