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研究生:包育甄
研究生(外文):pao yu chen
論文名稱:分析表現Epstein-Barr病毒蛋白質EBNA1細胞中分泌性蛋白質之特性
論文名稱(外文):Identification and characterization of secreted proteins in EBV-encoded EBNA1-expressing cells
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:2007
畢業學年度:95
語文別:英文
論文頁數:51
中文關鍵詞:分泌性蛋白質Epstein-Barr 病毒
外文關鍵詞:EBVEBNA1secreted proteins
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中文摘要

EBNA1 (EB 病毒核抗原 1) 是 EB 病毒中唯一在不同潛伏週期都會表現的病毒蛋白質。EBNA1 是一個多功能的蛋白質,具有使細胞轉形、抗凋零的功能,也負責寄主細胞中 EB 病毒游離染色體的維持及其潛伏期基因的活化。為了尋找更多適合作為診斷與治療的生物標誌 (biomarker),我們利用比較穩定表現和不表現 EBNA1 的 293 細胞培養液,結合二維電泳與質譜儀實驗鑑定差異表現的分泌性蛋白質。經由免疫轉漬法確認,蛋白質 peroxiredoxin 2 (PRDX2)、heat shock 70kDa protein 8 (HSPA8)、lactate dehydrogenase B (LDHB) 和 NIMA (never in mitosis gene a)-related kinase 2 (NEK2) 會在 293-EBNA1 細胞中大量表現,而蛋白質 agrin (AGRN) 的表現量在 293-EBNA1 細胞中會減少。並利用即時定量 RT-PCR 分析這些基因的轉錄程度,其中 HSPA8、PRDX2、NEK2 和 AGRN 有 1.5 倍以上的增加。所以在 293-EBNA1 細胞中,HSPA8、PRDX2、NEK2 的表現量增加是在轉錄時就受到調控,而 LDHB 則在轉譯成蛋白質時受到調控而增加表現量。此外,AGRN 轉錄程度增加但是蛋白質表現量卻減少,推測是受到 EBNA1 轉譯後修飾的調控而影響蛋白質穩定度。我們再進一步以暫時性表現 EBNA1 的細胞中驗證之前鑑定的差異性分泌蛋白質,最後只有 AGRN 的蛋白質表現量在被 EBNA1 腺病毒感染的鼻咽癌細胞培養液中仍然會減少,其它的蛋白質在細胞培樣液中的表現量並沒有差異,不過暫時性表現 EBNA1 的細胞系統仍然可以再修正、調整。本研究找出可能受到 EBNA1 調控的分泌性蛋白質,而這些分泌性蛋白質有潛力作為 EBV 相關疾病診斷偵測用的標誌。
Abstract
The Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein expressed in all EBV-associated malignancies. EBNA1 is a multifunctional protein with transformation ability, anti-apoptotic properties, and EBNA1 is involved in the maintenance, replication and transcriptional activation of the EBV genome. In order to search “biomarkers” that can be used for tumor diagnosis we utilize in vitro culture system with cells stably expressed EBNA1 to identify the differentially expressed secreted proteins. Culture supernatants of cells expressing EBNA1 and vector containing control are analyzed by 2-DE and MALDI-TOF MS, and confirmed by immunoblotting. As a result of three independent experiments, peroxiredoxin 2 (PRDX2), heat shock 70kDa protein 8 (HSPA8), lactate dehydrogenase B (LDHB), and NIMA (never in mitosis gene a)-related kinase 2 (NEK2) have been consistently identified in cultured supernatants of 293-EBNA1 cells, at a relatively higher level as compared with control 293-neo cells. And agrin (AGRN) is low-expression in 293-EBNA1 culture supernatants. Transcriptional level of HSPA8, PRDX2, AGRN, and NEK2 were 1.5-fold higher in 293-EBNA1 cells when compared with that of 293-neo cells. Experimental results indicate that HSPA8, PRDX2, and NEK2 could be up-regulated at transcriptional level in 293-EBNA1 cells; and LDHB may be up-regulated at translational level. Besides, protein AGRN may be down-regulated through post-translational modification in cells. We also further confirmed the previous identified secreted proteins in transient EBNA1-expression systems, and only AGRN showed the low-expression in supernatants of recombinant EBNA1 adenovirus infected NPC cells. Therefore, protein AGRN is consistently down-regulated in different EBNA1-expression systems. Our study identified the differentially expressed secreted proteins in EBNA1-expressing cells and these proteins could be potential prognostic markers for EBNA1-evolved tumors.
Contents

指導教授推薦書…………………………………………………………………
口試委員會審定書………………………………………………………………
授權書…………………………………………………………………………....iii
誌謝……………………………………………………………………………....iv
中文摘要……………………………………………………………………….....v
English abstract…………………………………………………………………..vi
Introduction…………………………………………………………………....…..1
Specific Aims……………………………………………………………….…..…9
Materials and Methods…………………………………………………………...10
Results………………………………..……………...…………………….….….17
Discussion………………..………………………………………………….…...21
References…………..…………………………………………………………....28
Figures and Tables………………………………………………………………..37
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