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研究生:鍾佳麗
研究生(外文):Chia-Li Chung
論文名稱:研究肝生長因子對於細胞-細胞黏著蛋白表現的影響
論文名稱(外文):Study the effect of hepatocyte growth factor on the expression of cell-cell adhesion proteins
指導教授:吳華林
指導教授(外文):Hua-Lin Wu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:76
中文關鍵詞:肝生長因子人類凝血酶調節素
外文關鍵詞:Hepatocyte growth factorthrombomodulin
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肝細胞生長因子 (hepatocyte growth factor/scatter factor;簡稱HGF/SF) 是一個多功能細胞激素 (cytokine) ,已知在人類內皮細胞中可以調節細胞黏著分子的表現。HGF也是一個強而有力可促使肝細胞生長的胜肽 (peptide) ,在不同的細胞裡可以促進細胞增生,移動,細胞型態改變以及血管新生的現象。最近的研究顯示,HGF造成E-cadherin減少進而使得細胞分離。另一項研究發現在人類乳癌細胞中,HGF會減少緊密連結 (tight junction) 之mRNA及蛋白質的表現,進而使得tight junction的功能遭受破壞。在過去我們所發表的研究結果中發現凝血酶調節素 (thrombomodulin;簡稱TM)會增強細胞之間的黏著進而造成細胞群集。在本研究中,我們發現HGF在牛動脈內皮細胞 (bovine aortic endothelial cells;簡稱BAECs) 會減少其TM的表現量,同時TM的表現量隨著HGF的濃度增加而顯著地下降。首先我們發現,加入 HGF 12小時後,牛動脈內皮細胞中的TM表現量會降低,這個現象不論在內皮細胞或上皮細胞皆可觀察到。當以HGF處理狗腎上皮細胞 (Madin-Darby canine kidney;簡稱MDCK) 、人類臍靜脈內皮細胞皆可引起TM的下降。進一步研究HGF降低TM細胞內含量的機制。
利用反轉錄酶—聚合連鎖反應偵測HGF處理後TM mRNA的變化,結果發現TM mRNA的表現量並不受影響表示HGF所引起之TM降解作用不是經由減少TM mRNA的合成。接著分別以各種蛋白質分解酶抑制劑 (protease inhibitor) ,吞噬作用抑制劑(cytochalasin D;簡稱 CD) ,蛋白酶體抑制劑 (MG132) 以及溶酶體抑制劑(ammonium chloride)處理BAEC觀察TM的變化,結果顯示上述之抑制劑皆可減緩HGF所引起之TM降解作用,表示TM的下降與內吞作用有關。另外,當我們以tyrosine kinase抑制劑 (k252a) 處理細胞後,TM的下降也可被抑制,表示HGF之接受體c-Met的活化也與TM的降解有關。
綜合以上的研究結果,我們認為HGF在細胞上引起之TM減少現象是經由三個可能的路徑,分別是:(1) 增加蛋白水解酶 (protease) 的活性,進而切除細胞膜上的TM。(2) 引發內吞作用,將細胞膜上的TM送至蛋白酶體 (proteasome) 和溶酶體 (lysosome) 進行裂解作用。 (3) 活化c-Met受體進而引發內吞作用及增加蛋白分解酶活性。
Hepatocyte growth factor/scatter factor (HGF/SF) is a multi-functional cytokine that has been shown to regulate the expression of cell adhesion molecules in human endothelial cells. HGF, a well-known peptide as a potent stimulator of hepatocyte growth, can promote proliferation, motility, morphogenesis, and angiogenesis in many types of cells including tumor cells. One recent study has shown that HGF downregulates functional E-cadherin, which prevents cell dissociation. Another report has suggested that HGF disrupts tight junction function in human breast cancer cells by affecting changes in the expression of tight junction molecules at both the mRNA and protein levels. In the previous studies, we reported that the lectin-like domain of thrombomodulin (TM) prompted the clustering of cells in close proximity with one another by enhancing cell-to-cell adhesion through a Ca2+ -dependent interaction of TM molecules. In this study, we found that HGF downregulated TM expression in bovine aortic endothelial cells (BAECs). The effect of HGF was both endothelial cells-specific and epithelial cells-specific since other cells types, such as MDCK cells and HUVEC cells, had the same effect. The protease inhibitors were used to inhibit this effect to determine the mechanism of TM downregulation by HGF. The result showed that the downregulation of TM by HGF was caused by matrix metalloproteinases (MMPs) and serine proteases. Pretreatment with the internalization, proteasome or lysosome inhibitors, and then the treatment with HGF did not decline the expression of TM in BAECs. Furthermore, the result of RT-PCR showed that the downregulation of TM expression was not due to the decrease on RNA expression.
Based on these results, we suggested that HGF induced downregulation of TM expression through the induction of protease activity and proteasome-lysosome degradation pathway but not by the downregulation of its transcription level. Taken together, our current hypotheses concerning the degradation process of the TM are as followings. After ligand stimulation, the induction of protease activity resulted in the shedding of TM. Another hypothesis is that the c-Met receptor and TM may form a complex which is degraded by the ubiquitin-proteasome proteolytic machinery or lysosomes.
中文摘要........................................... 1
英文摘要........................................... 3
誌謝............................................... 5
目錄............................................... 6
表、圖目錄......................................... 8
附錄目錄........................................... 9
縮寫檢索表......................................... 10
儀器............................................... 12
藥品............................................... 15
序論............................................... 20
一、肝細胞生長因子......................... 20
二、人類凝血酶調節素....................... 21
三、膜蛋白脫落途徑......................... 22
四、蛋白質的降解途徑....................... 25
五、研究動機............................... 26
實驗方法........................................... 27
一、細胞培養方法 27
二、蛋白質基本操作技術 29
A. 蛋白質收集 29
B. 蛋白質濃度測定 29
C. SDS-PAGE製備 31
D. SDS-PAGE電泳分析 33
E. 西方墨點法 (Western blot) 34
三、反轉錄酶-聚合酶連鎖反應 36
A. RNA萃取 (RNA extraction) 36
B. 反轉錄 38
C. 聚合酶連鎖反應 (PCR) 39
結果............................................... 42
討論............................................... 46
參考文獻........................................... 49
結果圖表........................................... 60
附錄............................................... 73
自述............................................... 76
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