Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 5, Pages 1446-1451Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0507367103
Keywords
p53; DNA damage
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Funding
- NCI NIH HHS [R01 CA098601, P30 CA016672, CA16672, CA 098601] Funding Source: Medline
- NIEHS NIH HHS [T32 ES 07247, ES 07784, P30 ES007784, T32 ES007247] Funding Source: Medline
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Overexpression of the c-myc oncogene contributes to the development of a significant number of human cancers. In response to deregulated Myc activity, the p53 tumor suppressor is activated to promote apoptosis and inhibit tumor formation. Here we demonstrate that p53 induction in response to Myc overexpression requires the ataxia-telangiectasia mutated (ATM) kinase, a major regulator of the cellular response to DNA double-strand breaks. In a transgenic mouse model overexpressing Myc in squamous epithelial tissues, inactivation of Atm suppresses apoptosis and accelerates tumorigenesis. Deregulated Myc expression induces DNA damage in primary transgenic keratinocytes and the formation of gamma H2AX and phospho-SMC1 foci in transgenic tissue. These findings suggest that Myc overexpression causes DNA damage in vivo and that the ATM-dependent response to this damage is critical for p53 activation, apoptosis, and the suppression of tumor development.
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