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• W1993099215 abstract "Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DCATM is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. ATM deficiency is also associated with increased oxidative stress, and ATM has been implicated in metabolic regulation. The mechanisms responsible for crosstalk between oxidative stress and metabolic pathways are not fully understood, but are important since tumors often exhibit elevated ROS, and redox pathways may be therapeutic targets.We report a novel cytoplasmic pathway whereby ATM activates the TSC2 tumor suppressor, via LKB1 and AMPK in response to ROS, distinct from that of nuclear ATM in the DNA damage response. Knockout MEFs and siRNA approaches illustrated that mTORC1 suppression by ROS was dependent upon Tsc2 and ATM, and independent of p53. Reconstitution of LKB1-deficient HeLa S3 cells with wild-type LKB1 restored mTORC1 repression by ROS, while reconstitution of a mutant LKB1 lacking the ATM phosphorylation site did not. An in vivo cell-based functional assay revealed that a Tsc2 mutant lacking AMPK phosphorylation sites was deficient in repressing mTORC1 activity in response to H22, directly implicating AMPK as the mediator of ATM signaling to Tsc2. We also demonstrated that ATM activation of the LKB1-AMPK pathway was responsible for TSC2-mediated mTORC1 repression exclusively in the cytoplasm with subcellular fractionation and leptomycin B.Importantly, elevated ROS and dysregulation of mTORC1 in both ATM-deficient and Tsc2-deficient cells was inhibited with rapamycin. We also show for that rapamycin rescued lymphomagenesis in Atm-deficient mice, resulting in enhanced survival.mTORC1 negatively regulates autophagy, a cellular process which degrades organelles and long-lived proteins as a survival mechanism, but can also cause cell death. We tested the hypothesis that repression of mTORC1 by ROS results in induction of autophagy. Electron microscopy analysis demonstrated enhanced formation of autophagosomes in response to ROS. In MCF7 and SKOV-3 cells stably expressing GFP-LC3, a marker of autophagosomes, we observed an increase in punctate GFP-labeled autophagosomes, consistent with autophagy induction. A necessary step during autophagosome formation is lipidation of the cytosolic form of LC3 (LC3 I) to LC3 II, which can be detected as a mobility shift by western analysis. Western analysis confirmed that LC3 II was increased, and concomitantly, the autophagic substrate p62 was decreased, in response to ROS-mediated mTORC1 repression.Together, our results identify a pathway for ATM activation of TSC2 to regulate mTORC1 signaling and autophagy in response to ROS, identifying a new integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4831." @default.
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• W1993099215 date "2010-04-15" @default.
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• W1993099215 title "Abstract 4831: ATM signals to TSC2 in the cytoplasm to regulate mTORC1 and autophagy in response to ROS" @default.
• W1993099215 doi "https://doi.org/10.1158/1538-7445.am10-4831" @default.
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