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系統識別號 U0026-2001201216181500
論文名稱(中文) Tie2-R849W在血管細胞中的生物功能
論文名稱(英文) The biological functions of Tie2-R849W in vascular cells
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 100
學期 1
出版年 101
研究生(中文) 黃議賢
研究生(英文) Yi-Hsien Huang
學號 s5893141
學位類別 博士
語文別 英文
論文頁數 99頁
口試委員 指導教授-吳梨華
召集委員-江美治
口試委員-林以行
口試委員-裘正健
口試委員-徐麗芬
中文關鍵字 血管形成不良  血管內皮生長因子  鹼性纖維細胞生長因子  內皮細胞  平滑肌肉細胞 
英文關鍵字 venous malformations  vascular endothelial growth factor  basic fibroblast growth factor  endothelial cell  smooth muscle cell 
學科別分類
中文摘要 Tie2主要表現在內皮細胞,主要為維持血管的形成與成熟。家族性的靜脈血管形成不良(VMs)主要是由於Tie2的激酶活化區域的氨基酸序列發生點突變,使得精氨酸變成為色胺酸(Tie2-R849W)。雖然STAT1蛋白只受到Tie2-R849W而非Tie2-WT所活化,但是對於其活化在血管新生中所扮演的功能仍然未知。在本次研究中,我們比較在血管內皮細胞(HUVECs)中,Tie2-WT,Tie2-K855A (kinase dead),Tie2-R849W這三種不同基因型的Tie2對於細胞以及訊息傳遞的影響。當細胞大量表現這三種不同基因型的Tie2,我們發現大量表現Tie2會降低細胞的增生,此外相較於Tie2-K855A以及其原生型,持續性活化的Tie2-R849W對於血清所引起的細胞凋亡有最佳的抵抗性,但是對於內皮細胞在Matrigel形成管腔的能力則是最低的,這暗示著Tie2-R849W具有抗血管新生的能力。我們同時也發現,Tie2-R849W會透過活化STAT1蛋白質的磷酸化並調控IRF-1啟動子的活性。雖然STAT1的磷酸化需要JNK以及p38MAPK的活化,但是只有JNK的活化才是Tie2-R849W調控IRF-1啟動子活性所必需的。接著為了避免內生性Tie2的原生型干擾,我們利用缺乏內生性Tie2的內皮細胞大量表現抗shRNA降低表現的Tie2-R849W*以及Tie2-WT*,評估Tie2-R849W對於內皮細胞的增生,移動,及管腔形成能力以及平滑肌肉細胞移動等與血管生成與成熟的能力。我們發現Tie2-R849W透過誘發STAT1(Y701)的磷酸化,降低內皮細胞移動以及血管形成的能力,並且降低VEGF-A所引起的STAT3(Y705)的磷酸化。而活化的STAT1可透過直接降低STAT3蛋白質結合至bFGF的啟動子區域(-997到-989),拮抗VEGF-A所誘發的bFGF基因的表現;反之,當STAT1的表現受到抑制時,可以降低Tie2-R849W抑制血管新生的能力。此外,使用bFGF中和性抗體或是持續的STAT1活化都具有類Tie2-R849W的效果,會抑制條件培養基吸引血管平滑肌肉細胞的能力。綜合以上結果,Tie2-R849W藉由誘發STAT1的活化來破壞VEGF-A透過STAT3所傳遞的的訊息路徑。由此可知,在STAT1與STAT3之間活性的平衡是Tie2所傳遞的血管新生必需要的訊息傳遞。
英文摘要 Tie2 is predominantly expressed in endothelial cells and required for blood vessel formation and maintenance. A missense mutation from arginine to tryphtophan in the kinase domain of Tie2 (Tie2-R849W) is associated with a familial type of venous malformations (VMs). Although STAT1 is distinctly induced by Tie2-R849W but not its wild-type counterpart (Tie2-WT), the exact function of this activating mutation in angiogenesis remains elusive. In this study, we compared the cell behaviors and signaling pathways mediated by wild-type Tie2-WT, kinase-dead Tie2-K855A, and constitutively active Tie2-R849W in human umbilical vein endothelial cells (HUVECs). When cells overexpressing Tie2-R849W, K855A and Tie2-WT, we found that ectopic Tie2 reduced cells proliferation and serum withdrawal induced apoptosis. When comparing R849W with K855A and its wild-type, constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures on Matrigel, indicating an anti-angiogenic role of Tie2-R849W. We also found that Tie2-R849W induced STAT1 tyrosine phosphorylation and upregulated the promoter activity of INF-regulatory factor 1 (IRF 1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Next, we compared the angiogenic modulatory effect of Tie2-R849W with Tie2-WT, and delineated the responsible mechanism. HUVECs lack of endogenous Tie2 were used for studying the effects of ectopic shRNA-resistant Tie2 variant expression, WT* and R849W*, on angiogenesis by using cell proliferation, migration and tube formation assays. Tie2-R849W* but not Tie2-WT* decreased endothelial cells migration and tube formation via induced STAT1 tyrosine (Y701) phosphorylation and impaired the ability of VEGF-A to induce activating STAT3 phosphorylation at Y705. The induced STAT1 activation antagonized VEGF-A induction on bFGF mRNA expression by decreasing a direct binding of STAT3 protein to a consensus STAT-binding site in the proximal bFGF promoter region at positions -997 to -989 bp from transcription start site. Knocking down STAT1 expression reduced the inhibitory effect of Tie2-R849W on angiogenesis. Moreover, bFGF neutralization or constitutive STAT1 activation, reminiscence of Tie2-R849W expression, suppressed the ability of conditioned medium (CM) to recruit vascular supporting smooth muscle cells. Taken together, Tie2-R849W impaired VEGF-A-mediated STAT3 signaling by inducing a functional activation of STAT1. A balancing activity of STAT1 and STAT3 is essential for Tie2-mediated angiogenic cascades.
