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THE MECHANISMS OF ANTI-APOPTOTIC EFFECTS BY HEPATITIS C VIRUS CORE PROTEIN

丙型肝炎病毒核心蛋白抗凋亡作用机制

基本信息

批准号：
11670292
负责人：
HIJIKATA Makoto
金额：
$ 2.3万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670292/
关键词：
hepatitis C virus hepatitis hepatocellular carcinoma persistent infection apoptosis NF-κB MAP kinase Elk1 MAPK 細胞増殖ウイルス持続感染コアタンパク質粗面小胞体

项目摘要

To clarifiy the molecular mechanism of hepatitis and hepatocellular carcinoma caused by hepatitis C virus (HCV), we analysed the mechanism of anti-apoptotic effect by HCV core protein in this research project. The achievements are listed bellow.1. Results obtained from analysis of the molecular mechanism for activation of cellular transcription factor NF-κB by HCV core protein which is thought be one of important machinary for the anti-apoptotic effect of the core portein. are shown as follows ;(1) From th edeletion analysis and and the observation of subcellular localization, it was revealed that the localization of the HCV core protein in the cytoplasm, especially on the endoplasmic reticulum membranes, is important for the NF-κB activation. .(2) We found that the minimum region required for NF-κB activation just like as authentic core protein is located at the amino-terminal portion, from aa20 to aa80, of the HCV core protein.(3) We are trying to characterize several cDNA clones obtained by yeast two hybrid system using the region from aa 20 to aa 80 of the core as a bait.(4) We showed that the core protein enhanced the NF-κB activity induced by the overexpression of IKKβ, which is a kinase for the phosphorylation of IκB, without augmentation of IKKβ activity, suggesting that the core protein affects the point downstream of IKKβin thee NF-κB activation pathway to enhance the NF-κB activity.2. We analysed the molecular mechanism of activation of MAP kinase pathway by the core protein and obtained the results showing that the coree protein augments the activity of transcription factor Elk1 by the unknow mechaism which is different from the well-known kination reaction.Since the activation of the tramscription factors by the HCV core protein seems to be closely related with the suppression of apoptosis, persistent infection of HCV, and hepatocellular carcinogenesis, further analysis of molecular mechanisms is now underway.

为阐明丙型肝炎病毒（HCV）引起肝炎和肝癌的分子机制，本研究分析了HCV核心蛋白抗细胞凋亡的作用机制。取得的成果如下：1.结果表明，HCV核心蛋白激活细胞转录因子NF-κB B的分子机制是其抗凋亡作用的重要机制之一。如下所示;（1）电泳分析和亚细胞定位观察结果表明，HCV核心蛋白在细胞质中的定位，尤其是在内质网膜上的定位，对NF-κB的激活起重要作用。. (2)我们发现NF-κB活化所需的最小区域就像真正的核心蛋白一样位于HCV核心蛋白的氨基末端部分，从aa 20到aa 80。(3)我们试图用酵母双杂交系统获得的几个cDNA克隆，用核心区的aa 20到aa 80作为诱饵。(4)结果显示，核心蛋白增强了由IKKβ（一种IκB磷酸化的激酶）过表达诱导的NF-κB活性，而不增强IKKβ活性，提示核心蛋白影响了NF-κB活化途径中IKKβ下游位点，从而增强了NF-κB活性.我们分析了HCV核心蛋白激活MAP激酶途径的分子机制，结果表明，HCV核心蛋白通过与已知的激活反应不同的未知机制增强转录因子Elk 1的活性，由于HCV核心蛋白激活转录因子与抑制细胞凋亡、HCV持续感染、和肝细胞癌的发生，分子机制的进一步分析正在进行中。