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研究生:陳中瑜
研究生(外文):Chung-Yu Chen
論文名稱:分析EB病毒潛伏性膜蛋白第一型調控DNAmethyltransferase3a及3b之機制
論文名稱(外文):Regulation of DNA methyltransferase 3a and 3b by Epstein-Barr virus latent membrane protein 1 (LMP1)
指導教授:張玉生張玉生引用關係
指導教授(外文):Yu-Sun Chang
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:49
中文關鍵詞:潛伏性膜蛋白第一型DNA甲基化鼻咽癌多型性
外文關鍵詞:DNA methyltransferase 3a and 3bLMP1NPCpolymorphism
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鼻咽癌(NPC)是與EB病毒相關的癌症之ㄧ,其中,病毒蛋白質,潛伏性膜蛋白第一型(LMP1),是EB病毒的致癌蛋白質,已經被報導可活化DNA甲基轉移酶(DNA methyltransferases1, 3a and 3b),而LMP1對細胞內DNA甲基化(DNA methylation)的調控有其重要性。DNA甲基化被視為是一種重要的外基因修飾(epigenetic modification)機制,藉此過程可調控基因表現,而異常的DNA甲基化也已被證實與癌症的發生有關,因此,經由LMP1所引起的DNA甲基化可能在鼻咽癌致癌化的過程中扮演著重要角色。在此研究中,我們發現LMP1會誘導dnmt3a和dnmt3b基因的轉錄表現。近期報導因為dnmt3b在第-283個核苷酸有T->C的多型性(polymorphism)現象,會影響dnmt3b基因的表現,進而與肺癌的發生有密切關聯。為了評估台灣鼻咽癌病人是何基因型,我們利用單一核酸多型性(single nucleotide polymorphism, SNP)檢測系統,檢驗鼻咽癌的檢體和細胞株,結果顯示,得鼻咽癌的台灣人在dnmt3b -283T對偶基因有較高的分布趨勢。另外,我們證明LMP1會活化dnmt3b -283T 的對偶基因,卻不會活化-283C的對偶基因。綜合實驗結果,鼻咽癌的發生可能受到遺傳性和外遺傳性(genetic and epigenetic)因素結合的影響。我們進一步研究LMP1是否會影響dnmt3b異構物(dnmt3b splice variants),以及Dnmt3a和Dnmt3b的蛋白質表現,結果顯示LMP1對dnmt3a和dnmt3b的後轉錄和轉譯表現並沒有明顯調控。本篇研究提供有關LMP1調控dnmt3a和dnm3b機制的重要資訊。
In EBV-associated cancers such as nasopharyngeal cancer (NPC), the viral encoded oncogene product, latent membrane protein 1 (LMP1) can activate DNA methyltransferases (Dnmt1, 3a and 3b), strongly implying the role of LMP1 in manipulating the cellular DNA methylation machinery. DNA methylation is an important epigenetic modification, which regulates gene expression. Improper DNA methylation has been demonstrated to be associated with increasing risk of cancers. Thus, LMP1-mediated DNA methylation may play a role in the tumorigenesis of NPC. In this study, we demonstrated that LMP1 induces the transcription of dnmt3a and dnmt3b genes. Recent report suggested that dnmt3b -283T->C polymorphism influenced dnmt3b expression, which was correlated with lung cancer risk. To determine which genotype is prevalent in NPC patients in Taiwan, we examined this single nucleotide polymorphism (SNP) in NPC biopsies and three NPC cell lines. Our data demonstrated that Taiwanese with NPC have a higher frequency of dnmt3b -283T allele. In addition, dnmt3b -283T allele, but not -283C allele can be activated by LMP1. Thus, these data suggest that EBV infection contribute both genetic and epigenetic susceptibility to NPC. Furthermore, we investigated the potential dnmt3b splice variants and protein expression of Dnmt3a and Dnmt3b in the presence or absence of LMP1. Results indicated that there is no obvious regulation of the post-transcriptional and translational levels of dnmt3a and dnmt3b by LMP1. This study should provide important information regarding the regulation of dnmt3a and dnmt3b genes by LMP1.
Contents
指導教授推薦書.........................................................................................
口試委員會審定書......................................................................................
授權書.......................................................................................................iii
中文摘要...................................................................................................iv
English abstract…………………………………………………………...v
致謝……………………………………………………………………...vi
Introduction………………………………………………………………1
Rationale and significance of this study………………………………….7
Materials and methods……………………………………………………9
Results…………………………………………………………………...13
Discussion……………………………………………………………….18
Reference………………………………………………………………..23
Figures and tables……………………………………………………….31
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