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首页> 外文期刊>Molecular and Cellular Biology >Activation of p53 Function by Human Transcriptional Coactivator PC4: Role of Protein-Protein Interaction, DNA Bending, and Posttranslational Modifications
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Activation of p53 Function by Human Transcriptional Coactivator PC4: Role of Protein-Protein Interaction, DNA Bending, and Posttranslational Modifications

机译：通过人类转录共激活因子PC4激活p53功能：蛋白质-蛋白质相互作用，DNA弯曲和翻译后修饰的作用

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摘要

Tumor suppressor p53 controls cell cycle checkpoints and apoptosis via the transactivation of several genes that are involved in these processes. The functions of p53 are regulated by a wide variety of proteins, which interact with it either directly or indirectly. The multifunctional human transcriptional coactivator PC4 interacts with p53 in vivo and in vitro and regulates its function. Here we report the molecular mechanisms of the PC4-mediated activation of p53 function. PC4 interacts with the DNA binding and C-terminal domains of p53 through its DNA binding domain, which is essential for the stimulation of p53 DNA binding. Remarkably, ligation-mediated circularization assays reveal that PC4 induces significant bending in the DNA double helix. Deletion mutants defective in DNA bending are found to be impaired in activating p53-mediated DNA binding and apoptosis. Furthermore, acetylation of PC4 enhances, while phosphorylation abolishes, its ability to bend DNA, activate p53 DNA binding, and, thereby, regulate p53 functions. In conclusion, PC4 activates p53 recruitment to p53-responsive promoters (Bax and p21) in vivo through its interaction with p53 and by providing bent substrate for p53 recruitment. These results elucidate the general molecular mechanisms of activation of p53 function, mediated by its coactivators.
机译：肿瘤抑制因子p53通过与这些过程有关的几个基因的反式激活来控制细胞周期检查点和细胞凋亡。 p53的功能受多种蛋白质调节，这些蛋白质直接或间接与其相互作用。多功能人类转录共激活因子PC4在体内和体外与p53相互作用并调节其功能。在这里我们报告了P​​C4介导的p53功能激活的分子机制。 PC4通过其DNA结合域与p53的DNA结合域和C末端域相互作用，这对刺激p53 DNA结合至关重要。值得注意的是，连接介导的环化分析表明PC4在DNA双螺旋中诱导了明显的弯曲。发现DNA弯曲缺陷的缺失突变体在激活p53介导的DNA结合和凋亡中受损。此外，PC4的乙酰化增强了磷酸化的能力，而磷酸化则消除了其弯曲DNA，激活p53 DNA结合从而调节p53功能的能力。总之，PC4通过与p53相互作用并为p53募集提供弯曲的底物，在体内激活p53募集至p53反应性启动子（ Bax 和 p21 ）。这些结果阐明了由其共激活因子介导的p53功能激活的一般分子机制。

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