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研究生:許佩真
研究生(外文):Pei-Jen Hsu
論文名稱:富含白胺酸重複之G蛋白偶合受體LGR4、5和6之訊息傳遞路徑探討與配體研究
論文名稱(外文):Identification of ligands and signaling pathways for orphan leucine-rich repeat-containing G protein-coupled receptors, LGR4,5 and 6.
指導教授:羅清維
指導教授(外文):Ching-Wei Luo
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生命科學暨基因體科學研究所
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:2009
畢業學年度:97
語文別:中文
論文頁數:86
中文關鍵詞:G蛋白偶合受體孤兒受體白胺酸重複序列睪丸卵巢
外文關鍵詞:GPCRorphan receptorleucine-rich repeattestisovary
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Leucine-rich repeat-containing G protein-coupled receptors(LGRs)是一種G蛋白偶合受體。LGRs家族又分成A、B和C三個子群,其中A和C子群成員的配體與生理角色皆被探討與證實,但B群成員仍是孤兒受體,包括LGR4、LGR5和LGR6,因此,我們想要進一步探討LGR4-6的生理意義。近年來發現:LGR4和LGR5在癌細胞中會過量表現。為了瞭解有哪些細胞癌化的訊號會與LGR4-6進行交互作用,我們選用HeLa和NIH:OVCAR-3細胞株作測試。發現細胞在EGF刺激下,LGR4~6 mRNA表現量會因EGF劑量的增加而有明顯的減少;此外EGF也會使HEK-293T細胞膜上的LGR4表現有減少的趨勢,推測EGF會促進LGR4進行內吞作用。從先前的文獻得知:LGR4會活化EGF受體。而依據我們實驗顯示EGF會抑制LGR4~6表現,因此推測EGF對LGR4表現有負迴饋的作用。
先前實驗室從大鼠卵巢cDNA中,擴增出LGR4的選擇性剪接片段。經由蛋白質序列比對後,發現此片段只包括LGR4的膜外區,因此,我們將其命名為LGR4 ectodomain,簡稱為4ED。我們的實驗則將以LGR4和4ED為主軸,探討其在生殖系統發育中的生理角色。依據4ED的結構特性,我們推測其為LGR4的拮抗劑。為了證明4ED的角色,我們藉由anti-FLAG親合性管柱,從轉殖有FLAG-4ED質體的HEK-293T細胞中,純化出重組蛋白質,並將此蛋白質進行小鼠腹腔注射。經由免疫組織化學法和即時聚合連鎖反應,發現睪丸中的雌激素受體甲型表現量大幅減少,此表現型與LGR4基因剔除鼠相似,因而證實4ED扮演著LGR4拮抗劑的角色。此外,我們發現在大鼠超排卵週期中,LGR4 mRNA表現量會受到促性腺激素的調控;而且,經由西方墨點法,我們也可以從牛的卵巢濾泡液中偵測到4ED的存在。因此,在SD大鼠超排卵模型中,我們設計以腹腔注射PMSG和FLAG-4ED蛋白。實驗結果發現:相較於只注射PMSG的對照組,同時注射PMSG和FLAG-4ED會導致卵巢重量稍微增加,並且雌激素受體甲型、乙型和固醇類生成酵素基因mRNA表現量也有減少的趨勢。據此推論LGR4和4ED在卵巢週期中,可以調控固醇類生成酵素基因的表現,進而影響卵巢的發育。
Leucine-rich repeat-containing G protein-coupled receptors(LGRs)belong to the superfamily of G-protein coupled receptors (GPCRs). LGRs, classified into three subgroups (group A, B and C), are evolutionarily and structurally related. Although the group A and group C have been found to be receptors for glycoprotein hormones and relaxin-related ligands, respectively, the functions and cognate ligands of the group B LGRs, comprising mammalian LGR4~6, remain unclear. Therefore, we aim to study the pathways and physiological roles of orphan LGR4~6. Previous studies indicate that LGR4 and LGR5 expression correlates with tumor progression. We found the EGF treatment causes a dose-dependent inhibition of LGR4~6 mRNA expression in HeLa and NIH:OVCAR-3 cells. In addition, FLAG-LGR4 cell-surface expresion on the HEK-293T cells was reduced by EGF treatment,suggesting that the EGF treatment can induce endocytosis of LGR4~6.
