HBx蛋白逃避E3泛素连接酶Siah-1降解的分子机制研究

项目名称： HBx蛋白逃避E3泛素连接酶Siah-1降解的分子机制研究

项目编号： No.81201521

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： 赵晶

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 乙肝病毒（HBV）编码的HBx是多功能原癌蛋白，其表达水平与肝癌发展密切相关。泛素-蛋白酶体途径是细胞降解HBx蛋白的重要方式。我们前期研究发现， E3泛素连接酶Siah-1能介导HBx的泛素化并使其通过蛋白酶体途径降解，从而抑制HBx的转录激活作用。但Siah-1不能降解肝癌中有致癌作用的HBx缺失截短体，并且DNA损伤和炎症调节因子TNF-α刺激都能抑制Siah-1介导的HBx降解。因此我们推测，在肝癌发展进程中，HBx能够逃避Siah-1的降解，增强其致癌潜能。本课题将研究HBx缺失截短体、DNA损伤和TNF-α刺激对Siah-1与HBx互作及共定位的影响，探讨相关激酶ATM/ATR及IKK对Siah-1的磷酸化修饰作用，检测磷酸化的Siah-1对降解HBx的影响，从而阐明HBx逃避Siah-1降解的分子机制，以期更全面了解HBx与肝癌发生发展的机制，为开发新型肝癌防治策略奠定基础。

中文关键词： 肝癌；HBx；Siah-1；胃癌；长链非编码RNA

英文摘要： Hepatitis B viral X protein (HBx) is a multifunctional virus oncoprotein and HBx expression level closely correlates with the progression of hepatocellular carcinoma (HCC).HBx protein can be degraded via the ubiquitin-proteasome pathway which is important for the host to regulate the stability of HBx. Our previous study has reported that Siah-1 as a novel E3 ligase facilitates poly-ubiquitylation and proteasomal degradation of HBx,and co-expression of Siah-1 attenuated the transcriptional transactivation of HBx. However,Siah-1 failed to mediate the degradation of truncated HBx, and DNA damage and proinflammatory cytokine TNF-a also blocked HBx degradation mediated by Siah-1. Considering that HCC malignant process is commonly accompanied with C-terminal deletion of HBx gene, DNA damage and proinflammatory cytokines secretion,we hypothesize that the specific microenvironment of HCC development may protect HBx from degradation mediated by Siah-1 so that there is more HBx protein to promote HCC development. In this study, we will study the interaction, co-localization changes between HBx and Siah-1 in the situations as above; the important regulating mechanism of related kinase such as ATM/ATR and IKK in the process; detect the change of Siah-1 phosphorylation which may disrupt the interaction between Siah-1 and HBx

英文关键词： hepatocellular carcinoma；HBx；Siah-1；gastric cancer；long non-coding RNAs