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The mTOR pathway negatively controls ATM by up-regulating miRNAs

Changxian Shen1, Peter J Houghton

  • 1Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 3, 2013
PubMed

Insights

Mammalian target of rapamycin (mTOR) signaling suppresses the ataxia telangiectasia mutated (ATM) checkpoint in sarcoma by increasing microRNAs that target ATM. Inhibiting mTOR boosts ATM levels, revealing a negative feedback loop crucial for genome integrity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The ataxia telangiectasia mutated (ATM) checkpoint is vital for maintaining genome integrity.
  • Dysregulation of ATM signaling is implicated in various cancers, including childhood sarcoma.

Purpose of the Study:

  • To investigate the regulatory relationship between mammalian target of rapamycin (mTOR) signaling and the ATM checkpoint in the context of sarcoma.
  • To identify the molecular mechanisms by which mTOR influences ATM activity.

Main Methods:

  • Utilized mouse sarcoma xenografts and cultured sarcoma cells.
  • Employed pharmacological inhibition and genetic down-regulation of the mTOR pathway.
  • Analyzed ATM mRNA and protein levels.
  • Investigated the role of specific microRNAs (miRNAs) and signaling pathways (S6K1/2).

Main Results:

  • mTOR signaling suppresses ATM in childhood sarcoma by up-regulating miRNAs (miR-18a, miR-421) that target ATM.
  • Inhibition or genetic down-regulation of mTOR led to increased ATM mRNA and protein.
  • mTOR Complex 1 (mTORC1) suppresses ATM through S6K1/2 signaling pathways.
  • Identified a negative feedback loop between ATM and mTOR signaling.

Conclusions:

  • Oncogenic growth signals may promote tumorigenesis by suppressing the ATM checkpoint via the mTOR pathway.
  • Targeting the mTOR-ATM axis could offer novel therapeutic strategies for sarcoma.
Keywords:
childhood cancerkinase inhibitor

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