論文目次 中文摘要 i
ABSTRACT iii
誌謝 v
TABLE of CONTENT vii
TABLES, FIGURES AND APPENDIX CONTENTS xi
ABBREVIATIONS xvi
CHAPTER 1 INTRODUCTION 1
1-1 Vascular development 1
1-2 Vasculogenesis and angiogenesis 1
1-3 VEGF-A 2
1-4 Fibroblast growth factors (FGFs) 3
1-5 Angiopoietins (Angs) 4
1-6 Tie receptors 5
1-7 Venous malformations (VMs) 6
1-8 STAT and angiogenesis 6
1-9 Specific aims 8
CHAPTER 2 MATERIALAS AND METHODS 9
2-1 Materials 9
2-2 Cell culture 11
2-3 Venous smooth muscle cells isolation 11
2-4 Construction of adenoviral vectors expressing Tie2 or STAT1C. 11
2-5 Construction of Tie2 shRNA lentivirus 12
2-6 Lentivirus infection 13
2-7 Adenovirus infection 13
2-8 Migration assay 13
2-9 Cell proliferation assay 14
2-10 Tube formation assay 14
2-11 Measurement of surface Tie2 by flow cytometry 14
2-12 Apoptosis assay 15
2-13 Nuclear and cytosol fractionation 15
2-14 Immunofluorescence microscopy 16
2-15 Western blotting and immunoprecipitation 16
2-16 Chromatin immunoprecipitation (ChIP) assay 16
2-17 Cytokine array in conditioned media (CM) 17
2-18 bFGF promoter constructs 18
2-19 bFGF ELISA assay 18
2-20 Transient transfection and luciferase-reporter assay 18
2-21 Semi-quantitative RT-PCR 19
2-22 Statistical analysis 19
CHAPTER 3 RESULTS 21
3-1 Tie2-R849W induces activating STAT1 phosphorylation at tyrosine 701 21
3-1-1 Ectopic expression of Tie2-WT and Tie2-R849W differentially induces Tie2 autophosphorylation 21
3-1-2 The effects of Tie2 variants in HUVEC 21
3-1-3 Tie2-R849W induces STAT1 phosphorylation through direct association 22
3-2 Tie2-R849W activates STAT1 and modulates gene expression 23
3-2-1 Subcellular localization and transcriptional regulation of phosphotyrosyl STAT1 induced by Tie2-R849W 23
3-2-2 The signaling pathways involve in Tie2-R849W-mediated STAT1 activation and IRF promoter activity. 24
3-3 STAT1activation induced by Tie2-R849W acts as a negative regulator in angiogenesis 25
3-3-1 Functional restoration of Tie2* expression in KD Tie2-null HUVECs 25
3-3-2 Tie2-R849W* decreases migration and tube formation in HUVECs 26
3-3-3 Constitutively active STAT1 decreases migration and tube formation in HUVECs 26
3-3-4 Tie2-R849W* decreases SMCs migration 27
3-4 Decreasing VEGF-A mediated STAT3 tyrosine phosphorylation in Tie2-R849W expressing HUVEC partly is via activating STAT1 phosphorylation 28
3-4-1 Tie2-849W* attenuates VEGF-A induced STAT3 phosphorylation 28
3-4-2 Constitutive STAT1 decreases VEGF-A mediated STAT3 phosphorylation 28
3-5 Tie2-R849W decreases VEGF-A induced bFGF expression via STAT1 induction and reduction of STAT3 binding to the promoter 29
3-5-1 Tie2-R849W* reduces STAT3 nuclear translocation induced by VEGF-A 29
3-5-2 Constitutive STAT1 activation decreases bFGF expression 29
3-5-3 Tie2-R849W* inhibits a direct binding of STAT3 to the bFGF promoter induced by VEGF-A 30
3-6 Tie2-R849W decreases the SMCs recruitment by down-regulating bFGF expression 31
3-7 Absence of STAT1 activation suppresses the inhibitory effect of Tie2-R849W mutant on endothelial cells 32
CHAPTER 4 DISCUSSION 34
4-1 Differential effect of Tie2-R849W and its wildtype on EC proliferation, migration, tube formation and survival 34
4-2 Differential recruitment of STAT protein by Tie2-R849W and its wildtype counterpart 34
4-3 Differential effect of Tie2-R849W and its wildtype counterpart on vascular SMCs 35
4-4 The signaling pathway involved in STAT1 activation by Tie2-R849W 35
4-5 Context-dependent STAT1 activation mediated by Tie2-R849W in endothelial cells 36
4-6 Tie2-R849W influences VEGF-A mediated gene expression through STAT1 activation 36
4-7 The possible mechanism involves in Tie2-R849W induced VMs 38
CHAPTER 5 CONCLUSION 40
REFERENCES 41
CURRICULUM VITAE 98

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