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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 胡孟君 | |
dc.contributor.author | Feng-Ming Yang | en |
dc.contributor.author | 楊豐名 | zh_TW |
dc.date.accessioned | 2021-06-15T07:06:26Z | - |
dc.date.available | 2014-03-03 | |
dc.date.copyright | 2011-03-03 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-11-24 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48648 | - |
dc.description.abstract | 核受器同源體-1 (Liver receptor homolog-1; LRH-1;NR5A2)為孤兒核受器家族的成員之一,會穩定的表現在細胞核中調控基因表現。本篇研究中,我們在LRH-1上確認了兩段具有功能的核輸入訊號(nuclear localization signals, NLSs),稱為NLS1與NLS2。NLS1位在DNA binding domain,胺基酸序列範圍在117-169並涵蓋了此區的第二個zinc finger。突變結果顯示,zinc finger結構及其兩側的鹼性胺基酸對NLS1核輸入功能具有重要性。NLS2的胺基酸序列範圍為169-204,位於Ftz-F1 box上,符合典型的bipartite NLS。單一存在的NLS1或NLS2都具有將LRH-1運送到細胞核的能力,且胞外實驗顯示兩者分別與importin α 或importin β有交互作用,說明了LRH-1主要是透過importin α/β的機制運送進入細胞核。此外,NLSs上重要的三組鹼性胺基酸的突變也會影響LRH-1的DNA鍵結和轉錄之功能。
LRH-1在細胞核的分布會受到SUMO修飾作用的影響。SUMO鍵結會引導LRH-1至核小體,而降低其轉錄活性。胞外實驗顯示,lysine289會與SUMO-1產生鍵結。然而,在COS-7細胞中lysine173或289的突變,會降低SUMO-1的鍵結作用,亦會阻止LRH-1位移到核小體,顯示lysine173和289為SUMO-1修飾作用的兩個重要位置。在分離的大鼠granulosa 細胞中,五個單一lysine的突變並不影響LRH-1位移至核小體,需同時有三到五個lysines的突變位置,才能阻止此作用。這些結果顯示,LRH-1具有多個SUMO-1鍵結區,在不同的細胞會造成不同的修飾作用。在大鼠granulosa細胞中,forskolin和cholera toxin的處理能減低LRH-1至核小體的位移,進一步的分析顯示,forskolin會影響sumoylation的動態平衡,可能因此降低SUMO的作用而阻斷LRH-1位移到核小體。 總結來說,本篇論文說明,LRH-1的轉錄作用會受到過核輸入系統和SUMO修飾作用所調控。 | zh_TW |
dc.description.abstract | Liver receptor homolog-1 (LRH-1; NR5A2), is an orphan nuclear receptor that is localized to the nucleus for the regulation of gene expression. In this study, I characterized two functional nuclear localization signals (NLSs) in LRH-1. The first motif, NLS1 (residues 117-168), overlaps the second zinc finger in the DNA binding domain. Mutagenesis analysis showed that the zinc finger structure and two basic clusters on either side of the zinc finger loop are critical for nuclear localization directed by NLS1. The motif NLS2 (residues 169-204) is located in the Ftz-F1 box that contains a bipartite signal. Either NLS1 or NLS2 alone was sufficient to target full-length LRH-1 to the nucleus. Both NLS1 and NLS2 interacted with importin α and importin β in vitro, suggesting that importins mediate the nuclear transport of LRH-1. Three crucial basic clusters in the NLSs are also involved in the DNA binding and transcriptional activities of LRH-1.
