Skp2泛素化调控Aurora B的作用与机制

项目名称： Skp2泛素化调控Aurora B的作用与机制

项目编号： No.81201550

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 吴娟

作者单位： 广州医科大学

项目金额： 25万元

中文摘要： Skp2属于泛素化E3连接酶，在很多肿瘤组织中存在高表达。Skp2通过调节ATM活化及DNA修复而调控DNA损伤应答，从而在调控基因组稳定性方面发挥重要功能。Aurora B是有丝分裂纺锤体检验点调控通路中的关键蛋白，具有磷酸化活化ATM的功能。我们的预实验表明：Skp2与Aurora B存在着相互作用，且Skp2可以引起Aurora B泛素化。 而且，在Skp2稳定敲低细胞株中，我们发现Aurora B的下游基因，H3及CENP-3的活化形式，Pho-H3及Pho-CENP3水平均有下降。因而，本项目将深入研究Skp2诱导的Aurora B泛素化调控机制及其在有丝分裂通路信号传导中的重要作用，并利用免疫组化实验分析肿瘤组织中二者的相互关系。研究结果将为Skp2在维持基因组稳定性作用研究拓宽新的渠道，为Skp2作为癌基因提供新的证据支持，更为将来Skp2作为肿瘤治疗靶点提供新的理论依据。

中文关键词： 基因组稳定性；细胞有丝分裂；Skp2；泛素化；肿瘤治疗靶点

英文摘要： Skp2 is an F-box protein，which is a component of Skp2 SCF E3 complex that plays an important role in cell cycle progression, oncogenesisis, invasion, metastasis and so on. Skp2 is found to be overexpressed in various cancer types. Our recent reasearch demonstrate that Skp2 plays an important role in DNA damage response by regulating ATM activation and homologous recombination (HR) repair, indicating that Skp2 is required for the maintenance of genomic stability. Aurora B is a key kinase in the spindle checkpoint pathway. Aurora-B phosphorylates ATM on serine 1403, which is essential for the activation of the spindle checkpoint. Our data show that Skp2 can interact with Aurora B. As an E3 ligase, Skp2 can triger Aurora B ubiquitination. Furthermore, when we knock down Skp2 expression, the activity of Aurora B and its downstream targets decreased. Therefore, in this study, first we will make the mechanisim more clear Skp2 can interact and further ubiquitinates Aurora B. Here we aim to investigate the role of Skp2-mediated Aurora B ubiquitination in mitotic progression and cytokinesis, and also analyze the relationship of Skp2 and Aurora B in several cancer samples by histochemistry. Our study will bring great value for the mechanism study of spindle checkpoint, and also provide a new direction for the study of

英文关键词： genomic stability；cell mitosis；Skp2；ubiquitination；target for cancer treatment