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研究生：	黃雅慧 Huang, Ya-Hui
論文名稱：	Protein tyrosine phosphatases(s)在調控血管新生上所扮演的角色 Characterization of protein tyrosine phosphatases(s) involved in the regulation of angiogenesis
指導教授：	吳梨華 Wu, Li-Wha
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2003
畢業學年度：	91
語文別：	英文
論文頁數：	54
中文關鍵詞：	血管新生、PTP-PEST 、內皮細胞
外文關鍵詞：	endothelial cells, angiogenesis, PTP-PEST, protein tyrosine phosphatase
相關次數：	點閱：135 下載：6
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在調控許多細胞內基本的訊息傳遞中，tyrosine phosphorylation扮演著一個相當重要的角色，包括調控細胞的移動，增生，分化，代謝，細胞週期，細胞與細胞的溝通，基因的轉錄，離子通道，免疫反應及細胞的存活等方面。此外，在內皮細胞的調控中，tyrosine phosphorylation也扮演著舉足輕重的角色。目前已知，血管的建立及重建是以旁分泌(paracrine)的方式調控。而在其中的許多訊息傳遞因子皆是透過結合到固定的protein tyrosine kinase接受器上，而將訊息往下傳。在in vivo中，tyrosine phosphorylation為一種可逆且為動態的過程，而protein phosphorylation的情況是由protein tyrosine kinases (PTKs)和protein tyrosine phosphatases (PTPs)共同調節。就如同已經被研究的相當清楚的PTKs，PTPs也是由一個由相當多成員所組成的酵素家族。目前對於某些內皮細胞專一PTKs的角色和機轉的探討已經有相當不錯的了解，但是對於內皮細胞專一的PTPs則仍了解不深。利用degenerate primers尋找內皮細胞表現的PTPs的過程中，共找到9個在人類臍帶靜脈內皮細胞中表現的PTPs。PTP-PEST，一個已知和細胞移動及細胞附著的訊息傳遞路徑相關的PTP，能在內皮細胞中表現。因為血管新生的一個重要指標就是細胞的移動，因此我們推論PTP-PEST可能在血管新生中扮演一個角色。利用電穿孔法(electroporation)，我們能成功的在內皮細胞中將PTP-PEST過度表現(overexpression)及基因減弱(利用載體為基礎的RNAi干擾技術)。而在血管新生相關的功能性分析方面，首先在管狀形成實驗中，當PTP-PEST被大量表現或是基因減弱時，都會損害內皮細胞所形成的管狀結構和減低管狀密度。然而在同樣的實驗狀況下，內皮細胞的移動速度卻反之增加，但是細胞增生速度卻不受影響。雖然仍需要更多的實驗來解答細胞移動和管狀形成結構有著相對的結果，但是PTP-PEST似乎在內皮細胞中對細胞的移動和管狀形成的調控上扮演著重要角色。

Tyrosine phosphorylation is a critical event in signal transduction pathway that regulates fundamental cellular processes including cellular growth, cell migration, differentiation, metabolism, cell cycle, cell-cell communications, gene transcription, ion channels, the immune response, and survival. It is also critical for many endothelial cell processes. The establishment and remodeling of blood vessels is controlled by paracrine signals, many of which are protein ligands that bind to distinct receptor protein tyrosine kinases. In vivo, tyrosine phosphorylation is a reversible and dynamic process; protein phosphorylation states are governed by the opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Like the well-characterized PTKs, PTPs constitute a large and diverse family of enzyme. Although the role and mechanisms of certain endothelium-specific PTKs have been delineated, less is known about their PTPs counterparts. In the search for endothelial-expressed PTPs using degenerate primers, 9 PTPs were expressed in HUVECs. PTP-PEST, implicated in mitogenic signaling and cell-adhesion induced signaling, was expressed in endothelial cells. Because cell migration is also an important indicator of angiogenesis, we thus proposed that PTP-PEST might be a candidate PTP involved in the regulation of angiogenesis. Using electroporation, PTP-PEST was successfully overexpressed or knockdowned with RNAi in HUVECs. Through several angiogenic-associated functional assays, we found that the integrity and the layer number of tube structure were impaired, and tube density was decreased when PTP-PEST was disregulated either by overexpression or RNAi knockdown techniques. However, the endothelial migration rate was increased but proliferation rate was not influenced. Although more studies are needed to confirm the contradictory result from migration and tube formation assays, a tight control of PTP-PEST appears to play an important role for cell migration and tube formation in endothelial cells.

