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研究生:楊皓安
研究生(外文):DianeYang
論文名稱:探討KLF10調控COX-1在血管內皮細胞之功能與特性
論文名稱(外文):Functional characterization of KLF10 signaling-modulated gene, COX-1, in endothelial cells
指導教授:王建平王建平引用關係
指導教授(外文):Jiann-Ping Wang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生命科學系碩博士班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:48
中文關鍵詞:血管新生內皮細胞環氧合酶-1
外文關鍵詞:KLF10COX-1Angiogenesis
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Krüppel-like family (KLF) 為一群含有鋅指 (zinc finger) 結構的轉錄因子,並藉與目標基因啟動子直接結合的機制調控其轉錄,進而恆定許多重要的生理功能如生長發育、細胞分化及血管生成等。KLF家族中的成員之一,KLF10,已知在 TGF-beta 的訊息傳遞路徑中扮演著重要的角色。近來研究指出 KLF10 在 TGF-beta 的刺激下調控骨髓中 pro-angiogenic cells (PAC) 的分化,分化後的 PAC再藉由體內循環到組織受傷處進行血管新生以修復傷口;另一方面 KLF10 的基因剔除小鼠在上肢缺血手術實驗 (hindlimb ischemia) 後無法藉由血管新生回復被截斷的血流。此外 KLF10 的基因剔除小鼠於 Matrigel plug assay 顯示明顯的血管新生缺陷。這些新發現皆顯示KLF10參與在血管生成的過程中,但 KLF10 所涉及的血管新生成路徑仍尚未明瞭。
試驗以染色體免疫沉澱晶片 (ChIP-chip) 分析可能受 KLF10 調控的下游基因,其中環氧合酶-1 [cyclooxygenase 1 (COX-1; prostaglandin - endoperoxide synthase 1; PTGS1)] 為 KLF10 為眾目標基因之一。本論文陸續以啟動子活性分析(promoter activity assay)、電泳遷移率實驗 (electrophoretic mobility shift assay ; EMSA) 及染色質免疫共沉澱與聚合酶鏈鎖反應 (ChIP-PCR) 等實驗,先行確認了KLF10/COX-1 兩者間的調控關係,結果顯示 KLF10 可藉由結合到 COX-1 基因啟動子之 Sp/KLF 結合序列,以活化 COX-1 起動子轉錄。COX-1 在一般細胞中已知可催化前列腺素的生成反應,在血管內皮細胞能促使其進行血管新生,而在血小板則催化花生四烯酸 (arachidonic acid, AA) 所引起的血小板凝集。由反轉錄聚合酶鏈鎖反應 (RT-PCR) 與西方墨點染色法 (Western blot) 結果證實 KLF10 調控血管內皮細胞 COX-1 mRNA及蛋白質的表現。此外,為了深入探討 KLF10 所造成的影響是否也會反映在 COX-1 的功能上,論文再利用人類血管內皮細胞以細管形成試驗 (tube formation assay) 來評估血管新生;由結果發現在大量表現 KLF10 的基因轉染血管內皮細胞較控制組更快速並形成更多的血管管狀結構,此結果可被 COX-1 選擇性抑制劑 valeryl salicylate (VSA) 所壓抑。論文最後分析,KLF10 基因剃除鼠血小板亦如推測其凝集能力較正常小鼠者來的差。綜合上述的結果,KLF10 可藉由調控 COX-1 的表現量來進一步促使血管新生成以及血小板凝集。



