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ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Angela Alexander1, Sheng-Li Cai, Jinhee Kim

  • 1Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 18, 2010
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) protein senses cytoplasmic damage from reactive oxygen species (ROS). It activates pathways to repress mTORC1 and induce autophagy, crucial for cell survival and redox homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Ataxia-telangiectasia mutated (ATM) is a key sensor of DNA damage, regulating cell cycle checkpoints and DNA repair.
  • ATM deficiency is linked to increased reactive oxygen species (ROS) and metabolic dysregulation.
  • ROS plays a critical role in inflammation and chronic diseases like cancer and atherosclerosis.

Purpose of the Study:

  • To investigate the cytoplasmic role of ATM in responding to ROS-induced cellular damage.
  • To elucidate the molecular pathway by which ATM regulates metabolism and autophagy in response to ROS.

Main Methods:

  • Investigated ATM's cytoplasmic function in response to elevated ROS.
  • Utilized the LKB1/AMPK metabolic pathway to analyze ATM's activation of TSC2.
  • Assessed the impact of rapamycin on ATM-deficient cells and mice.

Main Results:

  • Identified a cytoplasmic ATM pathway that activates the TSC2 tumor suppressor in response to ROS.
  • Demonstrated that ATM activation of TSC2 represses mTORC1 and induces autophagy via the LKB1/AMPK pathway.
  • Showed that rapamycin inhibits elevated ROS and mTORC1 dysregulation in ATM-deficient cells, rescuing lymphomagenesis in mice.

Conclusions:

  • ATM has a cytoplasmic function in the cellular damage response to ROS.
  • This pathway integrates the DNA damage response with metabolism, protein synthesis, and cell survival pathways.
  • Targeting this pathway may offer therapeutic strategies for diseases associated with ROS and ATM deficiency.

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