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研究生:張雅婷
研究生(外文):Ya-Ting Chang
論文名稱:探討C型肝炎病毒核心蛋白對於WNT/beta-catenin訊號傳遞途徑之影響
論文名稱(外文):Effects of HCV core protein on WNT/beta-catenin pathway
指導教授:吳妍華
指導教授(外文):Yan-Hwa Wu Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:91
中文關鍵詞:C型肝炎病毒核心蛋白訊息傳遞
外文關鍵詞:HCVCoreWNTbeta-catenin
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C型肝炎病毒 (Hepatitis C virus,HCV) 為母體傳染及輸血傳染所引起非A、非B型肝炎之主要病原體,且持續性帶原感染經常導致慢性肝炎、肝硬化及肝細胞癌 (Hepatocellular carcinoma, HCC)。目前為止,對於C型肝炎病毒之致病機轉仍未清楚了解。在C型肝炎病毒產物中,核心蛋白已知調控諸多生理反應;其中包括組成病毒套膜、調控細胞基因之表現及藉由交互作用進而影響該蛋白之功能。由此可知,核心蛋白為多功能性蛋白且可能在C型肝炎病毒之致病機轉中扮演重要角色。分析核心蛋白持續表現細胞內之基因表現,結果發現參與WNT/beta-catenin signaling之因子APC及Frizzled-1之基因表現有所改變,且文獻報導肝細胞癌細胞中WNT2b及beta-catenin基因之表現有上升之現象,因此推測C型肝炎病毒核心蛋白與WNT/beta-catenin signaling之調控關係跟C型肝炎病毒可能導致肝細胞癌之機制有關。為了探討核心蛋白與WNT/beta-catenin signaling之調控關係,在WNT訊息外加與否情況下,測量含有人工合成TCF responsive element (TCF-RE) 報導子pTOPFLASH之活性,以了解核心蛋白調控WNT所活化之基因表現情況,結果發現在WNT訊息外加時,核心蛋白對此報導子之活性有一TCF-RE特異性之抑制作用。另外,使用含有WNT/beta-catenin signaling目標基因cyclin D1啟動子之報導子,發現在不同核心蛋白量之情況下,核心蛋白調控此啟動子活性之機制有所不同。核心蛋白在低表現量時,對cyclin D1啟動子活性有TCF-RE特異性之抑制作用,而在高表現量時,則藉由TCF-RE以外的區域調其控啟動子之活性。因此,核心蛋白會抑制由WNT訊息傳遞所活化之基因表現。為了探討核心蛋白調控WNT訊息傳遞路徑之可能機制,進一步分析訊息過程中最重要因子beta-catenin之表現量及其核轉移作用,發現核心蛋白對beta-catenin表現量及其核轉移作用並無影響,表示核心蛋白可能藉由其他途徑影響WNT/beta-catenin signaling。藉由西方墨點法觀察beta-catenin在不同細胞株之表現,發現在HuH-7、HeLa及H1299細胞株含有beta-catenin全長,而在HepG2及HuH-7(T)細胞株中除了beta-catenin全長外,還含有N端25-140胺基酸缺失之b-catenin突變型。在活體外及活體內結合試驗中,發現beta-catenin會與核心蛋白有交互作用。在活體外結合試驗中,利用核心蛋白c195及c122與HepG2 lysate進行結合。發現只有核心蛋白c195會與beta-catenin全長結合,核心蛋白C端123-191胺基酸區域對於核心蛋白與beta-catenin之結合作用很重要,且核心蛋白全長與trunacated核心蛋白c122皆會與b-catenin deletion mutant結合。分析beta-catenin與核心蛋白結合區域,知道以beta-catenin ARM 1-6區塊與核心蛋白結合。另外,利用HuH-7及含有beta-catenin deletion mutant之HepG2細胞株進行transient transfection assay。比較轉染核心蛋白c195及c122之結果,發現核心蛋白與beta-catenin之結合作用影響其對於pTOPFLASH之抑制作用。最後,利用大量表現beta-catenin活化目標基因之表現,發現核心蛋白會抑制此一活化效應。綜合以上結果,C型肝炎病毒核心蛋白會藉由與b-catenin之交互作用調控WNT訊息傳遞路徑,提供C型肝炎病毒可能之分子致病機轉。
Hepatitis C virus (HCV) is the main cause of the maternal non-A, non-B hepatitis and post-transfusion hepatitis. The persistent infection of HCV often leads to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) in the end. The pathogenesis of HCV persistent infection is not yet clear. Among the viral proteins of HCV, core protein is the most versatile protein. Core protein not only serves as the component of viral nucleocapsid, but also is involved in many processes including modulation of viral and cellular gene expression, interaction with several cellular factors and regulation of signaling pathways. The pathological diagnosis shows the HCV core protein-expressing transgenic mice develop HCC. Thus, this viral protein may play an important role in the pathogenic progress of HCV-related HCC. Based on the previous reports, we know that, in HCC patients, the gene expression of two factors (WNT2b, beta-catenin) on WNT/beta-catenin signaling is up-regulated. Our microarray data from HCV core-expressing cell line also showed that the gene expression of two factors (APC, Frizzled-1) on WNT signaling has alteration. Therefore, it is likely that HCV core protein interacts with WNT signaling pathway.
