臺灣博碩士論文加值系統

EB病毒（EBV）是屬於人類第四型皰疹病毒，可感染人類B淋巴球細胞及表皮細胞，並與巴克氏淋巴瘤及鼻咽癌有關。一般相信在這些腫瘤細胞中EBV是以潛伏的狀態存在，同時也會表現如EBNA-1及LMP-1等潛伏基因產物。
先前的研究指出，在第一型巴克氏淋巴瘤如Rael cells中，EBNA-1的訊息RNA是由Q啟動子所引導，而不同於活體外建立之淋巴芽細胞株，因為EBNA-1在活體外之淋巴芽細胞株中是由C/W啟動子所引導的。為了了解Q啟動子在第一型巴克氏淋巴瘤細胞中的活性調節機制，我將Q啟動子做一系列的刪除或突變，然後送入Rael cells中觀察其活性改變。結果指出在Q啟動子上從-125到-50區域刪除對Q啟動子的活性並不具重要性，而-50到-37區域刪除對Q啟動子的活性則有決定性的影響，會造成Q啟動子活性喪失。從-50到-37這段區域包含了一個細胞因子Smad4的蛋白附著點，若將Q啟動子上Smad4蛋白附著點以突變處理，則Q啟動子的活性也會降低約1/2到1/3。Smad4是屬於細胞激素TGF-訊息傳遞途徑中的中介物質，受到TGF-刺激後，Smad4可與Smad2/Smad3等細胞因子結合，進入細胞核中。我將Q啟動子與Smad3/Smad4一起送入Rael cells中並將細胞以TGF-處理。實驗結果顯示細胞在TGF-處理的情形下Q啟動子的活性約會降低製原來的1/2到1/3，而在電泳帶阻滯分析中也證實Smad4確實會與Q啟動子結合。本實驗證實了TGF-確實會經由Smad4來調降Q啟動子的活性，然而其真實的生物特性及其調節機制仍有待進一步的研究。

EBNA 1 gene of Epstein-Barr Virus (EBV) is transcribed from a latent promoter Qp in Burkitt’s lymphoma cell line, Rael, which is different from the Cp that is pre-ferentially activated in lymphoblastoid cell lines. In order to understand the mechanism that modulates the Qp activity, Qp and its deletion or site-specific mutant constructs were transfected into Rael cell and promoter activity was determined. Results showed that the region between —125 to —50 was not important for the minimal promoter activity of Qp. On the other hand, deletion to —37 reduced the promoter activity significantly. This region includes a binding motif recognized by Smad 4, a mediator involved in the TGF- signaling pathway. The binding was also proved by EMSA. Therefore, a site-specific mutation was made within this region and was then tested for its promoter activity. Data indicated the promoter activity was reduced to a basal level, and slightly higher then the deletion (-37) mutant. To analyze the effect of TGF- on Qp, promoter construct containing —50 to +20（pGL2B-50）and its Smad4 binding site mutant, pGL2B-50m4 were co-transfected with Smad3 and Smad4-expressing vector into Rael cells. The promoter strength was measured by the luciferase activity. Results showed that the minimal Qp（-50 to +20）activity was down-regulated upon TGF- stimulation through the Smad4 binding site. The mechanisms involved in this transcriptional repression and its biological significance were discussed.

Abstract 1
Introduction 3
Methods and materials 15
Results 22
Discussion 25
Reference 27
Figures 41
Tables 57

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