Zheng Hongwu, You Han, Zhou Xiao Zhen, Murray Stephen A, Uchida Takafumi, Wulf Gerburg, Gu Ling, Tang Xiaoren, Lu Kun Ping, Xiao Zhi-Xiong Jim
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Nature. 2002 Oct 24;419(6909):849-53. doi: 10.1038/nature01116. Epub 2002 Oct 2.
p53 is activated in response to various genotoxic stresses resulting in cell cycle arrest or apoptosis. 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. 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.
p53可响应各种基因毒性应激而被激活，从而导致细胞周期停滞或凋亡。已有充分证据表明，DNA损伤会导致p53磷酸化并激活（参考文献1 - 3），然而p53如何被激活仍未完全明确。在此我们报告，DNA损伤特异性地诱导p53在丝氨酸/苏氨酸 - 脯氨酸基序上磷酸化，这促进了其与肽基 - 脯氨酰异构酶家族成员Pin1的相互作用。此外，Pin1与p53的相互作用依赖于DNA损伤诱导的磷酸化。因此，Pin1刺激p53的DNA结合活性和反式激活功能。Pin1介导的p53激活需要WW结构域，一个磷酸化的丝氨酸/苏氨酸 - 脯氨酸基序相互作用模块，以及Pin1的异构酶活性。此外，缺乏Pin1的细胞在p53激活和p53蛋白的及时积累方面存在缺陷，并且在响应DNA损伤时表现出检查点控制受损。总之，这些数据提示了细胞对基因毒性应激反应中p53调控的一种机制。