TGF-beta is a vital cytokine known to participate in vascular formation and angiogenesis processes by modulating its several downstream factors. One of the TGF-beta inducible gene, Krüppel-like factor 10 (KLF10), is a zinc-finger transcription factors which play key regulatory roles in cellular growth, development, differentiation etc. Recent study has shown that KLF10 is involved in the process of angiogenesis by acting as a key transcriptional regulator of TGF-beta1 in pro-angiogenic cells (PAC) differentiation and function. KLF10–/– mice also displayed impaired blood flow recovery after hindlimb ischemia. However, the mechanism of KLF10 induced angiogenesis is still not well understood. From our ChIP-chip result, which have been adopt to elucidate the novel target genes and signaling cascades of KLF10, cyclooxygenase 1 (COX-1; prostaglandin-endoperoxide synthase 1; PTGS1) was identified to be one of the target genes that may be regulated by KLF10 through direct promoter binding. In order to investigate the function of KLF10/COX-1 axis, promoter activity, EMSA, ChIP-PCR, tube formation assays and platelet aggregation assays were serially performed. Using luciferase reporter assays, KLF10 was found to activate COX-1 promoter activity when overexpressed KLF10 in both endothelial cells: bEnd-3 and HUVEC. In the same experiment, the expression levels of COX-1 mRNA and protein were up-regulated by KLF10 transfected. It is known that COX-1 is the key enzyme in prostaglandin biosynthesis which further regulated angiogenesis in endothelial cells. In tube formation assay, KLF10 overexpressed endothelial cells formed organized tube-like structure better than in contrast to the control group. This KLF10-induced tube formation could be repressed by COX-1 selected inhibitor- valeryl salicylate. Moreover, KLF10-deficient mice perform weaker arachidonic acid-induced platelet aggregation. In sum, these results indicate an important role for KLF10 in angiogenesis and platelet aggregation through the activation of COX-1.
誌謝 I
中文摘要 II
Abstract IV
Contents VI
Figure Contents IX
Chapter 1 1
Introduction 1
1.1 Angiogenesis 1
1.1.1 Process of angiogenesis 1
1.2 TGF-beta signaling 1
1.2.1 Role of TGF-beta in angiogenesis 2
1.2.2 TGF-beta is involved in atherosclerosis 3
1.3 Krüpple like factors 3
1.3.1 Regulators of KLF10 4
1.3.2 Functions of KLF10 4
1.3.3 KLF10 participates in angiogenesis process 5
1.3.4 KLF10 is involved in multiple diseases 6
1.4 Physiological function of COX-1 6
1.4.1 Regulators of COX-1 7
1.4.2 COX-1 is involved in many diseases 8
1.5 Aims 9
Chapter 2 10
Materials and Methods 10
2.1 Cell culture 10
2.2 Plasmid construction 10
2.3 Transient transfection 11
2.4 Preparation of nuclear extracts 12
2.5 EMSA (Electrophoretic Mobility Shift Assay) 12
2.6 ChIP-PCR assays (Chromosome Immunoprecipitation PCR assays) 13
2.7 Dual-luciferase assay 14
2.8 Protein extraction 14
2.9 Western blotting 15
2.10 Reverse transcription PCR 15
2.11 Tube formation assay 16
2.12 Platelets aggregation assay 16
Chapter 3 18
Results 18
3.1 KLF10 interacts with COX-1 promoter by binding to specific Sp/KLF sequence. 18
3.1.1 COX-1 promoter as a possible target of KLF10 18
3.1.2 KLF10 forms a protein-DNA complex in COX-1 promoter region 18
3.1.3 KLF10 binding to COX-1 proximal Sp/KLF binding sequence 19
3.2 COX-1 transcription could be activated by TGF-beta 19
3.2.1 Construction of COX-1 promoter to pGL3 Luciferase Reporter Vector 19
3.2.2 TGF-beta activates COX-1 transcription 19
3.3 COX-1 promoter activities were activated by KLF10 20
3.3.1 KLF10 could active COX-1 promoter but not site-mutant promoter construct 20
3.3.2 KLF10 phosphrylation sites are all vital for COX-1 transcriptinal activation. 20
3.4 KLF10 modulates COX-1 expression in endothelial cells 20
3.4.1 Important function of COX-1 in endotheilal cells 20
3.4.2 COX-1 promoter activities increase with KLF10 level 21
3.4.3 Proximal Sp/KLF binding site is critical for COX-1 transcription activation 21
3.4.4 KLF10 modulates COX-1 protein expression 21
3.5 KLF10 enhances tube formation through COX-1 activation 22
3.5.1 KLF10 modulates mRNA and protein expression of COX-1 in HUVEC 22
3.5.2 HUVEC forms tube-like structure when overexpressed KLF10 22
3.6 Less extent of platelet aggregation in KLF10 knockout mice 23
Chapter 4 24
Discussion 24
4.1 KLF10 regulates COX-1 through binding Sp/KLF binding site 24
4.2 KLF10 as an activator in transcription regulation 24
4.3 Competition binding of Sp/KLF family protein in DNA 25
4.4 TGF-beta and estrogen as regulator of COX-1 25
4.5 Angiogenic switch regulated by TGF-beta 26
4.6 KLF10 enhances angiogenesis by modulating COX-1 27
4.7 TGF-beta might enhance angiogenesis by modulate KLF10/COX-1 axis. 27
4.8 Loss of KLF10 reduces arachidonic acid-induced platelet aggregation 28
Chapter 5 30
Conclusion 30
References 31





Figure Contents

Figure 1. KLF10 directly bind to COX-1 promoter through a serial assays including ChIP-chip, EMSA and ChIP-PCR. 41
Figure 2. COX-1 transcription activities could be activated by TGF-beta. 42
Figure 3. KLF10 directly bind to COX-1 promoter and further regulate its transcriptional activity. 43
Figure 4. Transcriptional and translational level analysis of COX-1 in KLF10 transfected mouse endothelial cells, bEnd.3. 44
Figure 5. Transcriptional and translational level analysis of COX-1 in KLF10 transfected human endothelial cells, HUVECs. 45
Figure 6. Images analysis of tube formation assay in human endothelial cells. 46
Figure 7. Comparison and quantification the phenomena of tube formation assay in different treatments. 47
Figure 8. Comparison the platelet aggregation between wild type and KLF10 gene deficient mice. 48

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