The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response
The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response
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DOI：
10.1038/nature01116
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发表时间：
2002-10-24
期刊：
影响因子：
64.8
通讯作者：
Xiao, ZXJ
中科院分区：
文献类型：
--
作者：
Zheng, HW;You, H;Xiao, ZXJ
p53响应于导致细胞周期停滞或凋亡的各种遗传毒性应激而被激活（1，2）。DNA损伤导致p53的磷酸化和活化是有据可查的（参考文献1-3），但p53是如何被活化的仍然没有完全了解。在这里，我们报道了DNA损伤特异性诱导p53在Ser/Thr-Pro基序上的磷酸化，这促进了其与肽基脯氨酰异构酶成员Pin 1的相互作用（4-9）。此外，Pin 1与p53的相互作用依赖于DNA损伤诱导的磷酸化。因此，Pin 1刺激DNA结合活性和p53的反式激活功能。Pin 1介导的p53激活需要WW结构域、磷酸化的Ser/Thr-Pro基序相互作用模块和Pin 1的异构酶活性。此外，Pin 1缺陷细胞在p53激活和p53蛋白的及时积累方面有缺陷，并且表现出对DNA损伤的响应的检查点控制受损。总之，这些数据表明，p53调控的遗传毒性应激细胞反应的机制。
p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis(1,2). It is well documented that DNA damage leads to phosphorylation and activation of p53 (refs 1-3), yet how p53 is activated is still not fully understood. Here we report that DNA damage specifically induces p53 phosphorylation on Ser/Thr-Pro motifs, which facilitates its interaction with Pin1, a member of peptidyl-prolyl isomerase(4-9). Furthermore, the interaction of Pin1 with p53 is dependent on the phosphorylation that is induced by DNA damage. Consequently, Pin1 stimulates the DNA-binding activity and transactivation function of p53. The Pin1-mediated p53 activation requires the WW domain, a phosphorylated Ser/Thr-Pro motif interaction module, and the isomerase activity of Pin1. Moreover, Pin1-deficient cells are defective in p53 activation and timely accumulation of p53 protein, and exhibit an impaired checkpoint control in response to DNA damage. Together, these data suggest a mechanism for p53 regulation in cellular response to genotoxic stress.