Phosphorylation of p53 serine 18 upregulates apoptosis to suppress Myc-induced tumorigenesis
Authors
Sluss, Hayla KarenGannon, Hugh S.
Coles, Andrew H.
Shen, Qichang
Eischen, Christine M.
Jones, Stephen N.
UMass Chan Affiliations
Department of Medicine, Division of Endocronology and MetabolismDepartment of Cell Biology
Document Type
Journal ArticlePublication Date
2010-02-11Keywords
Amino Acid SequenceAnimals
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
Cell Biology
Metadata
Show full item recordAbstract
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.Source
Mol Cancer Res. 2010 Feb;8(2):216-22. Epub 2010 Feb 9. Link to article on publisher's siteDOI
10.1158/1541-7786.MCR-09-0324Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36007Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/1541-7786.MCR-09-0324
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