Skip to main content
Journal cover image

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

Publication ,  Journal Article
Alexander, A; Cai, S-L; Kim, J; Nanez, A; Sahin, M; MacLean, KH; Inoki, K; Guan, K-L; Shen, J; Person, MD; Kusewitt, D; Mills, GB; Kastan, MB ...
Published in: Proc Natl Acad Sci U S A
March 2, 2010

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 2, 2010

Volume

107

Issue

9

Start / End Page

4153 / 4158

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Reactive Oxygen Species
  • Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oxidative Stress
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Alexander, A., Cai, S.-L., Kim, J., Nanez, A., Sahin, M., MacLean, K. H., … Walker, C. L. (2010). ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A, 107(9), 4153–4158. https://doi.org/10.1073/pnas.0913860107
Alexander, Angela, Sheng-Li Cai, Jinhee Kim, Adrian Nanez, Mustafa Sahin, Kirsteen H. MacLean, Ken Inoki, et al. “ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.Proc Natl Acad Sci U S A 107, no. 9 (March 2, 2010): 4153–58. https://doi.org/10.1073/pnas.0913860107.
Alexander A, Cai S-L, Kim J, Nanez A, Sahin M, MacLean KH, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4153–8.
Alexander, Angela, et al. “ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS.Proc Natl Acad Sci U S A, vol. 107, no. 9, Mar. 2010, pp. 4153–58. Pubmed, doi:10.1073/pnas.0913860107.
Alexander A, Cai S-L, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan K-L, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4153–4158.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 2, 2010

Volume

107

Issue

9

Start / End Page

4153 / 4158

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Signal Transduction
  • Reactive Oxygen Species
  • Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Oxidative Stress