細胞自噬作用的異常在癌症、神經及心血管退化性疾病的形成及抵抗外來病菌防禦作用上，扮演相當重要之角色。細胞自噬作用泛指將細胞質內容物吞噬，形成自噬泡，並送到溶酶體內降解的路徑，其主要功能在於分解胞質內未適當折疊或異常聚集的蛋白及清除老化破損之胞器，以維持胞內代謝衡定及生理功能之正常運作。細胞內噬作用路徑的ESCRT複合體在協助多囊泡體形成，在膜受體的循環利用，蛋白分選及囊泡傳輸作用扮演重要角色。腫瘤易感基因TSG101屬於ESCRT-I成員之一，負責調節多囊泡體形成及ESCRT功能，文獻指出缺乏TSG101的細胞內會有自噬泡累積的現象，顯示其可能參與自噬作用之調節。本論文研究中將細胞培養在無血清及養分困乏環境下，會使得TSG101及自噬作用標幟蛋白LC3-II及ATG3皆增加，顯示誘導細胞自噬作用也會提升細胞內TSG101含量。進一步以轉染siRNA或TSG101表現載體以抑制或過度表現TSG101蛋白來觀察其對轉染細胞之自噬作用相關標幟蛋白如LC3-I轉變成LC3-II、ATG3表現 及泛素修飾蛋白聚集物標幟p62蛋白表現之影響。結果顯示以siRNA抑制HeLa細胞中TSG101蛋白表現量會提升LC3-II、ATG3、p62或是被泛素修飾蛋白質的表現量，與前人之報導相符；但在神經母細胞瘤SH-SY5Y中抑制TSG101表現時，卻會降低LC3-II與被泛素修飾蛋白質的表現量，顯示在神經母細胞瘤SH-SY5Y中TSG101對細胞自噬途徑及泛素修飾蛋白之steady-state含量之調節可能扮演極關鍵之角色。當以表達外源性HA-TSG101方式提升胞內TSG101含量時，發現皆會有LC3-II增加之趨勢，而在HeLa子宮頸上皮細胞中更同時增加ATG3表現量。因此，我們推測TSG101可能會幫助穩定細胞自噬體的形成，但我們也不排除TSG101可能會參與調節自噬作用之最終步驟，亦即自噬體與溶酶體的融合作用，當增加細胞中的HA-TSG101時可能使自噬作用路徑的進行更順暢，因為細胞中的ATG3含量也扮隨著上升。此外，本研究中也建立了GFP-LC3穩定表現細胞株，並觀察到細胞質與核中皆有TSG101與GFP-LC3共位的現象，提供探討TSG101在細胞自噬路徑功能之另一研究探討契機。

Deregulation of autophagy plays an important role in the pathogenesis of diseases such as cancer, neuronal degenerative or cardiovascular disease. Autophagy is a process to engulf the cytoplasmic contents into autophagosome and deliver them for lysosomal degradation. Its major function is to clear unfolded protein or damage organelles for maintaining proper metabolic homeostasis and normal cell physiological activities. Autophagy and multivesicular bodies, MVBs, cooperate to regulate the turnover of intracellular macromolecule, defective organelles and signaling receptor. Endosomal sorting complex required for transport, ESCRT, is important for the formation of MVBs, which regulates membrane receptor recycling, protein sorting and vesicular trafficking. Tumor Susceptibility Gene 101(TSG101) is a member of ESCRT-I that plays an important role on MVBs formation and maintaining ESCRT function. Previous report indicated that autophagosome accumulation upon deprivation of TSG101, implying possible role of TSG101 during autophagic process. In this study, we observed the increase of TSG101 and autophagic marker proteins, such as LC3-II and ATG upon nutrient starvation. Furthermore, knockdown TSG101 in cervical carcinoma HeLa cell resulted in the elevation of LC3-II, ATG3 and ubiquitinated protein aggregates marker protein p62, which is congruous to other reports. However, in neuroblastoma SH-SY5Y cell, transfection of siRNA led to the decrease of LC-II and ubiquitinated protein level. These results indicated that TSG101 might be critical for autophagy and the maintenance of steady-state level of cellular ubiquitinated proteins. Ectopic upregulatory expression of HA-TSG101 led to the increase of LC3-II in both cell type. The elevation of ATG3 level is also observed in HeLa cell. Therefore, we speculated that TSG101 might be important for the formation of autophagosome, but our data did not exclude the possible role of TSG101 in regulation of the fusion of autophagosome and lysosome, because the increase of ATG3 indicated ectopic HA-TSG101 might facilitate the execution of autophagic flow. In addition, we have established GFP-LC3 expression cell lines. Our imaging data showed the colocalization of TSG101 and GFP-LC3 in both cytoplasm and nucleus that might be an interesting research topic for investigation the role of TSG101 in autophagic pathway.

致謝--------------------------------------------------------------2
中文摘要--------------------------------------------------------3
英文摘要--------------------------------------------------------5
前言--------------------------------------------------------------8
實驗目的--------------------------------------------------------20
材料與方法-----------------------------------------------------21
結果--------------------------------------------------------------34
討論--------------------------------------------------------------40
總結與展望-----------------------------------------------------49
參考文獻--------------------------------------------------------51
圖表--------------------------------------------------------------61
附錄--------------------------------------------------------------85

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