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Phosphorylation of Serine 18 Regulates Distinct p53 Functions in Mice

机译：丝氨酸18的磷酸化调节小鼠不同的p53功能。

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The p53 protein acts a tumor suppressor by inducing cell cycle arrest and apoptosis in response to DNA damage or oncogene activation. Recently, it has been proposed that phosphorylation of serine 15 in human p53 by ATM (mutated in ataxia telangiectasia) kinase induces p53 activity by interfering with the Mdm2-p53 complex formation and inhibiting Mdm2-mediated destabilization of p53. Serine 18 in murine p53 has been implicated in mediating an ATM- and ataxia telangiectasia-related kinase-dependent growth arrest. To explore further the physiological significance of phosphorylation of p53 on Ser18, we generated mice bearing a serine-to-alanine mutation in p53. Analysis of apoptosis in thymocytes and splenocytes following DNA damage revealed that phosphorylation of serine 18 was required for robust p53-mediated apoptosis. Surprisingly, p53Ser18 phosphorylation did not alter the proliferation rate of embryonic fibroblasts or the p53-mediated G1 arrest induced by DNA damage. In addition, endogenous basal levels and DNA damage-induced levels of p53 were not affected by p53Ser18 phosphorylation. p53Ala18 mice developed normally and were not susceptible to spontaneous tumorigenesis, and the reduced apoptotic function of p53Ala18 did not rescue the embryo-lethal phenotype of Mdm2-null mice. These results indicate that phosphorylation of the ATM target site on p53 specifically regulates p53 apoptotic function and further reveal that phosphorylation of p53 serine 18 is not required for p53-mediated tumor suppression.
机译：p53蛋白通过诱导细胞周期停滞和凋亡来响应DNA损伤或致癌基因激活，从而起到抑癌作用。最近，有人提出通过ATM（在共济失调毛细血管扩张症中突变）ATM使人p53中的丝氨酸15磷酸化，通过干扰Mdm2-p53复合物的形成并抑制Mdm2介导的p53去稳定作用来诱导p53活性。鼠p53中的丝氨酸18参与介导ATM和共济失调的毛细血管扩张相关激酶依赖性生长停滞。为了进一步探讨Ser18上p53磷酸化的生理学意义，我们生成了在p53中带有丝氨酸至丙氨酸突变的小鼠。 DNA损伤后胸腺细胞和脾细胞凋亡的分析表明，强大的p53介导的凋亡需要丝氨酸18的磷酸化。令人惊讶的是，p53Ser18的磷酸化并没有改变胚胎成纤维细胞的增殖速率，也没有改变DNA损伤诱导的p53介导的G 1 阻滞。此外，内源性基础水平和DNA损伤诱导的p53水平不受p53Ser18磷酸化的影响。 p53Ala18小鼠正常发育，不易自发发生肿瘤，p53Ala18的凋亡功能降低不能挽救Mdm2无小鼠的胚胎致死表型。这些结果表明p53上的ATM靶位点的磷酸化特异性地调节p53的凋亡功能，并且进一步揭示p53介导的肿瘤抑制不需要p53丝氨酸18的磷酸化。

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