Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4153-8. doi: 10.1073/pnas.0913860107. Epub 2010 Feb 16.
Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.
共济失调毛细血管扩张突变基因（ATM）是一种细胞损伤传感器，它协调细胞周期与损伤反应检查点和 DNA 修复，以维持基因组完整性。然而，ATM 也被牵涉到代谢调节中，ATM 缺乏与活性氧（ROS）的升高有关。ROS 在许多生理和病理生理过程中起核心作用，包括炎症和动脉粥样硬化和癌症等慢性疾病，突出了参与氧化还原平衡的细胞途径的重要性。我们已经确定了 ATM 的细胞质功能，该功能参与细胞对 ROS 的损伤反应。我们表明，在 ROS 升高的情况下，ATM 通过 LKB1/AMPK 代谢途径在细胞质中激活 TSC2 肿瘤抑制因子，以抑制 mTORC1 并诱导自噬。重要的是，ATM 缺陷细胞中 ROS 升高和 mTORC1 失调被雷帕霉素抑制，雷帕霉素也挽救了 Atm 缺陷小鼠的淋巴瘤发生。我们的结果确定了 ROS 诱导的 ATM 激活 TSC2 的细胞质途径，以调节 mTORC1 信号和自噬，确定了细胞损伤反应与代谢、蛋白质合成和细胞存活关键途径的整合节点。
