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系統識別號 U0026-1001201311164300
論文名稱(中文) 一個嶄新的轉錄抑制複合物KLF12/hKID3參與在引發肝癌的B型肝炎病毒preS突變株表面基因失調的機轉
論文名稱(英文) A novel transcriptional repressor complex composed of KLF12/hKID3 involved in surface gene deregulation in a hepatocellular carcinoma-inducing hepatitis B virus preS mutant
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 1
出版年 102
研究生(中文) 洪偉珉
研究生(英文) Wei-Min Hung
學號 s46991059
學位類別 碩士
語文別 中文
論文頁數 96頁
口試委員 指導教授-呂政展
口試委員-劉校生
口試委員-王育民
口試委員-陳炳焜
中文關鍵字 B型肝炎病毒  preS突變株  表面基因  轉錄抑制複合物  KLF12  hKID3 
英文關鍵字 hepatitis B virus  preS mutant  surface gene  transcriptional repressor complex  KLF12  hKID3 
學科別分類
中文摘要 B型肝炎病毒(HBV)的基因組為部分雙股DNA,大小約為3,200個核苷酸。HBV具有四個主要的基因,分別為表面(S)基因、核心外套蛋白(C)基因、聚合酶(P)基因以及X基因。其中的表面基因被兩個起始密碼子(start codons)分為三個部分:preS1、preS2及S。 HBV的感染與慢性肝炎以及一些較嚴重的肝臟疾病(如肝硬化或肝癌等)息息相關。先前的研究已指出,若被帶有preS deletion的HBV突變株感染會更容易產生肝硬化或是肝癌。另外,若轉殖小鼠帶有preS2起始密碼子的點突變(ATG變為ATA)以及preS2 domain N端缺失的HBV基因組,也會使小鼠產生肝癌。這些preS的突變將會導致表面基因的失調。因此在本篇實驗中,我們將探討在HBV preS2 domain的N端是否有轉錄因子參與在表面基因的調控當中。由Linker-scanning (LS)的實驗以及生物資訊學的分析,我們發現兩個轉錄因子KLF12以及hKID3,這兩個因子均座落在LS1區域中。在LS1做了兩個點突變,發現會使表面基因的表現上升,同時也發現preS mRNA也會增加。而在以shRNA抑制KLF12或是hKID3的表現,也看到相同的結果。而藉由凝膠遷移電泳分析與染色質免疫沉澱的結果,證實KLF12確實是結合到LS1這個區域中。由先前的研究指出,KLF12需與co-repressor CtBP1結合才能執行其抑制的作用。不過出乎意料的是,若抑制KLF12的co-repressor CtBP1並不會影響表面基因的表現。因這兩個因子的結合區域是完全重疊,因此我們便推測這兩個因子間是否有交互作用。由免疫共沉澱及GST沉澱試驗證實KLF12確實會與hKID3結合。因此在本研究中我們發現了一個嶄新的轉錄抑制複合物KLF12/hKID3會調控HBV表面基因的表現。
英文摘要 The hepatitis B virus (HBV) genome is composed of partially double-stranded DNA of about 3.2kb. It has the capacity to encode four overlapping genes, i.e. S (surface), C (nucleocapsid), P (polymerase) and X gene. The HBV surface gene is divided into three parts by two internal start codons: preS1, preS2 and the S region. HBV infection is associated with chronic hepatitis and advanced liver diseases (eg, liver cirrhosis, hepatocellular carcinoma (HCC)). Longitudinal studies have shown that chronic HBV infection with preS deletion mutants is more likely to develop cirrhosis and HCC than with wild type surface gene. Transgenic mice with a point mutation in preS2 translation initiation codon and a deletion in N-terminus of preS2 in full length HBV genome was recently shown to induce HCC. The mutations in the preS2 domain have led to the deregulation of surface gene expression. In this study, we aim to identify if transcription factors within N-terminus of preS2 domain were involved in the regulation of surface gene. Linker-scanning (LS) experiments and bioinformatic search have identified transcriptional repressors, KLF12 (AP2rep) and hKID3 (ZNF354C) localized within LS1. Double point mutations within LS1 region rendered major surface protein expression elevated, which was accompanied by increased preS mRNA expression. Similar observations were made in knock-down of either KLF12 or hKID3 by shRNA. These data indicate KLF12 may bind to LS1. The results were further confirmed by EMSA, supershift assay and chromatinimmunoprecipitation assay. KLF12 is known to cooperate with CtBP1 to exert its repressive effect. Unexpectedly, knockdown of KLF12 corepressor CtBP1 did not have effect on major surface protein expression and S promoter reporter activity. As the binding sites for both KLF12 and hKID3 overlap exactly, we hypothesizeded that KLF12 may interact with hKID3. We demonstrated that KLF12 interacted with hKID3 by co-immunoprecipitation and GST pull-down assays. In conclusion, these results showed that a novel repressor complex (KLF12 and hKID3) within HBV preS2 domain N-terminal region is involved in the regulation of major surface gene but also preS1 transcription.
論文目次 中文摘要 I
ABSTRACT III
致謝 V
目錄 VI
緒論 1
材料與方法 12
結果 25
討論 37
參考資料 42
表格 50
結果圖 51
附錄 89
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