臺灣博碩士論文加值系統

人類疱疹病毒第八型（Human Herpesvirus8,HHV-8）又稱為卡波西氏肉瘤疱疹病毒(KSHV)，為引起卡波西氏肉瘤(Kaposi’s sarcoma,KS）之病因，HHV-8 DNA在KS病患的背部根神經節與HIV陽性病患不明腦炎的大腦活檢樣本中被發現。HHV-8包含的89個ORFs中有若干ORFs與細胞基因同源，能編碼干擾免疫系統蛋白，參與核酸代謝的酶和細胞生長調節因數等。ORF K12可編譯成Kaposin蛋白，可能促進細胞增生。為了進一步了解人類疱疹病毒Kaposin蛋白與腦部病變之相關性，以噬菌體表達人腦cDNA基因庫的技術，找尋與人類疱疹病毒第八型Kaposin蛋白作用之神經因子。結果表現人腦細胞septin4 cDNA之噬菌體被篩選出來。Kaposin蛋白與septin4重組蛋白間專一性結合經免疫沉澱法證實兩者確實有交互作用的關係。藉共軛焦顯微鏡的觀察Kaposin與septin4共同轉染之SK-N-SH與TE671細胞確認kaposin與septin4在細胞內有同位化現象。深入作用機轉探討發現kaposin有anti-septin4抑制caspase3活性及active caspase3生成。此外NFκB與Ap-1啟動子結合冷光報導基因之細胞內訊息傳遞偵測系統推測kaposin可能藉活化AP-1因子干擾septin4傳達細胞凋亡途徑有關。本論文將有助於深入探討人類疱疹病毒第八型Kaposin蛋白可能的致病機制。

Human herpesvirus 8 (HHV-8) referred to as Kaposi’s sarcoma- associated herpesvirus (KSHV) is forms of Kaposi’s sarcoma. HHV-8 DNA was detected in dorsal root ganglia of KS patients, cerebrospinal fluid of human immunodeficiency virus-positive patients, and brain biopsy specimens from patients with unexplained encephalitis. The genome of HHV-8 contains 89 ORFs, some ORFs with homologous to cellular genes encode to interfere with host immune system, enzymes of nucleotide metabolism, and growth factors. The kaposin protein derived from ORF K12 has been reported to stimulate cell proliferation. In the study, we investigate protein-protein interaction of HHV-8 ORF K12 with neural cell factors using phage display human brain cDNA library. After six-run biopanning, septin4 that interacted with the kaposin protein has been identified. Co-immunoprecipitation showed the binding interaction of recombinant kaposin protein with septin4 protein. In addition, conforcol immunofluorescence assay demonstrated co-locolization of HHV-8 kaposin protein with septin4 protein in SK-N-SH and TE671 cells. Moreover, caspase3 assay showed that the kaposin protein inhibited septin4-induced apoptosis. NFκB-luciferase and Ap-1-luciferase cis-acting reporters revealed that the kaposin protein activated Ap-1 promoter, being associated with the inhibitory affect on septin4-mediated apoptosis. This study will be helpful for insights into the role of the kaposin protein in the HHV-8 pathogenesis.

目 錄
中文摘要 Ι

英文摘要 Ⅱ
致謝 Ⅲ
目錄 Ⅴ
圖目錄 Ⅸ
表格目錄 Ⅹ
附錄目錄 ⅩⅠ

第一章 前言 01
第二章 文獻探討 03
2.1 人類疱疹病毒（Human herpesvirus） 01
2.2 人類疱疹病毒第八型（HHV-8） 03
2.2.1 背景 03
2.2.2 傳播途徑 05
2.2.3 病毒特性及功能 06
2.2.4 Kaposin蛋白 09
2.3 細胞凋亡 09
2.3.1 參與分子 10
2.3.2 傳遞路徑 11
2.4 功能性基因體-噬菌體呈現技術 12
2.4.1 原理 12
2.4.2 應用 14
2.5 SEPTIN家族蛋白 16
2.5.1 SEPTIN4蛋白 17
第三章 實驗測略
第四章 材料與方法 18

