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系統識別號 U0026-0812200911033441
論文名稱(中文) 人類凝血酶調節素生理功能之探討
論文名稱(英文) Study On the Physiological Functions of Human Thrombomodulin
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 92
學期 1
出版年 93
研究生(中文) 黃蕙君
研究生(英文) huey-chun huang
學號 s5885102
學位類別 博士
語文別 中文
論文頁數 124頁
口試委員 指導教授-施桂月
口試委員-吳華林
召集委員-林淑華
口試委員-黃德富
口試委員-任卓穎
中文關鍵字 細胞訊息傳遞  細胞間附著  凝血酶  胞噬作用  凝血酶調節素 
英文關鍵字 cell-cell adhesion  signal transduction pathway  internalization  thrombomodulin  thrombin 
學科別分類
中文摘要 凝血酶調節素廣泛分佈於體內不同組織細胞的表面,它是身體中重要的抗凝血分子,主要是藉著結合凝血酶而限制凝血酶的促凝血活性及生理活性,另外凝血酶-凝血酶調節素複合物可以活化protein C成activated protein C (APC),APC 轉而分解活化型凝血因子五和凝血因子八,進一步抑制凝固路徑的進行及凝血酶的產生。科學家們利用包括生化分析及基因改造老鼠等方法探討凝血酶調節素的生理功能,發現凝血酶調節素也扮演抑制血塊溶解,抗發炎反應,抑制腫瘤細胞增生,維持正常的懷孕過程及胚胎發育等重要角色。臨床的研究結果則顯示凝血酶調節素基因的變異與血栓疾病之好發率有關,在腫瘤疾病方面,凝血酶調節素的表現量隨著腫瘤的惡化呈現下降趨勢,顯示凝血酶調節素參與調控多種的生理功能。

我們推論凝血酶調節素結合凝血酶一方面會改變凝血酶構型,一方面可以將凝血酶吞噬入細胞內,而調控凝血酶活性。本論文在人類胚胎腎臟細胞HEK293上表現融接綠色螢光蛋白的凝血酶調節素,以共軛焦顯微鏡觀察當給予凝血酶的刺激後,凝血酶調節素蛋白的移動方式,我們發現凝血酶會誘導凝血酶調節素以caveolae 胞器包裹的方式被吞噬,進入細胞內的凝血酶調節素會再回復到細胞表面,凝血酶被吞噬後則留在細胞質中,若是截去凝血酶調節素N端lectin-like domain ,則凝血酶-凝血酶調節素複合物無法自細胞膜上被吞噬。相同的細胞進行凝血酶激活細胞訊息因子ERK的變化分析,發現凝血酶活化pERK 只出現在第15至30分鐘時,一旦細胞表現正常的,或截短lectin-like domain 型凝血酶調節素,pERK 活化都會延長超過2個小時。藥物cytochalasin D可以抑制凝血酶-凝血酶調節素複合物的被吞噬,卻不會對凝血酶調節素調控凝血酶活化訊息傳遞的能力造成影響。由實驗結果可知,凝血酶調節素會藉著細胞吞噬及recycle 方式吞噬凝血酶以調控細胞外凝血酶的活性,且此吞噬作用需要凝血酶調節素的lectin-like domain 參與,不過此種胞噬作用與凝血酶調節素延長凝血酶活化ERK的能力無關。
本論文第二部分的研究是探討凝血酶調節素作為細胞間附著因子的能力及機制,本論文選用一株不會表現E-cadherin 的人類黑色素細胞株 A2058 作為研究的細胞模式。實驗發現表現凝血酶調節素的A2058細胞會聚集生長,型態也轉變成似上皮細胞(epithelial-like),相較之下,缺乏lectin-like domain 的凝血酶調節素則沒有誘發細胞聚集生長的能力,由共軛焦顯微鏡也觀察到凝血酶調節素集中分佈在細胞間鄰接處,且這種緊密相鄰使得蛋白質分子通透細胞間隙的能力下降,此外,加入拮抗lectin-like domain 功能的抗體,或是耗盡細胞培養液中的鈣離子,都會破壞凝血酶調節素媒介的A2058 細胞間附著。這些現象另一株表現內生性凝血酶調節素的人類皮膚細胞株HaCaT 中也得到證實,顯示凝血酶調節素以鈣離子依賴型式維繫細胞間的附著。進一步分析凝血酶調節素的lectin-like domain 及cytoplasmic domain發現,lectin-like domain可結合例如mannose 的醣類分子,cytoplasmic domain 可能連結細胞骨架,如此可以輔助凝血酶調節素架構成更穩定的細胞間吸附作用,此外凝血酶調節素促使細胞間吸附作用,進而抑制此種腫瘤細胞在老鼠體內形成腫瘤的能力。
綜而言之,本研究證實凝血酶調節素結合凝血酶後會藉著吞噬作用使凝血酶進入細胞內,以調控細胞外凝血酶的濃度,而凝血酶調節素則再回到細胞表面執行其功能;凝血酶調節素也會修飾凝血酶活化細胞內的訊息路徑,詳細的機轉仍需進一步研究,但延長ERK的活化與凝血酶調節素吞噬凝血酶作用無關;此外本論文也還證實凝血酶調節素具有作為細胞間吸附分子的特性,它可以加強細胞間的聚集,進而抑制腫瘤細胞的不當生長。


英文摘要 for thrombin's activity in a physiologically important natural anticoagulant system. Formation of the thrombin–TM complex limits thrombin's procoagulant and cellular-activating functions and results in thrombin-mediated catalytic transformation of protein C (PC) into activated PC (APC), which in turn down-regulates thrombin generation by degrading coagulation factors Va and VIIIa. Biochemical and structural investigations, combined with in vivo analyses of genetically engineered mice have revealed new, and in part PC- and thrombin-independent aspects of TM function in fibrinolysis, inflammation, proliferation, and embryogenesis. Sporadic mutations in the TM gene occur in patients with thromboembolic disease. Clinical studies also revealed an inverse correlation between TM expression and tumor progression. These findings have highlighted a much more extended possible involvement of TM in the physiological condition.