We recently found a natural LGR4 splice variant, 4ED, which encodes only the ectodomain of LGR4. It has been demonstrated that the soluble extracellular fragments of known LGRs are able to bind to their respective ligands and serve as functional antagonists. We therefore hypothesized that 4ED can bind the endogenous ligand of LGR4 to counteract its physiological functions. To obtain the recombinant 4ED protein for animal treatments, a construct containing the FLAG-tagged 4ED was used for HEK-293T cell transfection followed by protein purification. After intraperitoneal injection of purified FLAG-4ED into newborn C57BL/6J mice for 3 weeks, our real-time PCR and IHC analysis showed a significant decrease of estrogen receptor (ER) expression in the testis, consisting with the phenotype shown in the LGR4-null mice. This data indicates our purified 4ED can play as an antagonist of LGR4. Further, we also found the ovarian expression of LGR4 mRNA was controlled by gonadotropins whereas the 4ED protein can be detected in the bovine follicular fluid. Therefore, in addition to the testicular tests, we also explored the 4ED effects in the ovary. In rat superovulatory models, treatments with PMSG together with FLAG-4ED increase the ovarian weight but decrease the mRNA expression of the ERalpha、ERbeta and steroidogenic genes in contrast to those with PMSG only. In conclusion, the balance between the LGR4 and 4ED levels in the ovary may play an important role in the regulation of ovarian steroidogenesis and development.
目錄

中文摘要...................................................1
英文摘要...................................................3
壹、序論
1-1 G蛋白偶合受體..........................................5
1-2 富含白胺酸重複之G蛋白偶合受體家族......................6
1-3 孤兒B群富含白胺酸重複之G蛋白偶合受體家族...............7
1-3-1 富含白胺酸重複之G蛋白偶合受體4(LGR4)............8
1-3-2 富含白胺酸重複之G蛋白偶合受體5(LGR5)............9
1-3-3 富含白胺酸重複之G蛋白偶合受體6(LGR6)...........10
1-4 生殖系統與B群富含白胺酸重複之G蛋白偶合受體家族的關係..10
1-4-1 LGRs對雄性生殖系統的影響...........................11
1-4-2 LGRs對雌性生殖系統的影響...........................11
1-5 研究動機與實驗設計....................................12
貳、實驗材料與方法
2-1 實驗動物..............................................13
2-2 材料..................................................13
2-3 細胞培養(Cell culture)..............................13
2-3-1 HEK-293T細胞株之培養...............................14
2-3-2 HeLa細胞株之培養...................................14
2-3-3 T-47D細胞株之培養..................................14
2-3-4 NIH:OVCAR-3細胞株之培養............................15
2-4 核糖核酸萃取(RNA extraction).........................15
2-5 互補去氧核醣核酸之製備(cDNA preparation)............16
2-6 聚合酶連鎖反應(Polymerase chain reaction)與定量聚合酶連鎖反應(Quantitative real-time polymerase chain reaction)................................................16
2-7 小量質體DNA之萃取(Plasmid DNA isolation)............17
2-8 定點突變(Site-directed mutagenesis).................18
2-9 細胞轉染(Cell transfection).........................18
2-10 細胞膜酵素連結免疫吸附法(Cell-surface ELISA).......19
2-11 細胞免疫化學染色(Immunocytochemistry)..............20
2-12 細胞內冷光酶(Luciferase)與β-半乳糖苷酶(β-galactosidase)含量偵測...................................21
