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MEDICAL SCIENCES
ATM promotes apoptosis and suppresses tumorigenesis in response to Myc
,¶
*Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville, TX 78957; Division of Pharmacology and Toxicology, University of Texas, Austin, TX 78712; and Department of Veterinary Sciences, University of Texas M. D. Anderson Cancer Center, Bastrop, TX 78602
Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA and approved December 9, 2005 (received for review August 23, 2005)
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 
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.
p53 | DNA damage
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Freely available online through the PNAS open access option.
Abbreviations: IR, ionizing radiation; NHF, normal human fibroblast; AT, ataxia-telangiectasia; AdMyc, adenovirus expressing Myc; AdGFP, adenovirus expressing GFP.
Present address: St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
¶ To whom correspondence should be addressed at: Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, 1808 Park Road 1C, P.O. Box 389, Smithville, TX 78957. E-mail: djohnson{at}mdanderson.org.
© 2006 by The National Academy of Sciences of the USA
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