臺灣博碩士論文加值系統

Epstein-Barr病毒(EBV)是一種廣泛存在於人體的病毒，與人類數種惡性腫瘤相關，包括風土性巴克氏淋巴癌(Burkitt掇 lymphoma)、霍奇金氏症(Hodgkin掇 disease)、鼻咽癌(nasopharyngeal)及器官移植後淋巴癌(post-transplantation lymphoma)。只有少數病毒基因在腫瘤細胞中會表現，而其中潛伏性膜蛋白一號(LMP1)是潛伏性基因裡唯一典型的非淋巴細胞之致癌蛋白，它能使Rat-1纖維母細胞及NIH3T3細胞表現惡性轉型能力。LMP1是一種膜蛋白，已知與TNF接受器有部分相似，故LMP1的作用功能被認為是模擬持續活化之接受器，已知參與了細胞內數種訊號傳遞途徑。但在文獻中所瞭解之LMP1的數種結合分子對其致癌機制仍無法完全解釋，故本論文之標的是篩選出新的LMP1結合分子，希望由此增加對LMP1致癌機制之瞭解。
本論文中使用酵母菌雙雜交分析法以潛伏性膜蛋白一號之C端序列為餌，篩選出全新的LMP1的結合分子BRAM1，一BMP接受器一號之接合分子一號，並在生體內及生體外實驗上證明其皆具結合能力，加以免疫螢光染色及共軛焦顯微鏡觀察法之佐證，觀查發現其分布位置具有交集。進而以酵母菌雙雜交分析法來探究此二蛋白分別之結合區域，結果發現當BRAM1蛋白C端序列的MYND區域受到裁切或對LMP1 C端序列的CTAR2區域加以裁切破壞則兩蛋白結合能力消失，證明其結合區域正位於其上。而文獻中已知CTAR2區域對LMP1所造成之核蛋白NF-kB活化作用及JNK訊號傳遞具決定性地位。進而本論文證實BRAM1會干擾LMP1活化核蛋白NF-kB之作用，但對LMP1活化JNK訊號傳遞方面則不見影響。由於已知LMP1蛋白之CTAR2區域會和一TNF-a接受器結合死亡區域蛋白(TRADD)結合，所以本論文進而去瞭解BRAM1是否影響TNF-a的訊號傳遞途徑，結果證實對TNF-a所造成之核蛋白NF-kB活化作用及JNK訊號傳遞的確受BRAM1所干擾。進一步探究其作用机制，發現BRAM1會干擾TNF-a及LMP1所造成IkBa之磷酸化程度並延遲其崩解作用。另外，文獻中已知LMP1具有阻礙TNF-a所引發之細胞毒殺的能力，而BRAM1會干擾此項LMP1之能力。因此綜觀BRAM1對LMP1的功能而言，其應扮演一負向調節者角色。

Latent membrane protein 1 (LMP1), a major oncoprotein encoded by Epstein-Barr virus (EBV), has been shown to be involved in cellular signaling pathways. In this thesis, we tried to identify new targets of LMP1 signaling that may help to explain the role of LMP1 in non-lymphocyte cell transformation. Using yeast two-hybrid screening method with the C-terminal sequence of LMP1 as the bait, we found that BMP receptor-associated molecule 1 (BRAM1) associated with LMP1 in vitro and in vivo. This finding was supported by cotransfection experiments and examined by immunoassays and confocal microscopy. The association involves mainly the C-terminal half, the MYND domain, of BRAM1 and the CTAR2 region of LMP 1. The latter is critical for LMP1-mediated NF-kB and JNK signaling pathways, suggesting the role of BRAM1 in LMP1 signaling. To test this hypothesis, we examined the effect of BRAM1 on the induction of NF-kB and JNK activation by LMP1. We demonstrate that BRAM1 interferes with LMP1-mediated NF-kB activation in BALB/c3T3 cells. Since LMP1-induced NF-kB activation through the NIK-IKK-IkB pathway, we thus examined the protein level of total and phosphorylation form of IkBa in the presence and absence of BRAM1. The results indicated that BRAM1 decreased the phosphorylation of IkBa and delayed the degradation of total IkBa in the presence of LMP1. Since the CTAR2 region interacts with the TNF-a receptor-associated death domain protein (TRADD), it is interesting to find that BRAM1 also interferes with NF-kB activation mediated by TNF-a. Since the CTAR2 region of LMP1 is critical for LMP1-mediated JNK activation, we examined the effect of BRAM1 on the JNK activation mediated by LMP1, TNF-a treatment and overexpression of LTbR. We found that BRAM1 plays a role either in LTbR-mediated or in TNF-a mediated JNK activation but not in LMP1-mediated JNK activation. To further examine the role of BRAM1 in LMP1 signaling, we observed that BRAM1 disrupts the resistance of LMP1-expressing cells to TNF-a-induced cytotoxicity. Thus, we propose that BRAM1, a molecule uniquely associated with LMP1, functions as a negative regulator of LMP1-mediated biological functions.

