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首页> 外文期刊>Molecular and Cellular Biology >Mutations in Proline 82 of p53 Impair Its Activation by Pin1 and Chk2 in Response to DNA Damage
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Mutations in Proline 82 of p53 Impair Its Activation by Pin1 and Chk2 in Response to DNA Damage

机译：p53脯氨酸82中的突变削弱了Pin1和Chk2对DNA损伤的激活作用

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Tumor suppression by the p53 protein largely depends on the elimination of damaged cells by apoptosis. Mutations in the polyproline region (PPR) of p53 impair its apoptotic function. Deletion of the PPR renders p53 more sensitive to inhibition by Mdm2 via an unknown mechanism. We have explored the mechanism by which the PPR modulates the p53/Mdm2 loop. Proline 82 of p53 was identified to be essential for its interaction with the checkpoint kinase 2 (Chk2) and consequent phosphorylation of p53 on serine 20, following DNA damage. These physical and functional interactions are regulated by Pin1 through cis-trans isomerization of proline 82. Our study unravels the pathway by which Pin1 activates p53 in response to DNA damage and explains how Pin1 protects p53 from Mdm2. Further, we propose a role for Pin1-dependent induction of p53 conformational change as a mechanism responsible for the enhanced interaction between p53 and Chk2 following DNA damage. Importantly, our findings elucidate the selection for mutations in the Pin1 target Thr81/Pro82 motif within the PPR of p53 in human cancer.
机译：p53蛋白抑制肿瘤很大程度上取决于细胞凋亡对受损细胞的清除作用。 p53的多脯氨酸区域（PPR）中的突变会削弱其凋亡功能。通过未知机制，PPR的缺失使p53对Mdm2的抑制作用更加敏感。我们已经探索了PPR调节p53 / Mdm2回路的机制。已确定p53的脯氨酸82是其与检查点激酶2（Chk2）相互作用以及随后DNA损伤后丝氨酸20上p53磷酸化所必需的。这些物理和功能相互作用受脯氨酸82的 cis - trans 异构化的Pin1调控。我们的研究揭示了Pin1激活p53响应DNA损伤的途径，并解释了如何Pin1保护p53不受Mdm2的影响。此外，我们提出了Pin1依赖性诱导p53构象变化的作用，该机制是负责DNA损伤后p53和Chk2之间增强相互作用的机制。重要的是，我们的发现阐明了在人类癌症中p53的PPR中Pin1靶Thr81 / Pro82基序中突变的选择。

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