To investigate the effect of HCV core protein on WNT signaling, the activity of artificial T cell factor response element (TCF-RE) containing reporter, pTOPFLASH, was addressed by the reporter assay in WNT-ON and WNT-OFF conditions. HCV core protein suppressed the TCF-RE specific gene expression in both conditions. To further examine the suppressive effect of core protein, the promoter activity of target gene, such as cyclin D1 promoter, was measured. Our results indicate that HCV core protein modulated the activity of cyclin D1 promoter in different ways. When WNT signaling was turned on, HCV core protein at low expression level suppressed the activity of cyclin D1 promoter via TCF-RE, but via the region other than TCF-RE when core protein was present at high expression level. Hence, HCV core protein could repress the activation of target gene expression on WNT signaling. To elucidate the possible mechanism of core protein in WNT signaling, we analyzed the expression and nuclear translocation of beta-catenin protein. There was no difference in both aspects indicating that HCV core protein modulated WNT/beta-catenin pathway through other mechanisms.
The interaction between HCV core protein and beta-catenin was demonstrated by in vitro GST pull-down assay and in vivo co-immunoprecipitation assay. The results of domain mapping indicated that the interaction domain was located in the C-terminal amino acid residues 123-191 of HCV core protein and ARM repeats 1-6 region of beta-catenin. According to in vitro binding assay, we found the different binding between beta-catenin variants and HCV core protein variants. Moreover, HCV core protein could repress the activation effect induced by beta-catenin overexpression. In summary, HCV core protein could modulate the WNT/beta-catenin pathway via interacting with the major effector, beta-catenin.
目錄
中文摘要 1
英文摘要 3
壹、緒論 5
一、C型肝炎病毒(Hepatitis C Virus, HCV) 5
1. 概述 5
2. C型肝炎病毒核心蛋白 6
3. C型肝炎病毒非結構蛋白 6
二、C型肝炎病毒核心蛋白(Hepatitis C Virus Core protein) 7
1. 簡介 7
2. 蛋白構造 8
3. 分布位置 8
4. 核心蛋白在病毒結構上扮演之角色 9
5. 核心蛋白與其他細胞因子之交互作用 9
6. 核心蛋白與宿主細胞凋亡途徑之關係 9
7. 核心蛋白之轉形能力 10
8. 核心蛋白調控宿主細胞及病毒基因之表現 10
9. 核心蛋白與訊息傳遞路徑 10
三、WNT訊息傳遞路徑 (Wnt signaling pathway) 12
1. WNT family 12
2. WNT signaling pathway 13
3. WNT/b-catenin訊息傳遞路徑之調控機制 15
四、b-catenin 19
1. Human b-catenin gene : CTNNB1 19
2. b-catenin 蛋白之結構 19
3. b-catenin為具有雙重功能之蛋白 20
4. b-catenin在WNT訊息傳遞過程所扮演之角色 20
5. b-catenin在腫瘤生成過程扮演之角色 22
貳、實驗材料與方法 23
一、實驗材料: 23
1. 菌株 23
2. 細胞株 23
3. 培養基與培養液 24
4. 質體 24
5. 溶液 28
6. 化學藥品 31
7. 酵素 25
8. 抗體 31
二、實驗方法: 32
1. 轉形作用於大腸桿菌 (Transformation) 32
2. 質體製備 32
3. 聚合鏈鎖反應 (Polymerase chain reaction) 33
4. 細胞培養 34
5. 細胞轉染作用(Transfection) 34
6. WNT treatment 35
7. SDS-聚丙烯醯胺凝膠電泳(Sodium dodecyl sulfate-polyacryl-amide gel electrophoresis, SDS-PAGE) 35
8. 西方墨點法 (Western blot) 36
9. Fractionation technique 36
10. 共同免疫沉澱法 (Co-immunoprecipitation) 36
11. Glutathione-S-tranferase pull down assay 37
12. Luciferase 活性測定分析 37
參、實驗結果 39
一、C型肝炎病毒核心蛋白影響WNT/b-catenin訊息傳遞路徑所調控目標基因之表現 39
1. C型肝炎病毒核心蛋白調控TCF reporter 之表現 39
2. C型肝炎病毒核心蛋白調控cyclin D1 promoter reporter 之表現 41
二、C型肝炎病毒核心蛋白對於b-catenin之影響 42
1. C型肝炎病毒核心蛋白對於b-catenin表現量之影響 42
2. C型肝炎病毒核心蛋白對於b-catenin核轉移作用之影響 43
三、C型肝炎病毒核心蛋白與b-catenin之交互作用 43
1. C型肝炎病毒核心蛋白與b-catenin之結合作用 43
2. 分析b-catenin與C型肝炎病毒核心蛋白結合之區域 44
3. C型肝炎病毒核心蛋白與b-catenin之結合作用對其抑制作用之影響 45
4. C型肝炎病毒核心蛋白調控b-catenin所活化之目標基因表現 46
肆、討論 47
一、C型肝炎病毒核心蛋白對WNT訊息傳遞路徑所活化基因表現之調控 47
1. C型肝炎病毒核心蛋白對於TCF-dependent transcription之調控作用 47
二、C型肝炎病毒核心核心蛋白對於b-catenin表現及核轉移之影響 49
三、C型肝炎病毒核心蛋白與b-catenin之交互作用在核心蛋白調控WNT訊息傳遞過程所扮演之角色 49
伍、參考文獻 52
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