Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression

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.