Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2010 Feb 15;5(2):e9199. doi: 10.1371/journal.pone.0009199.
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.
IGF/mTOR 通路受营养物质、生长因子、能量状态和细胞应激调节，调节各种生物体的衰老。SIRT1 是一种 NAD+依赖性去乙酰化酶，已知可调节模型生物中热量限制介导的长寿，并且与胰岛素/IGF 信号通路有关。在这里，我们研究了 SIRT1 对营养物质和细胞应激的反应对 mTOR 信号的潜在调节作用。我们证明 SIRT1 缺乏会导致 mTOR 信号升高，而应激条件并不能消除这种升高。SIRT1 激活剂白藜芦醇以 SIRT1 依赖性方式降低 mTOR 活性，而 SIRT1 抑制剂烟酰胺则增强 mTOR 活性。此外，我们证明 SIRT1 与 TSC2 相互作用，TSC2 是 mTORC1 上游 mTOR 抑制复合物的一个组成部分，并以 TSC2 依赖性方式调节 mTOR 信号。这些结果表明，SIRT1 通过 TSC1/2 复合物负调节 mTOR 信号。
