腫瘤易感基因101（TSG101）為ESCRT-I（endosomal sorting complex required for transport complex I）複合體的成員之一，參與蛋白質分選及囊泡運輸，因此為細胞之生長及分化所必需。過去研究顯示TSG101能參與細胞自噬作用之調節，但詳細機制不明。據實驗室學長以TSG101為餌進行酵母菌雙雜交實驗結果，發現TSG101與Snapin蛋白有交互作用。Snapin最早因與SNAP25交互作用並促進神經傳遞物質釋放之活性而被發現，近期研究則指出其在細胞自噬與晚期內含體熟成及囊泡運輸扮演重要角色。然而，Snapin與內含體之連結蛋白仍未被報導。因此，TSG101與Snapin兩蛋白交互作用之生理意義值得進一步加以釐清。本研究首先利用Pull-down實驗及免疫共沉澱分析驗證兩蛋白間之交互作用。後續我們以共軛焦顯微鏡螢光影像分析發現：在子宮頸癌細胞HeLa中，兩者在細胞質內具點狀共位，且該兩蛋白皆與晚期內含體標誌Rab7共位，顯示其交互作用可能發生於晚期內含體上。而在未分化NSC-34類運動神經元細胞或誘導分化之NSC-34（NSC-34D）細胞中，皆觀察到兩蛋白在細胞質有點狀共位現象，在已分化NSC-34D之神經突中亦可觀察到兩蛋白之點狀共位。而我們的活體螢光顯微鏡縮時攝影觀察結果，亦發現兩蛋白之點狀共位於NSC-34之細胞質，或於NSC-34D之神經突中共同移動，再次驗證兩蛋白質之共位現象，並指出兩蛋白之交互作用可能具有神經生理相關功能。綜上所述，TSG101與Snapin蛋白具交互作用，該交互作用可能參與內溶酶體運輸路徑，而其在神經細胞之生理意義有待進一步釐清。

Tumor susceptibility gene 101(TSG101) has important physiological functions in the regulation of cell cycle and membrane trafficking. TSG101 is essential for cell growth, proliferation, and survival, and also for the development of an organism. As a component of ESCRT(Endosomal Sorting Complex Required for Transport) complex I, TSG101 plays an important role in protein sorting and vesicular transportation. Recently, a study done by an ex-member of our laboratory indicated TSG101 is involved in the regulation of autophagy, but the detail still unclear. Our yeast-two-hybrid screening had found TSG101 can interact with Snapin, which can enhance the release of neurotransmitte. Recent reports indicate that Snapin plays an important part both in autophagy, endosomal maturation and vesicular transportation. However, the linkage between Snapin and late endosome is unknown. The interaction between TSG101 and Snapin therefore is a valuable issue to pursue. In the result of present study, GST-snapin pull down mixture showed the presence of TSG101. Our co-immunoprecipitation result also demonstrated the interaction between TSG101 and snapin. To investigate whether TSG101 colocalize with snapin, we have analyzed intracellular localization of these two proteins in HeLa, a cervical carcinoma cell, and in NSC-34, a motor neuron-like cell, through confocal microscopy. Our results indicated the colocalization of TSG101 and snapin in the vesicle-like structure within the cytosol both of HeLa and NSC-34 cell. Another confocal image showed that both TSG101 and snapin colocalized with a late endosome marker Rab7, but not with early endosome marker Rab5 in HeLa cell. In addition, TSG101 and snapin coloclized within soma as well as neurite in differentiated NSC-34(NSC-34D) cell. The time lapse fluorescent image acquisition of live NSC-34 and NSC-34D expressing cells futher confirmed the colocalization of TSG101 and Snapin. Our results also showed that the vesicle-like structure containing both proteins moves alone the neurite in NSC-34D. Taken together, there is an interaction between TSG101 and Snapin that may be involved in the endo-lysosomal pathway. Moreover, the neurophysiological significance of this interaction awaits further investigation.

標題
頁數
致謝 iii
摘要 iv
Abstract v
目錄 vii
縮寫表 ix
前言 1
一、TSG101相關背景 1
1、TSG101的發現與癌症的相關性 1
2、TSG101蛋白之結構及其功能 2
3、TSG101與內含體運輸 4
二、Snapin的發現、結構與功能 6
1、Snapin的發現與SNARE複合體 6
2、Snapin與內溶酶體系統 8
3、Snapin的其他功能 9
材料與方法 11
一、質體備製 11
二、融合蛋白之表現與純化 14
三、In vitro pull-down assay 17
四、細胞培養 18
五、真核細胞轉染 20
六、西方墨點法分析 22
七、免疫共沉澱分析 24
八、共軛焦顯微鏡影像分析 25
九、活體螢光顯微鏡縮時攝影觀察 27
十、小鼠myoblast分離與初級細胞培養 27
十一、Myotube及NSC-34細胞共同培養及電生理技術 29
結果 31
一、TSG101與Snapin間交互作用之確認 31
二、細胞中TSG101及Snapin之共位影像觀察 32
三、小鼠NSC-34D及肌肉母細胞共同培養模式之電生理測試 35
四、Snapin蛋白之同源二聚體的表現分析 36
討論 38
引用文獻 45
圖表 56
附錄 82

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