Table of Contents

List of Tables and Figures………………………………………….   I
Abstract in Chinese…………………………………………………  III
Abstract in English………………………………………………….  V

1.	Introduction
1.1  Tumor growth and neovasculature………………………………  1
1.2  Protein tyrosine phosphorylation………………………………..  2
1.3  Protein tyrosine phosphorylation and angiogenesis……………..  3
1.4  Protein tyrosine phosphatases and PTP-PEST…………………..  4
1.5  Characteristics of PTP-PEST……………………………………  5
1.6  The phenotypes of cells with overexpression or knockout of PTP-PEST………………………………………………………  6
1.7	RNA interference with knockdown the gene expression……….  7
1.8	The role of PTP-PEST in the regulation of angiogenesis………  7

2.	Materials and methods
2.1	  Reagents………………………………………………………..   9
2.2	  Constructs………………………………………………………  10
2.3	Human umbilical vein endothelial cells (HUVECs) isolation and maintenance……………………………………………………  11
2.4	  Cell cultures…………………………………………………….  11
2.5	  Total RNA & poly(A) RNA isolation…………………………..  12
2.6	Reverse Transcription (RT)-Polymerase Chain Reaction (PCR) for the Isolation of Partial PTPs cDNA from human umbilical vein endothelial cells……………………………………………….  12
2.7	  Transient transfection…………….…………………………….  13
2.8	  Protein lysate preparation………………………………………  14
2.9	  Immunoprecipitation and Western blot analysis……………….  15
2.10	Luciferase assay……………………………………………….  15
2.11  Matrigel tube formation assays……………………………….  16
2.12  Migration assay……………………………………………….  16
2.13  HUVECs proliferation assay (doubling time experiment)……  17
2.14  Statistical analysis……………………………………………..  17

3.  Results
3.1  VEGF and protein tyrosine phosphorylation………………….  18
3.2  Identification of PTPs expressed in human umbilical vein endothelial cells (HUVECs) …………………………………  18
3.3  PTP-PEST……………………………………………………..  19
3.4  Northern blot analysis of PTP-PEST in the presence of growth factor and/or angiogenic inhibitor……………………………  20
3.5  Overexpression of PTP-PEST in HUVECs with electroporation
…………………………………………………………………  20
3.6  Vector-based RNAi knocked down the exogenous expression of PTP-PEST gene………………………………………………  21
3.7 Vector-based RNAi specifically knocked down endogenous PTP-PEST in HUVEC……………………………………….  22
3.8  Overexpression and knockdown of PTP-PEST impaired the tube structure integrity and decreased tube density……………….  22
3.9  Overexpression and knockdown of PTP-PEST would increase the migration rate of HUVECs…………………………………….  23
3.10  The proliferation activity of HUVECs was not changed under the overexpression or knockdown of PTP-PEST………………….  23

4.  Discussion
4.1  Searching for novel or endothelial-cell expressed PTPs……..   24
4.2  The correlation of PTP-PEST with angiogenesis …………….   25
4.3  The regulation of angiogenesis with PTP-PEST……………...   26
4.4  The regulation of PTP-PEST with fibronectin………………..   28

5.  References
………………………………………………………………………   30
List of Table and Figures


Table 1. The 9 PTPs identified using RT-PCR with degenerate primers specific for the conserved domain in the catalytic region…… 40
Figure 1. Dosage effect of VEGF on tyrosine phosphorylation status of cellular proteins……………………………………………… 41
Figure 2. Time-dependent phosphorylation status of several candidate proteins in the presence of 10ng/ml VEGF………………….. 42
Figure 3. The flow chart of PCR with degenerate primers and the gel picture of some selected clones……………………………… 43
Figure 4. The gene expression profile about the correlation of the PTPs with cancers………………………………………………….. 44 
Figure 5. The mRNA expression level of PTP-PEST was not changed in the treatment of bFGF and/or TNP-470……………………... 45
Figure 6. The transfection efficiency of HUVECs using electroporation and GFP as a reporter gene………………………………….. 46
Figure 7. The luciferase activity of HUVECs was increased after transfected pCMV-luc+-PEST construct into 293 cells………47
Figure 8. The luciferase activity was knockdowned to a distinct level by co-transfection of siPEST-1 or siPEST-2 and a construct containing PTP-PEST and luciferase fusion gene (pCMV-luc+-PEST)…………………………………………...48
Figure 9. The siRNA knockdown efficiency for targeting PTP-PEST in protein levels………………………………………………. 49
Figure 10. The mRNA expression level of PTP-PEST in HUVECs was knockdowned by siPEST-2…………………………………...50
Figure 11a. The tube structure and integrity were impaired in knockdown and overexpression system after 6-h seeding in Matrigel.…... 51
Figure 11b. The tube density in knockdown and overexpression of PTP-PEST were both decreased.…………………………….. 52
Figure 12. The migratory ability of overexpression and knockdown system were both increased………………………………….. 53
Figure 13.  The proliferation rates of PTP-PEST overexpressed HUVECs had no difference compared with mock-transfected HUVECs, neither did the siPEST-1 or siPEST-2 knockdown HUVECs…………………………………………………….. 54
                                    

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