Phosphorylation of serine 18 regulates distinct p53 functions in mice
Phosphorylation of serine 18 regulates distinct p53 functions in mice
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DOI：
10.1128/mcb.24.3.976-984.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Jones, SN
中科院分区：
文献类型：
--
作者：
Sluss, HK;Armata, H;Jones, SN
p53蛋白作为肿瘤抑制因子，在DNA损伤或癌基因激活时诱导细胞周期阻滞和凋亡。最近，有人提出，ATM （ataxia毛细血管扩张症突变）激酶磷酸化人类p53中的丝氨酸15，通过干扰Mdm2-p53复合物的形成和抑制mdm2介导的p53的不稳定来诱导p53活性。小鼠p53中的丝氨酸18参与介导ATM和共济失调毛细血管扩张相关的激酶依赖性生长阻滞。为了进一步探索p53 Ser18磷酸化的生理意义，我们制造了p53丝氨酸到丙氨酸突变的小鼠。DNA损伤后胸腺细胞和脾细胞的凋亡分析表明，丝氨酸18的磷酸化是p53介导的强大凋亡所必需的。令人惊讶的是，p53Ser18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小鼠发育正常，不容易自发肿瘤发生，p53Ala18凋亡功能的降低并不能挽救mdm2缺失小鼠的胚胎致死性表型。这些结果表明，p53上ATM靶位点的磷酸化特异性调节了p53的凋亡功能，并进一步揭示p53丝氨酸18的磷酸化并不需要p53介导的肿瘤抑制。
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 G(1) 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.