Мақола

Phosphorylation of murine p53 at Ser-18 regulates the p53 responses to DNA damage

Connie ChaoDivision of Biology and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Biology Department, Brookhaven National Laboratory, Upton, NY 11973Shinichi SaitoDivision of Biology and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Biology Department, Brookhaven National Laboratory, Upton, NY 11973Carl W. AndersonDivision of Biology and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Biology Department, Brookhaven National Laboratory, Upton, NY 11973Ettore AppellaDivision of Biology and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Biology Department, Brookhaven National Laboratory, Upton, NY 11973Yang XuDivision of Biology and Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322; Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Biology Department, Brookhaven National Laboratory, Upton, NY 11973

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Аннотация

Ser-15 of human p53 (corresponding to Ser-18 of mouse p53) is phosphorylated by ataxia-telangiectasia mutated (ATM) family kinases in response to ionizing radiation (IR) and UV light. To determine the effects of phosphorylation of endogenous murine p53 at Ser-18 on biological responses to DNA damage, we introduced a missense mutation (Ser-18 to Ala) by homologous recombination into both alleles of the endogenous p53 gene in mouse embryonic stem (ES) cells. Our analyses showed that phosphorylation of murine p53 at Ser-18 in response to IR or UV radiation was required for a full p53-mediated response to these DNA damage-inducing agents. In contrast, phosphorylation of p53 at Ser-18 was not required for ATM-dependent cellular resistance after exposure to IR. Additionally, efficient acetylation of the C terminus of p53 in response to DNA damage did not require phosphorylation of murine p53 at Ser-18.

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Идентификаторлар

DOI: 10.1073/pnas.220252297

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