I further showed that nuclear localization of LRH-1 was regulated by SUMO modification. SUMO conjugation targets LRH-1 to the transcriptionally inactive nuclear bodies. Lysine 289 is the major site for SUMO-1 conjugation in vitro. However, in COS-7 cells, mutation of either K173 or K289 prevented translocation of LRH-1 into nuclear bodies and reduced the conjugation by SUMO-1, suggesting that K289 and K173 are two important sites involved in SUMO-1 modification. In granulosa cells, three or more altered lysine residues were required for nucleoplasm retention. This result suggests that multiple lysine residues are targets for SUMO conjugation in vivo and that granulosa cells are more sensitive to SUMO-1-mediated LRH-1 localization to nuclear bodies. Nuclear body localization of LRH-1 was suppressed by forskolin and cholera toxin. Forskolin treatment could change the dynamic process of sumoylation and repress LRH-1 targeting to nuclear speckles in rat granulosa cells. Take together, the result of this study suggest that transcription function of LRH-1 is maintained via the nucleocytoplasmic transport system and regulated by sumoylation. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T07:06:26Z (GMT). No. of bitstreams: 1 ntu-99-D93441001-1.pdf: 2734179 bytes, checksum: 8de1bb3578102c4da61171c2d0769adf (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iv TABLE OF CONTENTS vi LIST OF FIGURES viii ABBREVIATIONS USED ix Introduction 1 一、Liver receptor homolog-1 (LRH-1) 1 (1) Overview 1 (2) Domain structure 1 (3) Role in development 3 (4) Physiological function 4 二、Nuclear Transport 6 (1) Nuclear pore complex 6 (2) Nuclear transport mechanism 6 (3) Nuclear localization signal; NLS 7 三、SUMO modification of proteins 8 (1) Overview of SUMO conjugation 8 (2) Regulation of SUMO modification 9 (3) Function of SUMO modification 10 Aim of this study 11 Material and Methods 12 一、 Cell Culture 12 二、 Primary granulosa Cell isolation 12 三、 Plasmid constructs 12 四、 Luciferase assays 17 五、 Electroporation 18 六、 Western blotting 18 七、 Fluorescence microscopy 19 八、 Immunostaining 20 九、 ATP depletion 20 十、 RNA extraction and RT-PCR 20 十一、 In vitro sumoylation assay 22 十二、 GST-pull down 22 十三、 Electrophoretic mobility shift assay (EMSA) 23 Results 24 Identification of two putative nuclear localization domains in LRH-1 24 Identification of key residues for nuclear import in NLS1 and NLS2 25 Nuclear import mechanisms of LRH-1 NLS 27 Effect of NLS mutation on DNA binding and transactivity of LRH-1 28 Sumoylation affects the subnuclear localization of LRH-1 29 LRH-1 is modified by SUMO-1 in vitro 30 Sumoylation site lysine 289 negatively regulates LRH-1-mediated transcription 30 Lysine 173 and 289 are required for SUMO-1- mediated localization in nuclear bodies in COS-7 31 Multiple SUMO conjugation is associated with the targeting of LRH-1 into nuclear bodies that is inhibited by cAMP signaling 32 cAMP signaling pathway regulates the expression of sumoylation-related enzymes 34 The effect of cAMP on LRH-1 subnuclear localization in rat granulosa cells is prevented by UBC9 overexpression 35 Discussion 36 一、Nuclear Import 36 1. Two functional NLSs 36 2. Nuclear import mechanisms of NLSs 37 3. DNA binding and transcriptional activity of LRH-1 and its NLS mutants 38 二、SUMO effect 39 1. LRH-1 is modified by SUMO-1 39 2. The effect of cAMP on LRH-1 sumoylation 40 3. Proposed model of LRH-1 in rat granulosa cells 41 三、The role of sumoylation on nuclear import 42 四、LRH-1 in embryonic development. 43 References 44 Figure 56 | |
dc.language.iso | en | |
dc.title | 探討LRH-1核輸入訊號及sumoylation在細胞中運輸扮演的角色 | zh_TW |
dc.title | Regulation of LRH-1 cellular trafficking: Role of Nuclear localization signals and sumoylation | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 鐘邦柱,楊性芳,徐立中,黃娟娟 | |
dc.subject.keyword | 核受器同源體-1,核輸入訊號,SUMO-1基因,大鼠granulosa 細胞,核小體, | zh_TW |
dc.subject.keyword | LRH-1,nuclear localization signals,SUMO-1,rat granulosa cell,nuclear body, | en |
dc.relation.page | 75 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-11-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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