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 avariety of early-stage neoplasias. It has been proposed that this checkpoint responsefunctions to suppress the development of cancer. A recent report from our laboratorydemonstrates that ATM does indeed function to suppress t...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2006-04, Vol.5 (8), p.801-803
Main Authors: Hong, Sungki, Pusapati, Raju V., Powers, John T., Johnson, David G.
Format: Article
Language:English
Subjects:
Animals
Ataxia Telangiectasia Mutated Proteins
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cell Cycle Proteins - metabolism
Cycle
DNA Damage
DNA-Binding Proteins - metabolism
E2F1 Transcription Factor - metabolism
E2F1 Transcription Factor - physiology
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Landes
Mice
Mice, Transgenic
Oncogenes
Organogenesis
Protein-Serine-Threonine Kinases - metabolism
Proteins
Proto-Oncogene Proteins c-myc - metabolism
Proto-Oncogene Proteins c-myc - physiology
Signal Transduction
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - metabolism
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Summary:Activation of the ATM DNA damage response pathway is commonly observed in avariety of early-stage neoplasias. It has been proposed that this checkpoint responsefunctions to suppress the development of cancer. A recent report from our laboratorydemonstrates that ATM does indeed function to suppress tumorigenesis byresponding to at least some oncogenic stresses. Transgenic expression of Myc isfound to cause DNA damage in vivo and ATM is shown to respond to this damage byinducing the accumulation and phosphorylation of p53. In the absence of ATM, p53-dependent apoptosis is reduced and epithelial tumorigenesis is accelerated in Myctransgenic mice. Deregulated expression of the E2F1 transcription factor also elicitsan ATM-dependent checkpoint response that activates p53 and promotes apoptosis,although the mechanism by which E2F1 and Myc stimulate ATM may differ. Thesefindings have relevance for understanding why the ATM pathway is activated in manyhuman cancers, what generates the selective pressure for p53 inactivation duringtumorigenesis, and why AT patients and carriers are predisposed to developingcancer.
ISSN:1538-4101
1551-4005
DOI:10.4161/cc.5.8.2638