Phosphorylation of p53 Serine 18 Upregulates Apoptosis to Suppress Myc-Induced Tumorigenesis
Open Access
- 17 February 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 8 (2), 216-222
- https://doi.org/10.1158/1541-7786.mcr-09-0324
Abstract
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 NH2 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 Eμmyc 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 serine18 phosphorylation and Puma expression to promote apoptosis. Eμmyc transgenic mice develop B-cell lymphoma more rapidly when heterozygous or homozygous for p53S18A alleles. However, Eμmyc-induced tumorigenesis in p53S18A mice is slower than that observed in Eμmyc 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 Eμmyc 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. Mol Cancer Res; 8(2); 216–22Keywords
This publication has 36 references indexed in Scilit:
- Limited Role of Murine ATM in Oncogene-Induced Senescence and p53-Dependent Tumor SuppressionPLOS ONE, 2009
- MDM2, an introduction.2003
- Puma is an essential mediator of p53-dependent and -independent apoptotic pathwaysCancer Cell, 2003
- Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesisThe EMBO Journal, 2003
- Live or let die: the cell's response to p53Nature Reviews Cancer, 2002
- Assessing TP53 status in human tumours to evaluate clinical outcomeNature Reviews Cancer, 2001
- Post‐translational modifications and activation of p53 by genotoxic stressesJBIC Journal of Biological Inorganic Chemistry, 2001
- Phosphorylation of murine p53 at Ser-18 regulates the p53 responses to DNA damageProceedings of the National Academy of Sciences of the United States of America, 2000
- INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53Genes & Development, 1999
- Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesisGenes & Development, 1999