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系統識別號 U0026-2207201310134500
論文名稱(中文) 探討凝血酶調節素透過蛋白質激酶A路徑調控血管新生及腫瘤生成的角色
論文名稱(英文) The regulatory roles of thrombomodulin in angiogenesis and tumorigenesis through protein kinase A pathway
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 101
學期 2
出版年 102
研究生(中文) 卓家楓
研究生(英文) Chia-Fong Cho
學號 S58951031
學位類別 博士
語文別 英文
論文頁數 124頁
口試委員 指導教授-施桂月
口試委員-吳華林
口試委員-江美治
口試委員-簡偉明
口試委員-林淑華
口試委員-葉宏一
中文關鍵字 凝血酶調節素  血管新生  kringle 1-5  蛋白質激酶A  接觸性抑制 
英文關鍵字 thrombomodulin  angiogenesis  kringle 1-5  protein kinase A  contact inhibition 
學科別分類
中文摘要 凝血酶調節素 (thrombomodulin)簡稱TM,為一醣蛋白的接受器,TM是身體中重要的抗凝血分子,其主要功能是藉著結合凝血酶,進而限制凝血酶的促凝血活性及生理活性。TM廣泛表現在各種細胞上,顯示出除凝血相關功能外TM扮演其他維持正常生理功能的角色。然而除了抗凝血功能之外,對於內皮細胞中的TM的功能目前還不清楚。另外,喪失TM的表現與腫瘤的進程和轉移有關,但是對於TM如何去調控腫瘤的生成目前還未有詳細的分子機制。因此本篇論文中的第一部分是欲探討內皮細胞上TM透過結合一內生性的血管新生的抑制劑 kringle 1-5 (K1-5)來調控血管新生。結果顯示K1-5能與內皮細胞上的TM結合且直接結合於TM的類凝集素功能區( lectin-like domain)的位置。當K1-5結合到內皮細胞上的TM後,會活化蛋白質激酶A (protein kinase A, PKA)促使TM在內皮細胞的降解而抑制內皮細胞爬行和血管生成的能力。同時我們在細胞中大量表現TM基因,結果顯示出TM的表現可以增加細胞的爬行且K1-5能透和TM的類凝集素功能區結合來活化PKA路徑而抑制細胞的爬行。第二部分則是探討上皮細胞中的TM透過接觸性抑制(contact inhibition)調控細胞生長。結果顯示TM會大量表現於接觸性抑制的過程中,而大量表現的TM則會透過降低PKA的活性以及促使PKA 同功酶轉換(PKA isozyme switching) 來抑制細胞生長。透過本篇兩部分的研究結果顯示出TM透過PKA路徑不但在血管新生中扮演調節的功能之外,也能透過此路徑來調控細胞生長。因此本篇的研究提供了TM在正常生理功能或是在疾病狀態下的新的調控機制。
英文摘要 Thrombomodulin (TM) is a transmembrane glycoprotein that plays a major role in the anticoagulation process in endothelial cells. However, TM is expressed broadly in many cell types, suggesting that its presence is important for the maintenance of normal physiological functions other than anticoagulation in mammals. Other than its anticoagulatory property, the biological functions of TM in endothelial cells are mostly unknown. Furthermore, it has been shown that loss of TM expression in tumor cells is associated with tumor progression and metastasis. However, the detailed mechanism of TM in regulating tumor growth is still unknown. In the first part of this study, the regulatory role of TM was investigated in angiogenesis through interaction with an endogenous proteolytic fragment of human plasminogen, kringle 1-5 (K1-5). I found that K1-5 colocalized with TM and directly interacted with TM through the TM lectin-like domain and induced TM internalization and degradation in a protein kinase A (PKA) dependent pathway. Consistent with these findings, TM overexpression resulted in increased cell migration; moreover, K1-5 inhibited the increase of TM-mediated cell migration in a PKA dependent manner. In the second part of this study, I investigated the expression of TM in contact inhibition, which constrains epithelial cells growth, and loss of cell-cell contact inhibition can lead to dysregulated growth and tumor formation. The results showed that TM expression increased as cells approached confluence, which inhibits cell growth through contact inhibition, and that TM expression lowered PKA activity and induced PKA isozyme switching, leading to a reduction in cell growth. In conclusion, the present study showed that the expression of TM was downregulated by binding with K1-5 through a PKA dependent manner to regulate the processes of angiogenesis. Furthermore, TM inhibited cell growth through contact inhibition through PKA pathway. These results provide new insights into the mechanisms of TM in angiogenesis and tumorigenesis through regulating the PKA signaling pathway.
論文目次 ABSTRACT IN CHINESE 1
ABSTRACT 3
ACKNOWLEDGEMENT 5
CONTENTS 7
FIGURE CONTENTS 9
LIST OF ABBREVIATIONS 11
CHAPTER 1 INTRODUCTION 14
1-1 Introduction of thrombomodulin 14
1-2 Introduction of angiogenesis 18
1-3 Introduction of protein kinase A 19
1-4 Objectives of the study 22
CHAPTER 2 Human plasminogen kringle 1–5 inhibits angiogenesis and induces thrombomodulin degradation in a protein kinase A-dependent manner 23
2-1 Abstract 23
2-2 Introduction 24
2-3 Materials and methods 26
2-4 Results 35
2-5 Discussion 42
CHAPTER 3 Thrombomodulin mediates contact inhibition to suppress cell growth through regulation of protein kinase A pathway 47
3-1 Abstract 47
3-2 Introduction 48
3-3 Materials and methods 51
3-4 Results 57
3-6 Discussion 64
CHAPTER 4 DISCUSSION 69
CHAPTER 5 CONCLUSION 73
REFERENCES 74
FIGURES 89
PUBLICATION 124

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