Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis.
Activation of the ATM DNA damage response pathway is commonly observed in a variety of early-stage neoplasias. It has been proposed that this checkpoint response functions to suppress the development of cancer. A recent report from our laboratory demonstrates that ATM does indeed function to suppress tumorigenesis by responding to at least some oncogenic stresses. Transgenic expression of Myc is found to cause DNA damage in vivo and ATM is shown to respond to this damage by inducing the accumulation and phosphorylation of p53. In the absence of ATM, p53-dependent apoptosis is reduced and epithelial tumorigenesis is accelerated in Myc transgenic mice. Deregulated expression of the E2F1 transcription factor also elicits an ATM-dependent checkpoint response that activates p53 and promotes apoptosis, although the mechanism by which E2F1 and Myc stimulate ATM may differ. These findings have relevance for understanding why the ATM pathway is activated in many human cancers, what generates the selective pressure for p53 inactivation during tumorigenesis, and why AT patients and carriers are predisposed to developing cancer.
The University of Texas MD Anderson Cancer Center, Science Park Research Division, Department of Carcinogenesis, Smithville, Texas, USA.
Sungki
S
Hong
Raju V
RV
Pusapati
John T
JT
Powers
David G
DG
Johnson
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases