期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 9, 页码 4153-4158出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0913860107
关键词
autophagy; oxidative stress; signal transduction; cytoplasm; damage
资金
- National Institutes of Health (NIH) [R01 CA63613]
- University of Texas M. D. Anderson Cancer Center [ES007784, CA 16672]
- Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center [NIH] [P01 HD18655, R01 NS058956, R01 CA71387, R01 CA21765]
- Sowell-Huggins Fellowship
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.
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