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ATM promotes apoptosis and suppresses tumorigenesis in response to Myc

Raju V Pusapati1, Robert J Rounbehler, SungKi Hong

  • 1Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, 1808 Park Road 1C, Smithville, TX 78957, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 25, 2006
PubMed

Insights

Myc oncogene overexpression triggers DNA damage, activating the ATM kinase pathway. This ATM-dependent response is crucial for p53 activation, apoptosis, and suppressing tumor development in cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The c-myc oncogene is frequently overexpressed in human cancers.
  • The p53 tumor suppressor is activated by deregulated Myc activity to induce apoptosis and inhibit tumor formation.

Purpose of the Study:

  • To investigate the role of ataxia-telangiectasia mutated (ATM) kinase in p53 activation in response to Myc overexpression.
  • To determine if Myc-induced DNA damage triggers an ATM-dependent response critical for tumor suppression.

Main Methods:

  • Utilized a transgenic mouse model overexpressing Myc in squamous epithelial tissues.
  • Assessed apoptosis, tumorigenesis, and DNA damage markers (gammaH2AX, phospho-SMC1 foci) in primary keratinocytes and transgenic tissue.
  • Examined the effect of Atm inactivation on these processes.

Main Results:

  • p53 induction in response to Myc overexpression requires ATM kinase.
  • Inactivation of Atm suppressed apoptosis and accelerated tumorigenesis in the Myc transgenic model.
  • Deregulated Myc expression induced DNA damage and ATM-dependent markers in vivo.

Conclusions:

  • Myc overexpression causes DNA damage in vivo.
  • The ATM-dependent response to Myc-induced DNA damage is critical for p53 activation and apoptosis.
  • This pathway is essential for suppressing tumor development driven by Myc.

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