Phosphorylation of p53 serine 18 upregulates apoptosis to suppress Myc-induced tumorigenesis.

Sluss HK, Gannon H, Coles AH, Shen Q, Eischen CM, Jones SN
Mol Cancer Res. 2010 8 (2): 216-22

PMID: 20145032 · PMCID: PMC2829875 · DOI:10.1158/1541-7786.MCR-09-0324

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.

MeSH Terms (23)

Amino Acid Sequence Animals Animals, Genetically Modified Apoptosis Apoptosis Regulatory Proteins Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins Cell Transformation, Neoplastic DNA-Binding Proteins DNA Damage 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

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