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研究生:張淑如
研究生(外文):Shu-Ju Chang
論文名稱:ATP在人類子宮內膜基質細胞中所扮演角色之探討
論文名稱(外文):The Role of Adenosine Triphosphate in Human Endometrial Stromal Cells
指導教授:李怡萱李怡萱引用關係
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:131
中文關鍵詞:腺嘌呤核甘三磷酸嘌呤受體人類子宮內膜基質細胞MAPK 的訊息傳遞路徑
外文關鍵詞:extracellular ATPG protein-coupled P2Y receptorsP2Y2 purinoceptorhuman endometrial stromal cells (hESCs)mitogen-activated protein kinases (MAPKs)immediate early genes expressionmatrix metalloproteinases (MMPs)cell viability
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細胞外的腺嘌呤核甘三磷酸 (ATP) 主要與細胞膜上的P2Y嘌呤受體 (purinoceptor) 結合,進而引發一連串的細胞內訊息傳遞路徑; 據研究顯示,可對於多種不同的細胞類型引起各種不同的生物反應。研究證實在各種不同的生理系統中,ATP主要活化G-protein, phospholipase C (PLC), diacylglycerol (DAG), protein kinase C (PKC) 之細胞內訊息傳遞路徑。然而對於它在人類子宮內膜基質細胞的作用機制並不清楚。
本研究的設計主要分別從mRNA及protein level檢測人類子宮內膜基質細胞P2Y2嘌呤受體存在之情形。進而探討在人類子宮內膜基質細胞,細胞外的ATP活化mitogen-activated protein kinase (MAPK) 的訊息傳遞路徑及對早期即時表現(immediate early genes)基因和細胞生存能力(cell viability)的影響。研究的證實運用西方墨點分析法 (Western blot analysis)、基因組膜片分析法、細胞生存能力以MTT分析法。
分別從mRNA及protein level證實人類子宮內膜基質細胞存在有P2Y2嘌呤受體。西方墨點分析法 (Western blot analysis);以ERK1/ERK2 (p42mapk和p44mapk) 個別磷酸化形式的單株抗體來做偵測,證實ATP與UTP活化ERK1/2會隨濃度及時間的不同而產生變化。細胞以suramin ( P2-嘌呤受體拮抗劑),neomycin (PLC抑制劑),staurosporin (PKC抑制劑) or PD98059 (MEK,MAPK/ERK kinase, 抑制劑) 處理後,其因ATP而活化之ERK1/2的表現很明顯被弱化。以細胞免疫螢光染色法和Western blot analysis,證實ATP所引發活化之ERK1/2將訊息由細胞質轉移至細胞核時,活化之ERK1/2本身所產生之移位作用。在10μM ATP處理前先加入PD98059抑制劑則活化之ERK1/2本身所產生之移位作用的表現很明顯被弱化。為進一步探討ATP在細胞核內所引起之基因的改變及生長的改變;細胞以10μM ATP處理24小時後萃取其mRNA,使用經由mitogen的訊息傳遞鏈所引起matrix metalloproteinases (MMPs)表現之96個基因組膜片,相較於未經10μM ATP處理之對照組,證實MMP-2, -3, -10, -24的基因表現量有明顯增加;在10μM ATP處理前先加入PD98059抑制劑則MMP-2, -3, -10, -24的基因表現量很明顯被弱化。更進一步以RT-PCR半定量法證實不同劑量ATP對於MMP-2, -3, -10, -24的基因表現量之影響。細胞以10μM ATP處理30分鐘後萃取其mRNA,使用經由mitogen的訊息傳遞鏈所引起早期即時表現之23個基因組膜片,相較於未經10μM ATP處理之對照組,證實early growth response 1的基因表現量有明顯增加;在10μM ATP處理前先加入PD98059抑制劑則early growth response 1的基因表現量很明顯被弱化。以MTT assay分析cell viability,證實10μM ATP及100μM ATP藉由引發ERK1/2訊息傳遞路徑抑制cell viability。
在人類子宮內膜基質細胞之研究中所得到的結論,在細胞核內基因的影響方面--細胞外的ATP經由P2Y2/ PLC/PKC/ERK1/2的訊息傳遞路徑,使得MMP-2, -3, -10, -24的基因表現量和early growth response 1的基因表現量有明顯增加。在細胞生長的影響方面--細胞外的ATP經由P2Y2/ PLC/PKC/ERK1/2的訊息傳遞路徑抑制cell viability。
ATP is an extracellular signaling molecule that activates specific G protein-coupled P2Y receptors in most cell types to mediate diversely biological effects. ATP has been shown to activate the phospholipase C (PLC)/ diacylglycerol/ protein kinase C (PKC) pathway in various systems. However, little is known about the signaling events in human endometrial stromal cells (hESCs).
The objective of this study was to examine the presence of the P2Y2 receptor and the effects of exogenous ATP on the intracellular mitogen-activated protein kinases (MAPKs) signaling pathway, immediate early genes expression, and cell viability in hESCs. Western blot analysis, gene array analysis, and MTT assay for cell viability were performed.