21
4.1 實驗材料 21
4.1.1 病毒株 21
4.1.2 細胞株 21
4.1.3 大腸桿菌菌株 23
4.1.4 質體 23
4.1.5 引子 24
4.1.6 實驗試劑及緩衝液配製 25
4.1.7 抗體 25
4.1.8 儀器、器材 25
4.1.9 噬菌體呈現人腦cDNA基因庫 26
4.2 實驗方法 26
4.2.1 細胞冷凍 26
4.2.2 細胞解凍 26
4.2.3 病毒收取 27
4.2.4 病毒DNA的抽取 27
4.2.5 聚合酵素連鎖反應 28
4.2.6 質體純化 29
4.2.7 限制酵素的水解 29
4.2.8 質體的構築 : DNA接合 30
4.2.9 適應性細胞的製備 30
4.2.10 大腸桿菌之轉型 31
4.2.11 誘導大腸桿菌上乳糖啟動子表現蛋白 31
4.2.12 菌體超音波破碎 31
4.2.13 純化重組病毒蛋白質 32
4.2.14 蛋白質濃度測定 32
4.2.15 蛋白質之電泳分析 33
4.2.16 西方墨點法 34
4.2.17 DNA轉染 35
4.2.18 噬菌體的生長與儲存 36
4.2.19 測定噬菌體的效價 36
4.2.20 噬菌體篩選 36
4.2.21 噬菌體酵素連結免疫吸附分析 37
4.2.22 噬菌體DNA製備 38
4.2.23 共同免疫沉澱法 39
4.2.24 共同轉染 40
4.2.25 共同轉染免疫螢光染色法 41
4.2.26 caspase3 活性分析 41
4.2.27 建立穩定細胞的NFκb冷光試驗測定 42
4.2.28 建立穩定細胞的Ap-1冷光試驗測定 42
第五章 結果 43
5.1 鑑定與人類疱疹病毒蛋白Kaposin作用的細胞因子 43
5.1.1 人類疱疹病毒Kaposin重組蛋白的質體構築及蛋白質表現 43
5.1.2 以人類疱疹病毒Kaposin重組蛋白進行噬菌體篩選 44
5.2. Kaposin蛋白與人腦細胞因子Sept4蛋白之交互作用 45
5.2.1 人腦細胞因子sept4重組蛋白的質體構築及蛋白質表現
5.2.2 重組人腦細胞蛋白（septin4）與病毒蛋白共同免疫沈澱 45
45
5.2.3 進行細胞轉染人腦疱疹病毒kaposin蛋白質體構築 46
5.2.4 進行細胞轉染人腦細胞因子（septin4）質體構築 47
5.2.5 重組人腦細胞因子（septin4）與重組質體Kaposin進行共同 轉染 47
5.2.6 重組質體Kaposin與pDsREd-mitochondrial進行共同轉染 48
5.2.7 重組質體Kaposin與pDsREd-ER進行共同轉染 49
5.3 Kaposin蛋白與人腦細胞因子Sept4蛋白之關聯性 50
5.3.1 重組質體進行細胞轉染後細胞形態 50
5.3.2 重組人腦細胞因子septin4與Kaposin質體經細胞轉染進行 51
caspase3 activity assay
5.3.3 重組人腦細胞因子septin4與Kaposin質體經細胞轉染進行 caspase-3西方墨點法 52
5.3.4 重組人腦細胞因子septin4與Kaposin蛋白質體經細胞 轉染進行Bax西方墨點法 53
5.3.5 重組人腦細胞因子septin4與重組質體Kaposin建立穩定 細胞進行NFκb冷光試驗測定 53
5.3.6 重組人腦細胞因子septin4與重組質體Kaposin建立穩定 細胞進行AP-1冷光試驗測定
第六章 討論 54

56
6.1 與kaposin蛋白相互作用的神經細胞蛋白質 58
6.2 kaposin蛋白與神經細胞因子sept4蛋白相互作用 58
6.3 kaposin蛋白與神經細胞因子sept4蛋白相互作用的
關聯性 59
參考文獻 62
圖檔
表
附錄一
附錄二 69

96

98

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圖 目 錄

圖一 . ORF k12 PCR 電泳圖 69
圖二 . ORF k12與pET24a載體重組經轉形後PCR Rapid Screeing 電泳圖 70
圖三 . ORF k12/pET32a載體重組經轉形後PCR Rapid Screeing 電泳 71
圖四. 以西方墨點法鑑定經FPLC純化後ORF K12（kaposin）蛋白。 72
圖五 噬菌體親和性篩選（Bio-panningg）流程圖 73
圖六 噬菌體溶菌班試驗 74
圖七. 篩選後的噬菌體對人類疱疹病毒kaposin蛋白質進行ELISA 75
圖八. 噬菌體表現人腦細胞蛋白之cDNA 進行序列分析 76
圖九. 噬菌體25 PCR 電泳圖 77
圖十. 噬菌體25 PCR/pET24a載體重組經轉形後 pcr Rapid Screeing及質體限制酵素切割作用電泳圖 78
圖十一. 以西方墨點法鑑定經FPLC純化後phage25（septin4）蛋白。 79
圖十二. 人腦細胞重組蛋白septin4與人類疱疹病毒kaposin蛋白質進行共同免疫沈澱 (Co IP) 80
圖十三 .ORF k12/pcDNA3.1hisC載體重組經轉形後PCR Rapid Screeing 電泳圖 81
圖十四 .EGFP-ORF k12/pcDNA3.1 hisC載體重組經轉形後 PCR Rapid Screeing和質體限制酵素切割作用電泳圖 82
圖十五. 噬菌體25 PCR 電泳圖 83
圖十六. 噬菌體25 PCR/pDsRed1-1載體重組經轉形後pcr Rapid Screeing及質體限制酵素切割作用電泳圖 84
圖十七. 利用SK-N-SH neuro cell lines進行EGFP-K12與sept4重組質體共同轉染 85
圖十八. 利用TE671 neuro cell lines進行EGFP-K12與sept4重組質體共同轉染 86
圖十九. 利用TE671 neuro cell lines進行EGFP-K12與pDsRed- mitochondrial共同轉染 87
圖二十. 利用TE671 neuro cell lines進行EGFP-K12與pDsRed-ER共同轉染 88
圖二十一. TE671細胞轉染後細胞形態 89
圖二十二. 轉染細胞進行caspase3活性分析 90
圖二十三. 轉染細胞進行Anti-caspase3西方墨點法 91
圖二十四. 轉染細胞進行Anti-Bax西方墨點法 92
圖二十五. 建立穩定細胞冷光試驗測定NFκb活性分析 93
圖二十六. 建立穩定細胞冷光試驗測定AP-1活性分析 94
圖二十七. Kaposin和SEPT4交互作用的假設性路徑 95

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