2-13 建立持續表現特定質體的細胞(Establishment of stable cell lines)..............................................22
2-14 蛋白質之純化(Protein purification).................22
2-15蛋白質聚丙醯胺膠體電泳(Sodium dodecyl sulfate polyacrylamide gel electrophoresis;SDS-PAGE)............23
2-16 蛋白質轉印(Protein transfer).......................24
2-17 西方墨點法(Western blot)...........................25
2-18 組織切片的製備(Tissue section).....................25
2-19 免疫組織化學法(Immunohistochemistry) ..............26
2-20 偵測卵巢中黃體素(Progesterone)的含量...............28
2-21 統計分析(Statistical analysis).....................28
参、結果
PART-I 探討LGR4、LGR5和LGR6的訊息傳遞路徑
3-1 LGR4、LGR5和LGR6與細胞癌化訊號間的關係................30
3-3 LGR4與EGF的訊息傳遞路徑進行交互作用...................31
3-3 尋找LGR4~6孤兒受體的配體
3-3-1 偵測LGR4~6在細胞中的表現位置與表現量................32
3-3-2 測試篩選LGR4配體的分析系統..........................33
3-3-3 篩選LGR4的配體......................................34
PART-II 探討LGR4和4ED在生殖系統發育中的生理角色
3-4 LGR4在小鼠睪丸組織中的表現位置........................35
3-5 分析4ED是否為功能性蛋白
3-5-1 4ED重組蛋白的製備...................................35
3-5-2 4ED可拮抗LGR4在睪丸發育中的功能.....................36
3-6 探討LGR4在大鼠卵巢組織中的表現........................37
3-7 探討注射4ED對卵巢週期的影響...........................37
肆、討論
PART-I 探討LGR4、LGR5和LGR6的訊息傳遞路徑.................40
PART-II 探討LGR4和4ED在生殖系統發育中的生理角色...........43
伍、實驗結果
圖一 偵測各癌細胞株中內生性的LGR4、LGR5和LGR6表現.........47
圖二 EGF的刺激影響LGR4、LGR5和LGR6在癌細胞株中的表現......48
圖三 不同濃度的EGF刺激對LGR4、LGR5和LGR6基因表現的影響....49
圖四 不同EGF濃度刺激下偵測E2F3和E2F5在HeLa細胞中的表現....50
圖五 EGF在有或無E2F3的HeLa細胞中對LGR4表現的影響..........51
圖六 EGF對細胞膜上LGR4表現的影響..........................52
圖七 細胞化學免疫法偵測在EGF刺激下細胞膜上LGR4表現量的變化53
圖八 確認LGR4~6在HEK-293T細胞中的表現位置.................54
圖九 以cell-surface ELISA確認LGR4~6在HEK-293T細胞膜上的表現量........................................................55
圖十 探討表現LGR6的HEK-293T細胞是否走向細胞凋亡...........56
圖十一 偵測突變型LGR4的表現量與活性.......................57
圖十二 篩選大鼠和人類LGR4的配體...........................58
圖十三 以組織切片分析小鼠睪丸中LGR4的表現情形.............59
圖十四 以組織切片分析小鼠睪丸LGR4及Oct4的表現情形.........60
圖十五 重組4ED蛋白在不同細胞株的表現情形..................61
圖十六 重組4ED蛋白的純化情形..............................62
圖十七 小鼠注射4ED後體重與睪丸重量的變化..................63
圖十八 小鼠注射4ED後偵測睪丸中ERalpha、ERbeta及AQP1的變化.64
圖十九 以組織切片分析4ED對ERalpha表現的影響...............65
圖二十 以免疫組織螢光法分析睪丸中LGR4和ERalpha表現的相對位置........................................................66
圖二十一 偵測LGR4在卵巢四種細胞型態內的mRNA表現量.........67
圖二十二 分析第三及第八週大鼠卵巢中LGR4的表現.............68
圖二十三 偵測牛的卵巢濾泡液中的4ED........................69
圖二十四 注射4ED對卵巢重量與ERalpha、ERbeta和AQP1基因的影響........................................................70
圖二十五 卵巢的類固醇合成功能與LHR表現受到4ED的影響.......71
圖二十六 排卵後4ED的注射對ERalpha、ERbeta、AQP1基因和類固醇合成功能的影響............................................72
陸、附圖和附表
附圖一 LGRs家族的親緣關係分析.............................74
附圖二 LGR4的基因體結構與LGR4、4ED的蛋白質功能區域........75
附圖三 4ED的蛋白質序列....................................75
附表一 比較BMP拮抗劑與鞣化劑的半胱胺酸(Cysteine)排列方式........................................................76
附表二 引子序列 ..........................................77
柒、參考文獻..............................................80
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