Internalization of thrombin and the TM complex from the cell surface may regulate thrombin activity. Trafficking of the thrombin-TM complex was visualized by green fluorescent protein-tagged TM in human embryonic kidney (HEK293) cells. TM was internalized after thrombin treatment and was localized in discrete punctate vesicles; rhodamine-labeled thrombin was found in peri-nuclear regions. TM internalization occurred via caveolae-mediated pathways. After 60 minutes, TM returned to the cell surface, whereas thrombin remained in the cytosol. TM recycling was also demonstrated by monitoring TM antigen on the cell surface. Cytochalasin D blocked internalization; monensin inhibited TM recycling. No internalization of the lectin-like domain truncated TM [TMG(DL)] was observed in the cells after thrombin treatment. Thrombin induced a prolonged phosphorylation of extracellular signal-regulated kinase (ERK) in the TMG- or TMG(DL)-expressed cells whereas transiently activation in empty vector-transfected 293 cells. Moreover, disruption of internalization with cytochalasin D did not affect the sustained phosphorylation of ERK-1/2. It is concluded that TM could regulate thrombin activity by a cyclic trafficking mechanism; the lectin-like domain is essential for this process. However, the prolongation of thrombin-induced activation is independent on TM internalization.
Many recent studies have indicated that TM may possess functions distinct from its anticoagulant activity. In this study, the function of TM was studied in TM-negative melanoma A2058 cells transfected with TMG or TMG(DL). Confocal microscopy demonstrated that both TMG and TMG(DL) were distributed in the plasma membrane. TMG-expressed cells grew in culture as close clustered colonies, with TM localized prominently in the intercellular boundaries, while TMG(DL) expressed single cells dispersed in culture. Overexpression of TMG, but not TMG(DL), decreased monolayer permeability in vitro, and tumor growth in vivo. The cell-to-cell adhesion in TMG-expressed cells was Ca2+-dependent and was inhibited by monoclonal antibody against the lectin-like domain of TM. The effects of TM-mediated cellular adhesion were abolished by addition of mannose, chondroitin sulfate A, or chondroitin sulfate C. In addition, anti-lectin-like domain antibody disrupted the close clustering of HaCaT cells, the endogenous TM-expressed keratinocyte cell line derived from normal human epidermis. As demonstrated by double-labeling immunofluorescence staining, the TM and actin filament had similar distributions in the cortex region of the TMG-expressed cells. This thesis provides the evidence to show that TM can function as a Ca2+-dependent cell-to-cell adhesion molecule and binding of specific sugar to the lectin-like domain is essential for this specific function.
In summary, this thesis demonstratse that TM acts as a regulator of thrombin signaling events, but the modulation effect is independent of thrombin-induced internalization of TM receptor. Remarkably, all the findings have revealed novel roles of TM in the regulation of cellular adhesion, and have highlighted a possible extended involvement of TM in the regulation of tumor growth. The study of TM continues to generate many new and exciting hypotheses to be tested in the future.


