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Functional role of p53 N-terminal phosphorylation in regulating the p53 response to DNA damage

Abstract

Since the p53 tumor suppressor is mutated in over 50% of human cancers, understanding the mechanisms that regulate its function holds great importance for cancer therapy. In response to diverse stresses, p53 is activated as a potent transcription factor, and induces signals that prevent the proliferation of mutation-harboring cells, which may otherwise lead to cancer. Because of its protective role in maintaining genetic stability, p53 is aptly named "guardian of the genome." Exposure to DNA damage and other cellular stresses results in p53 phosphorylation at multiple serine and threonine residues at its N-terminus. These events are believed to play critical roles in regulating p53 stability and activity. Of particular interest is phosphorylation of mouse p53 at Ser18, which is mediated by members of the ATM family kinases that are also the master regulators of the cellular response to DNA damage. To address the physiological relevance of this event, we introduced a Ser18 to Alanine missense mutation into the endogenous p53 gene of mouse embryonic stem cells and generated germline p53S18A mice. Our analysis of cells from the p53S18A mice indicate that Ser18 phosphorylation is dispensable for p53 accumulation, but important for regulating p53 transcriptional activity in a cell type and promoter- specific manner. The defect in p53-dependent transactivation could be attributed to impaired recruitment of transcriptional coactivators, since the DNA binding activity of p53 after DNA damage to endogenous promoters was similar in both p53+/+ and p53S18A cells. To address whether p53 may be synergistically regulated by Ser18 and Ser23 phosphorylation, we simultaneously introduced Ser18/Ser23 to Ala mutations into the mouse germline. Our findings demonstrate that Ser18/Ser23 phosphorylation is important for activating p53-dependent apoptotic activity. Furthermore, while Ser18/Ser23 phosphorylation is important for spontaneous tumor suppression in aging animals, it is dispensable for p53- dependent tumor suppression in the presence of persistent genetic instability, such as that acquired through DNA repair deficiency. Thus p53 tumor suppressor activity is regulated through different mechanisms depending on the physiological context

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