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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳宏文(Hungwen Chen) | |
dc.contributor.author | Feng-Yu Liang | en |
dc.contributor.author | 梁鳳鈺 | zh_TW |
dc.date.accessioned | 2021-06-15T04:08:42Z | - |
dc.date.available | 2010-02-11 | |
dc.date.copyright | 2010-02-11 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-02-04 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/45203 | - |
dc.description.abstract | GCM1 (Glial cells missing homolog 1)是調控胎盤發育的重要轉錄因子(transcription factor),根據過去我們實驗室對GCM1研究發現:(1) GCM1可調控融合蛋白syncytin基因的表現,促使滋養葉胞層細胞(cytotrophoblast)融合成滋養葉融合層細胞(syncytiotrophoblast);(2) SCFFBW2複合體(complex)與磷酸化的GCM1作用促進GCM1汎素化(ubiquitination),進而由26S proteasome 進行蛋白質降解(degradation);(3) cAMP/PKA訊息路徑(signaling pathway)可促進CBP蛋白對GCM1蛋白質進行乙醯化(acetylation)修飾,使GCM1蛋白質免於被汎素化;(4)GCM1在子癲前症(preeclampsia)的胎盤組織表現減少。
子癲前症(preeclampsia)是一懷孕特有疾病,約有5-7%的妊娠婦女患此疾病。胎盤滋養葉細胞(trophoblast)的侵入和子宮螺旋形動脈(spiral arterial)的重塑(remodeling)不完整可能會導致胎盤細胞處於低氧狀態(hypoxia)。這些現象也被認為是引起子癲前症的主要原因,但低氧與子癲前症之間的關係目前並不清楚。GCM1及其調控的基因syncytin 1、syncytin 2和PGF (placental growth factor),在子癲前症胎盤組織皆減少。而PGF也是GCM1的調控基因,其對胎盤血管的新生扮演著重要的角色。 胎盤細胞BeWo和JEG-3在低氧狀態下,內生性的GCM1、syncytin 1、syncytin 2的mRNA明顯減少,而GCM1的蛋白量也隨之減少。BeWo細胞在CMV啟動子(cytomegalovirus promoter)之下,可穩定持續表現HA-GCM1的細胞株BeWo31,進行低氧或以CoCl2藥物模擬低氧狀態之實驗,其HA-GCM1的mRNA量不變;但HA-GCM1的蛋白量減少,由此實驗結果我們證明低氧造成GCM1蛋白質的降解。在低氧狀態下,胎盤細胞內活化型態的Akt (p-Thr308-Akt和p-Ser473-Akt)的蛋白量皆明顯減少,同時不活化型態的GSK-3β (p-Ser9-GSK-3β)也顯著減少。PI3K的抑制劑LY294002可以使HA-GCM1的蛋白量減少,在低氧下更為明顯,但GSK-3β的抑制劑LiCl可以制止因低氧引發GCM1的降解。我們證明低氧造成GCM1降解是藉抑制PI3K-Akt的訊息路徑,導致GSK-3β的活化。活化的GSK-3β對GCM1的Ser322磷酸化,促使磷酸化的GCM1與F-box protein FBW2作用,導致GCM1汎素化進而降解。因此,GCM1所調控的轉錄網絡受到抑制,進而在子癲前症的形成過程中,扮演重要的角色。 | zh_TW |
dc.description.abstract | Glial cells missing homolog 1 (GCM1) is a transcription factor critical for placental development. Our previous studies have demonstrated that (1) GCM1 is able to regulate syncytin gene expression in order to mediate fusion of cytotrophoblasts into multinucleated syncytiotrophoblasts, (2) the SCFFBW2 complex interacts with GCM1 in a phosphorylation-dependent manner and promotes GCM1 ubiquitination, (3) the cAMP-PKA pathway is able to enhance CBP-mediated acetylation of GCM1 to prevent GCM1 from ubiquitination, and (4) GCM1 gene expression is decreased in preeclampsia.
Preeclampsia is a major pregnancy-specific disorder affecting 5-7% of pregnancies worldwide. While hypoxia caused by incomplete trophoblast invasion and impaired spiral arterial remodeling is thought to be a major cause of preeclampsia, how hypoxia affects placental development remains uncertain. In preeclampsia, GCM1 and its target genes syncytin 1 and placental growth factor (PGF), important for syncytiotrophoblast formation and placental vasculogenesis, are all decreased. In this study, I present evidence that GCM1 is a major target of hypoxia associated with preeclampsia. Furthermore, hypoxia triggers GCM1 degradation by suppressing the PI3K-Akt signaling pathway, leading to GSK-3β activation. Activated GSK-3β phosphorylates GCM1 on Ser322, which in turn recruits the F-box protein FBW2, leading to GCM1 ubiquitination and degradation. Importantly, the GSK-3β inhibitor LiCl prevented hypoxia-induced GCM1 degradation. Overall, this study identifies a molecular basis for the disrupted GCM1 transcription network in preeclampsia and provides a potential avenue for therapeutic intervention. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T04:08:42Z (GMT). No. of bitstreams: 1 ntu-99-D90242001-1.pdf: 4116293 bytes, checksum: 12366b3496ff5dda10588d14decad301 (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 目錄………………………………………………………………… I