1. Introduction圪圪圪圪圪圪圪?圪圪.圪圪?..圪..?
1.1 Discovery of Epstein-Barr virus (EBV)圪.圪圪.圪圪圪?.圪..1
1.2 Biology of EBV圪.圪圪.圪圪圪圪圪圪圪??..圪.1
1.2.1 General characteristics圪.圪圪.圪圪圪圪??圪圪1
1.2.2 Gene expression during latent infection圪圪圪..圪圪.圪?.2
1.2.3 Characteristics of latent gene products圪圪圪?圪圪?圪.3
1.2.3.a LMP1.圪圪.圪圪圪圪圪...圪圪圪???
1.2.3.b LMP2A, 2B?圪圪.圪圪?..圪......圪圪.圪.?
1.2.3.c EBNA1圪.圪圪.圪圪圪..圪圪.圪圪.圪...7
1.2.3.d EBNA2圪.圪圪.圪圪圪.圪圪圪圪.?...?
1.2.3.e EBNA3A, 3B, 3C圪?圪??圪?.圪?..圪圪?
1.2.3.f EBNA-LP圪.圪圪.圪圪..圪?.圪圪...???0
1.2.3.g EBERs圪.圪圪.圪圪圪???.圪??..圪.12
1.2.4 Induction of lytic infection圪.圪圪.圪圪.圪...圪圪.?2
1.3 EBV-associated malignancies圪.圪圪.圪圪?.圪?..圪圪.14
1.3.1 Burkitt掇 lymphoma圪.圪圪.圪圪圪圪.圪..圪??5
1.3.2 Nasopharyngeal carcinoma圪.圪圪.圪圪圪?圪圪?5
1.3.3 Hodgkin掇 disease圪.圪圪.圪圪圪圪?圪?.圪?6
1.3.4 T cell lymphoma圪.圪圪.圪圪圪圪圪圪圪...?.17
1.4 Characteristics of BMP receptor associated molecule 1 (BRAM1)圪圪?18
1.5 The specific aims of this thesis圪圪圪圪圪圪?圪..圪.?.21
2. Materials and methods圪圪圪圪?圪圪....圪.圪圪?.圪.23
3. Results圪圪圪圪圪圪圪?圪圪?..圪圪??圪.. 31
3.1 BRAM1 is an LMP1-interacting protein圪圪圪圪圪圪.圪?.31
3.2 The C-terminal 116-amino acid sequence of BRAM1 specifically interacts with the CTAR 2 region of LMP1圪圪圪圪圪圪圪圪..?.圪.32
3.3 Cellular localization of LMP1 and BRAM1圪圪圪?.圪圪...??3
3.4 BRAM1 associates with LMP1 in vitro圪圪圪圪圪圪圪.?...34
3.5 BRAM1 associates with LMP1 in vivo圪圪圪圪圪..圪??.....35
3.6 BRAM1 associates with TRADD圪圪圪..圪圪圪圪圪?..35
3.7 BRAM1 associates with LTbR圪圪圪圪..圪圪圪.圪圪...36
3.8 BRAM1 interferes with LMP1-mediated NF-kB activation圪圪圪圪.37
3.9 BRAM1 interferes with TNF-a-mediated NF-kB activation 圪?..圪圪37
3.10 The negative regulatory of BRAM1 involved in the TNF-a-mediated NF-kB activation is through the N-terminus of BRAM1圪圪圪?..圪.圪39
3.11 Analysis of NF-kB activity in gel shift assays圪圪圪圪圪?圪39
3.12 BRAM1 does not influence the LMP1-mediated JNK pathway圪圪??0
3.13 BRAM1 interferes with TNF-a-mediated JNK pathway圪圪?圪...?0
3.14 BRAM1 interferes with LTbR-mediated JNK pathway圪圪?圪.圪41
3.15 BRAM1 interferes with LMP1-mediated MAP kinase activation圪圪...?1
3.16 BRAM1 interferes with IkBa phosphorylation and delays its degradation induced by LMP1 and TNF-a in 3T3 cells圪圪圪圪圪?....圪42
3.17 BRAM1 interferes with TNF-a and TAK1-mediated IKK activation圪圪43
3.18 BRAM1 inhibits the resistance of LMP1-expressing cells to TNF-a-induced cytotoxicity.圪圪圪圪圪圪圪圪圪圪.圪圪圪44
3.19 BRAM1 interferes with LMP1-mediated iNOS expression in RNA level?.?5
3.20 BRAM1 is a serine residue phosphorylated protein圪圪圪圪圪?6
4. Discussion圪圪圪圪圪圪圪圪.圪圪圪圪圪圪...48
5. References圪圪圪圪圪圪圪圪?.圪圪圪?.圪...?5
6. Figures圪圪圪圪圪圪圪圪?圪圪圪圪?圪?. 75
7. Tables圪圪圪圪圪圪圪圪圪圪?圪.圪圪圪.. 115

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