两个新的p53结合蛋白调控p53肿瘤抑制功能的机制研究

项目名称： 两个新的p53结合蛋白调控p53肿瘤抑制功能的机制研究

项目编号： No.31271479

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 张四清

作者单位： 厦门大学

项目金额： 80万元

中文摘要： p53是重要的抑癌基因，在50%的肿瘤中发生了突变，对其功能的调控至关重要。虽然p53蛋白翻译后修饰研究较详细，但另一重要调控机制：p53结合蛋白对p53功能的调控还亟待深入研究。我们前期工作用酵母双杂交筛选等手段发现了两个新的p53结合蛋白ZFP106和MCM7. 实验表明ZFP106能增强p53转录细胞凋亡基因的活性，或与p53共同发挥肿瘤抑制作用；而免疫荧光实验显示肿瘤细胞中过表达的MCM7将p53束缚在细胞质中，可能利用一种新机制使p53丧失功能。我们将结合ChIP assay和confocal microscopy技术深入分析ZFP106调控p53结合靶基因Promoter的能力及MCM7与p53在细胞中的共定位，探讨它们调控p53功能的新机制及在肿瘤发生中的作用。p53结合蛋白的研究成为近年来一个重要领域，我们的工作给p53研究提出了新问题，后续深入研究将争取新的突破.

中文关键词： p53；结合蛋白；调控；细胞生长；细胞凋亡

英文摘要： The p53 tumor-suppressor gene is mutated in as many as 50% of human tumours. The regulation of p53 is usually achieved by posttranslational modifications and through its interactions with various other proteins. To further investigate the regulation of p53 activity, we screened for p53-binding proteins using yeast two-hybrid system. ZFP106 was identified as a novel p53 interacting protein. It binds to p53 and enhances p53 mediated proapoptotic genes transcription. Furthermore, we found that MCM7 is another novel p53 binding protein. MCM7 associates with p53 and relocalizes p53 into the cytoplasm. The cytoplasmic sequestion of p53 by MCM7 may be a key mechanism of p53 inactivation through which MCM7 promotes cancer cell proliferation. In future studies we will further investigate whether ZFP106 regulate the DNA-binding activity of p53 to p53 target promoters with ChIP assay, and investigate the regulation of p53 cellular localization by MCM7 and its relevance in cancer.

英文关键词： p53；binding protein；regulate；cell growth；apoptosis