論文目次 目 錄
中文摘要………………………………………………………………..1
英文摘要………………………………………………………………..4
緒論……………………………………………………………………..7
研究動機與實驗設計………………………………………………….20
實驗材料與儀器
A. 細菌及細胞株……….………………………………………...24
B. 實驗動物…………………………………………….………...24
C. 試劑藥品……..………………………………………………..24
D. 抗體……….…………………………………………...………27
E. 耗材…………………………………………………………....29
F. 儀器…...………………………………………………….…....30
實驗方法
A. 人類凝血酶調節素基因的選殖及構築……………...………....32
B. 細胞培養及基因殖入(transfection)…………………………..…34
C. 測試穩定表現細胞株的凝血酶調節素活性及蛋白表現……...36
D. 雷射共軛焦顯微鏡…………………………………………..….38
E. 細胞功能測定………………………………………………..….39
F. 免疫螢光染色法……………………………………………..…..41
G. 流式細胞分析儀 (Flow Cytometer) 測定細胞表面凝血酶調節素抗原之表現………………………………………………….…..42
H. 蛋白質磷酸化作用…………………………………………...42
I. 老鼠模式分析腫瘤的生長……………………………………43
結果
一、建立研究凝血酶調節素功能的細胞模式…………………….44
二、凝血酶調節素進行胞噬作用(internalization)並會再回到細胞膜上(recycle)……………………………………………………...47
三、凝血酶調節素之lectin-like domain 具有促進 cell-cell adhesion 的功能...………………………………………………………..53
討論
一、凝血酶誘導凝血酶調節素 internalization 之研究…………...60
二. 凝血酶調節素具有cell-cell adhesion 功能的研究…..……….68
未來展望………………………………………………………………..77
參考文獻………………………………………………………………..81
圖表
Fig. 1. Schematic diagram illustrating TMG and TMG(DL) construction………………………………………………….….96
Fig. 2. Characterization of TM proteins by mouse anti-human TM antiserum………………………………………………………..97
Fig. 3. TM activity assay of A2058 cells stably expressing TMG and TMG(DL)……………………………………………………....98
Fig. 4. Confocal microscopy examination of the subcellular distribution of TM proteins and the cell morphology………….99
Fig. 5. Thrombin induced internalization of TM…………………...100
Fig. 6. Internalization and recycling of TM………………………..101
Fig. 7. Flow cytometry analysis of the surface TM during thrombin treatment……………………………………………………...102
Fig.8. Effects of cytochalasin D on the thrombin-induced internalization and the surface expression of TM…………….103
Fig. 9. Effects of monensin on the surface expression of TM……..104
Fig. 10. Localization of TMG(DL) molecule…………...………….105
Fig. 11. Co-localization of TMG with the caveolae in HEK293 cells after stimulation by thrombin…………………………...…….106
Fig. 12. Confocal analysis of subcellular distribution of TM proteins in HEK293 cells……………………………….………………107
Fig. 13. Kinetics of phosphorylation of ERKs after thrombin-induced stimulation…………………………………………………….108
Fig. 14. Phosphorylation of ERKs after thrombin-induced stimulation of HEK293 cells in the presence of cytochalasin D…………..109
Fig. 15. Effects of anti-TM antibodies on the organization of cell-cell adhesion junctions in TMG-expressed A2058 cells……….….110
Fig. 16. Overexpression of TMG decreases the A2058 cell monolayer permeability………………………………………….….….…111
Fig. 17. Localization of TM protein and effects of anti-TM antibodies on the cell-cell adhesion of HaCaT cells……………………...112
Fig. 18. TM participates in Ca2+-dependent cell-cell adhesion…….113
Fig. 19. In vivo tumor growth assay of TM-expressed A2058 melanoma cells………………………………………………..114
Fig. 20. Colocalization of TM and the actin in TMG-expressed cells……………………………………………………………115
Fig. 21. Effect of different carbohydrates on the cell adhesion of TMG cells……………………………………………………………116
Fig. 22. Effect of different carbohydrates on the cell adhesion of HaCaT cells….………………………………………………...117
附錄
附錄一:凝血酶調節素基因及相對胺基酸的序列.........................118
附錄二: Restriction Map and Multiple Cloning Site (MCS) of pEGFP-N1 vector………………………………………120
論文發表………………………………………………………………121

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