圖表目錄…………………………………………………………… III 中文摘要…………………………………………………………… V 英文摘要…………………………………………………………… VII 縮寫表……………………………………………………………… IX 第一章 續論………………………………………………………… 1 1.1 胎盤(Placenta)之簡介…………………………………… 1 1.1.1 人類胎盤的功能與構造……………………………… 1 1.1.2 人類胎盤之發育……………………………………… 2 1.1.3 滋養層細胞之發育…………………………………… 2 1.2 子癲前症(Preeclampsia)之簡介………………………… 4 1.3 胎盤低氧狀態(Hypoxia)之簡介…………………………… 6 1.4 GCM轉錄因子之簡介………………………………………… 8 1.4.1 gcm基因之表現………………………………………… 8 1.4.2 GCM蛋白質的結構與特性……………………………… 8 1.4.3 哺乳動物的GCM之簡介………………………………… 9 1.4.4 人類GCM1 (hGCM1)所扮演的角色…………………… 10 1.4.5 GCM1之後轉譯修飾…………………………………… 12 1.4.5.1 GCM1的磷酸化(Phosphorylation)……………… 12 1.4.5.2 GCM1的乙醯化作用(Acetylation)…………… 12 1.4.5.3 GCM1的去乙醯化(Deacetylation)……………… 13 1.4.5.4 GCM1的類汎素化作用(Sumoylation)…………… 13 1.5 GCM1之汎素化作用與降解……………………………………14 1.6 PI3K- AKT-GSK-3β pathway之簡介……………………… 15 1.7 研究動機及目標………………………………………………16 第二章 實驗材料與方法………………………………………………18 2.1 細胞培養(Cell Culture)…………………………………18 2.2 低氧(Hypoxia)處理………………………………………… 18 2.3 DNA電泳分析………………………………………………… 18 2.4 CaCl2轉染(CaCl2 Transfection)………………………… 19 2.5 Liposome轉染(Liposome Transfection)………………… 19 2.6 共同免疫沉澱法(Co-Immunoprecipitation)………………20 2.7 螢光報告基因Luciferase活性檢測(Luciferase Assay)…20 2.8 蛋白表現(Protein Expression)………………………… 21 2.9 GST沉澱試驗(GST Pull-Down Assay)………………………21 2.10 西方墨點法(Western Blotting)……………………… 22 2.11 核糖核酸萃取(RNA Extraction)……………………… 22 2.12 反轉錄聚合酶連鎖反應(Reverse Transcription Polymerase Chain Reaction: RT-PCR)………………………… 23 2.13 定量聚合酶連鎖反應(Quantitative Polymerase Chain Reaction; Q-PCR)……………………………………………………23 第三章 實驗結果…………………………………………………………………… 25 3.1 低氧促進GCM1的降解…………………………………………………… 25 3.2 在低氧下GSK-3β促進GCM1汎素化作用……………………………… 26 3.3 GCM1的Ser 322和Ser326之磷酸化對FBW2辨識是必需…………… 28 3.4 低氧狀態GSK-3β磷酸化GCM1的Ser322……………………………… 28 第四章 討論…………………………………………………………………………… 30 第五章 圖表………………………………………………………………………… 34 第六章 參考文獻…………………………………………………………………… 49 圖表目錄 圖1. 低氧狀態JEG-3細胞之GCM1、syncytin 1、syncytin 2 的mRNA表現量減少…………………………………………………………34 圖2. 低氧狀態BeWo細胞的GCM1蛋白量減少,且GCM1、syncytin 1、syncytin 2 的mRNA表現量亦減少……………………………………35 圖3. 低氧下BeWo31細胞內生性的GCM1、syncytin 1、syncytin 2的mRNA表現量減少…………………………………………………………36 圖4. 低氧造成HA-GCM1蛋白質的減少但不會影響HA-GCM1 mRNA的表現量…………………………………………………………………… 37 圖5. HA-GCM1蛋白質經CoCl2低氧處裡後會降解,當移除CoCl2其HA-GCM1蛋白量即可恢復……………………………………………… 38 圖6. 在低氧下HA-GCM1蛋白質的降解可被MG132可阻斷,但不受ALLM 的影響…………………………………………………… 39 圖7. 低氧不影響FBW2與UBE2D2 之mRNA表現量………………… 40 圖8. 低氧下胎盤細胞的Akt被抑制使GSK-3β被活化,影響GCM1蛋白量… 41 圖9. GCM1蛋白質的轉錄活性受PI3K-Akt調控………………………………… 42 圖10. GSK-3β的抑制劑減緩低氧所引發的GCM1降解………………………… 43 圖11. GSK-3β調控GCM1的汎素化作用和降解………………………………… 44 圖12. 確認GCM1被GSK-3β磷酸化的位置與C端的destruction motif……… 46 圖13. 低氧促進GCM1的Ser322磷酸化………………………………………… 48 圖14. 胎盤的低氧造成GCM1降解可能促成子癲前症發病的機制…………… 49 附圖一. 胎盤絨毛的發育過程……………………………………………………… 3 附圖二. 正常懷孕與子癲前症的細胞滋養層細胞侵入與螺旋形動脈重塑之比較……………………………………………………………………………… 5 附圖三. 母體與胎兒之界面在胎盤發育過程含氧狀態之剖面圖………………… 7 附圖四. 老鼠和人類的GCM1蛋白序列相似性比較……………………………… 11 附圖五. GCM1被降解的可能模式………………………………………………… 15 附圖六. PI3K-AKT-GSK-3β pathway之調控……………………………………… 16 | |
dc.language.iso | zh-TW | |
dc.title | 低氧引發GCM1降解的機制與子癲前症發病的關係 | zh_TW |
dc.title | Mechanism of hypoxia-induced GCM1 degradation:
Implications for the pathogenesis of preeclampsia | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 張震東(Geen-Dong Chang),李明亭(Ming-Ting Lee),黃銓珍(Chang-Jen Huang),張功耀,張茂山(Mau-Sun Chang) | |
dc.subject.keyword | GCM轉錄因子,子癲前症,低氧狀態, | zh_TW |
dc.subject.keyword | GCM1,preeclampsia,hypoxia, | en |
dc.relation.page | 55 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-02-04 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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