Phosphorylation of p53 serine 18 upregulates apoptosis to suppress Myc-induced tumorigenesis
Department of Cell Biology; Department of Medicine, Division of Endocronology and Metabolism
Medical Subject Headings
Amino Acid Sequence; Animals; Animals, Genetically Modified; Apoptosis; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Transformation, Neoplastic; DNA Damage; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Lymphoma, B-Cell; Mice; Mice, Inbred C57BL; Oncogenes; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Serine; Signal Transduction; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation
ATM and p53 are critical regulators of the cellular DNA damage response and function as potent tumor suppressors. In cells undergoing ionizing radiation, ATM is activated by double-strand DNA breaks and phosphorylates the NH(2) terminus of p53 at serine residue 18. We have previously generated mice bearing an amino acid substitution at this position (p53S18A) and documented a role for p53 phosphorylation in DNA damage-induced apoptosis. In this present study, we have crossed E mu myc transgenic mice with our p53S18A mice to explore a role for ATM-p53 signaling in response to oncogene-induced tumorigenesis. Similar to DNA damage induced by ionizing radiation, expression of c-Myc in pre-B cells induces p53 serine 18 phosphorylation and Puma expression to promote apoptosis. E mu myc transgenic mice develop B-cell lymphoma more rapidly when heterozygous or homozygous for p53S18A alleles. However, E mu myc-induced tumorigenesis in p53S18A mice is slower than that observed in E mu myc mice deficient for either p53 or ATM, indicating that both p53-induced apoptosis and p53-induced growth arrest contribute to the suppression of B-cell lymphoma formation in E mu myc mice. These findings further reveal that oncogene expression and DNA damage activate the same ATM-p53 signaling cascade in vivo to regulate apoptosis and tumorigenesis.
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Citation: Mol Cancer Res. 2010 Feb;8(2):216-22. Epub 2010 Feb 9. Link to article on publisher's site