The current study demonstrated the existence of the P2Y2 purinergic receptor at the mRNA and protein level in hESCs. UTP and ATP activated ERK1/2 in a dose- and time-dependent manner. Suramin (a P2-purinoceptor antagonist), neomycin (a PLC inhibitor), staurosporin (a PKC inhibitor), and PD98059 (a MEK inhibitor) significantly attenuated the ATP-induced activation of ERK1/2. Confocal microscopy and Western blot analysis showed an evident nuclear translocation of phosphorylated ERKs after 10 μM ATP treatment, but this effect was blocked by PD98059. To study the gene(s) induced by exogenous ATP, mRNA was extracted from hESCs in the presence or absence of 10 μM ATP. The gene array for 96 genes associated with members of human matrix metalloproteinases (MMPs) and adhesion molecules revealed that the expression of MMP-2, -3, -10, and -24 genes was increased and the effect was attenuated by PD98059. Furthermore, the effects of ATP on the expression of MMP genes were confirmed by semiquantitative RT-PCR. The gene array for 23 genes associated with members of the mitogenic pathway cascade and immediate early genes revealed that the expression of early growth response 1 was increased. In addition, MTT assay revealed an inhibition effect of ATP on cell viability.
ATP activated ERK1/2 through the P2Y2 purinoceptor/PLC/PKC/ERK signaling pathway and induced translocation of ERK1/2 into the nucleus. Further, ATP induced the expression of early growth response 1 and inhibited cell viability in hESCs. To our knowledge, this is the first demonstration of the ATP-induced nuclear translocation of phospho-ERK1/2 that mediates MMPs gene expression in human endometrial cells. These results support the notion that the ERK1/2 signaling pathway is involved in mediating ATP actions in the human reproductive system.
Contents
List of attached tables V
List of attached figures VI
List of figures VII
List of abbreviations VIII
Abatract in Chinese X
Abatract in English XI
Chapter 1 Introduction 1
1.1 Background 2
1.2 Adenosine 5''-triphosphate (ATP) 4
1.2.1 Chemical structure of ATP 4
1.2.2 Synthesis, storage and release of ATP 4
1.2.3 Purinergic hypothesis 5
1.2.4 Purinoceptor 5
1.3 The uterine endometrium 7
1.3.1 Structure and regulation of the MMPs 7
1.3.2 The endometrial stromal cells 8
1.4 Transmembrane signaling by G protein-coupled receptors 9
1.4.1 Introduction 9
1.4.2 The receptor-G protein-effector model of GPCR signaling 9
1.5 Phospholipase C 10
1.5.1 Introduction 10
1.5.2 Classification and structure 10
1.6 Protein kinase C 11
1.6.1 Introduction 11
1.6.2 Structure 11
1.6.3 Localization of PKC isozymes 11
1.6.4 The role of PKC 12
1.7 Mitogen-activated protein kinases (MAPKs) 13
1.7.1 Introduction 13
1.7.2 Classification and activation cascades 13
1.7.3. Regulatory mechanisms of ERK1/2 nuclear translocation 13
1.8 Hypothesis and specific aims of this study 15
Chapter 2 Materials and Methods 16
2.1 Tissue collection and human endometrial stromal cell cultures (hESCs) 17
2.2 Reagents and materials 17
2.3 Treatments 18
2.4 Total RNA isolation 19
2.5 RT-PCR 19
2.6 Western blot analysis 21
2.7 MAP Kinase Assay 22
2.8 Confocal fluorescence microscopy 23
2.9 Subcellular fractionation 23
2.10 Gene array analysis 24
2.11 MTT assay for cell viability 25
2.12 Statistical analysis 26
Chapter 3 Results and Discussion 27
Chapter 4 Summary 41
Chapter 5 Future studies 45
5.1 Background 46
5.2 Specific aims 48
5.3 Preliminary data 48
Chapter 6 References 49
Chapter 7 Attached tables 71
Chapter 8 Attached figure 76
Chapter 9 Figures 87
Chapter 10 Appendix (publications) 131















