Phosphorylation of p53 serine 18 upregulates apoptosis to suppress Myc-induced tumorigenesis.
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.
Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Hayla K
HK
Sluss
Hugh
H
Gannon
Andrew H
AH
Coles
Qichang
Q
Shen
Christine M
CM
Eischen
Stephen N
SN
Jones
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009857:Oncogenes / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489428:Myc protein, mouse; C488588:PUMA protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D012694:Serine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases