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Ser18 and 23 phosphorylation is required for p53‐dependent apoptosis and tumor suppression
Author(s) -
Chao Connie,
Herr Deron,
Chun Jerold,
Xu Yang
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601167
Subject(s) - biology , phosphorylation , apoptosis , microbiology and biotechnology , genetics , cancer research
Mouse p53 is phosphorylated at Ser18 and Ser23 after DNA damage. To determine whether these two phosphorylation events have synergistic functions in activating p53 responses, we simultaneously introduced Ser18/23 to Ala mutations into the endogenous p53 locus in mice. While partial defects in apoptosis are observed in p53 S18A and p53 S23A thymocytes exposed to IR, p53‐dependent apoptosis is essentially abolished in p53 S18/23A thymocytes, indicating that these two events have critical and synergistic roles in activating p53‐dependent apoptosis. In addition, p53 S18/23A , but not p53 S18A , could completely rescue embryonic lethality of Xrcc4 −/− mice that is caused by massive p53‐dependent neuronal apoptosis. However, certain p53‐dependent functions, including G 1 /S checkpoint and cellular senescence, are partially retained in p53 S18/23A cells. While p53 S18A mice are not cancer prone, p53 S18/23A mice developed a spectrum of malignancies distinct from p53 S23A and p53 −/− mice. Interestingly, Xrcc4 −/− p53 S18/23A mice fail to develop tumors like the pro‐B cell lymphomas uniformly developed in Xrcc4 −/− p53 −/− animals, but exhibit developmental defects typical of accelerated ageing. Therefore, Ser18 and Ser23 phosphorylation is important for p53‐dependent suppression of tumorigenesis in certain physiological context.