List of attached tables
Table 1 Characteristics of purine-regulated P2Y receptors 72
Table 2 Classification and characterization of the human matrix metalloproteinases
(MMPs) 73
Table 3 Domains arrangement of the human MMP 75





















List of attached figures
Fig. 1 Chemical structure of Adenosine Triphosphate 77
Fig. 2 Purinergic nerve 78
Fig. 3 Schematic representation of endometrial events during the menstrual cycle. 79
Fig. 4 The basic GPCR−G protein−effector model of GPCR signaling 80
Fig. 5 The molecular domain of PLC isozymes. 81
Fig. 6 PKC structure. 82
Fig. 7 Regulation of sequential kinase pathways that activate MAPKs. 83
Fig. 8 Signal-transduction pathways of receptors or stress-activated MAPKs. 84
Fig. 9 Regulatory mechanisms of ERK1/2 nuclear translocation 85
Fig. 10 Overview of p44/42 MAP Kinase Assay 86















List of figures
Fig. 1 Immunocytochemical staining for vimentin 88
Fig. 2 Standard curve for protein assay. 92
Fig. 3 Expression of P2U/P2Y2 receptor mRNA in human endometrial stromal cells (hESCs) 93
Fig. 4 Expression of the P2Y2 receptor protein level in hESCs 94 Fig. 5 Effect of ATP on MAPK activation 95
Fig. 6 Effect of UTP on MAPK activation 97
Fig. 7 P2-purinergic receptor and ATP-induced MAPK activation 99
Fig. 8 MAP kinase activity 103
Fig. 9 Subcellular ERK1/2 localization 105
Fig. 10 ATP induces nuclear translocation of ERK1/2 106
Fig. 11 Gene array analysis for MMPs 108
Fig. 12 Effect of ATP on MMP-2, -3, -10, and -24 expressions 110
Fig. 13 Gene array analysis for immediate early genes 114
Fig. 14 The effects of ATP on hESC proliferation 118
Fig. 15 Summary for hypothesis 122
Fig. 16 The relationship of ATP, hormone, and MAPK in hESCs 123
Fig. 17 The effect of ATP on MAPK activation in hESCs 124
Fig. 18 The effect of estradiol on MAPK activation in hESCs 126
Fig. 19 The effect of progesterone on MAPK activation in hESCs 128
Fig. 20 Summary for hypothesis 130




List of abbreviations

ATP Adenosine 5’-triphosphate
Ca2+ Calcium
cDNA Complementary deoxyribonucleic acid
DAG Diacylglycerol
DDT Dithiothreitol
DEPC Diethylpyrocarbonate
DMEM Dulbecco''s Modified Eagle Medium
dNTP Deoxynucleoside triphosphate
DNA Deoxyribonucleic acid
DNase Deoxyribonuclease
EDTA Ethylene diaminetetraacetic acid
E2 17??-estradiol
EGF Epidermal growth factor
ELISA Enzyme-linked immunosorbant assay
ER Endoplasmic reticulum
ERK1/2 Extracellular signal-regulated kinase 1/2
FBS Fetal bovine serum
GnRH Gonadotropin-releasing hormone
G-protein GTP-binding protein
GTP Guanosine triphosphate
h Hour
hESCs Human endometrial stromal cells
IP3 Inositol 1,4,5-trisphosphate
JNK/SAPK c-jun terminal kinase/stress-activated protein kinase
kDa Kilodaltons
?? Micro
MAPK Mitogen-activated protein kinase
MAPKKs(=MKK) MAPK kinases
MAPKKKs MAPKK kinases
MAPKKKKs MAPKKK kinases
MMP Matrix metalloproteinase
MEK 1/2 MAPK/ERK kinase 1/2
ml Milliliter
min Minute
mRNA Messenger ribonucleic acid
MT1-MMP Membrane type 1-MMP
MTT 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide
PAGE Polyacrylamide gel electrophoresis
PBS Phosphate buffered saline
PBS-G Phosphate buffered saline-gelatin
PCR Polymerase chain reaction
PIP2 Phosphatidylinositol 4,5-bisphosphate
PIP3 Phosphatidylinositol 3,4,5-triphosphate
PKC Protein kinase C
aPKC Atypical protein kinase C
cPKC Conventional protein kinase C
nPKC Novel protein kinase C
PLC Phospholipase C
PMSF Phenylmethylsulfonyl fluoride
rpm Revolutions per minute
RT Room temperature
RT-PCR Reverse transcription polymerase chain reaction
sec Second
SD Standard deviation
SE Standard error
SDS Sodium dodecyl sulphate
TE Tris-EDTA
TEMED N,N,N’,N’-tetramethylethlenediamine
TIMP Tissue inhibitors of metalloproteinases
Tris Tris(hydroxyl methyl) aminomethane
UTP Uridine 5’-triphosphate
v/v Volume per volume
w/v Weight per volume
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