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THE MECHANISMS OF CELL TRANSFORMATION INDUCED BY HEPATITIS CVIRUS

病毒性肝炎病毒诱导细胞转化的机制

基本信息

批准号：
09670325
负责人：
HIJIKATA Makoto
金额：
$ 1.73万
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：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

To reveal the molecular mechanisms of hepatitis and hepatocellular carcinoma closely related with the infection of hepatitis C virus (HCV), we investigated the changes of the gene expression in the HCV protein producing cultured cells originated from hepatocytes and analyzed the cellular factor interacting with HCV genome and its gene products. The results are followed ;1. We found a cellular factor interacting with the terminal fragment of HCV genome in the cell lysate by U.V.cross link method. We showed that the factor was the polypyrimidine tract binding protein.2. We obtained HepG2 cells producing a HCV proteins after specific concentration of the transiently plasmid transfected cells. The mRNA samples from the cells with and without HCV protein production were used for dot blothybridization experiment using more than 500 fragments of the cellular genes as targets. However no drastic change of the expression was found.3. We found that the concentrated HepG2 cells producing HCV prot … More eins became resistant against Fas and tumor necrosis factor (TNF)-alpha mediated apoptosis This function was appeared to be responsible to the core protein among a HCV proteins.4. We revealed that the core protein functioned as an anti-apoptotic factor by synergistic enhancement of NF-kappaB activity induced by apoptotic signals, anti Fas antibody and TNF-alpha in certain cells. We also found that there was a NF-kappaB-independent anti-apoptotic pathway by HCV core protein.5. We showed that the core protein have a potential to transform a certain cells cooperatively with an oncogenic protein, Ras.6. The core protein was revealed to have a potential to activate the cell proliferation through the activation of MAP kinase cascade. We consider that the anti-apoptotic effect and transforming potential of the core protein may contribute to the persistent infection of HCV and cause of hepatocellular carcinoma.Further analysis of molecular mechanisms of these functions of the core protein is underway. Less

为揭示与丙型肝炎病毒（HCV）感染密切相关的肝炎和肝癌发生的分子机制，我们研究了来源于肝细胞的HCV蛋白产生细胞基因表达的变化，分析了与HCV基因组及其基因产物相互作用的细胞因子。研究结果如下：1.我们用紫外交联法在细胞裂解液中发现了一种与HCV基因组末端片段相互作用的细胞因子。我们发现该因子是多聚嘧啶束结合蛋白.经特定浓度的瞬时质粒转染细胞后，我们获得了产生HCV蛋白的HepG 2细胞。将来自具有和不具有HCV蛋白产生的细胞的mRNA样品用于使用超过500个细胞基因片段作为靶标的斑点杂交实验。但没有发现明显的表达变化.我们发现浓缩的HepG 2细胞产生HCV蛋白， ...更多信息细胞对Fas和肿瘤坏死因子（TNF-α）介导的细胞凋亡产生抵抗，这种功能似乎与HCV蛋白中的核心蛋白有关.我们发现，在某些细胞中，核心蛋白通过协同增强由凋亡信号、抗Fas抗体和TNF-α诱导的NF-κ B活性而起抗凋亡因子的作用。我们还发现HCV核心蛋白存在一条非NF-κ B依赖的抗凋亡通路.我们发现核心蛋白具有与致癌蛋白Ras协同转化某些细胞的潜力。核心蛋白具有通过激活MAP激酶级联反应来激活细胞增殖的潜力。我们认为核心蛋白的抗凋亡作用和转化潜能可能与HCV的持续感染和肝癌的发生有关，其分子机制的研究正在进行中。少