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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡孟君 | |
| dc.contributor.author | Jou-Yin Meng | en |
| dc.contributor.author | 孟柔吟 | zh_TW |
| dc.date.accessioned | 2021-06-16T02:36:49Z | - |
| dc.date.available | 2025-07-24 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-07-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54020 | - |
| dc.description.abstract | Liver receptor homolog-1 (LRH-1；NR5A2) 隸屬於孤兒核受器，主要表現在肝臟、腸道、胰臟以及卵巢。LRH-1對於細胞增生、發育、膽固醇運輸、膽酸恆定以及固醇類荷爾蒙的生成等扮演重要的角色。LRH-1為轉錄因子會和輔因子產生交互作用，進而調控下游基因的表現。本論文發現LRH-1會調控E3連接酶RNF138 (RING finger protein 138) 蛋白質量，並與RNF138有交互作用。當RNF138與LRH-1同時轉染於HEK293T中，會使RNF138蛋白質的量降低，並且具有劑量依賴性。利用蛋白質衰減測定，發現LRH-1可降低RNF138蛋白質的穩定性；若給予蛋白酶體抑制劑MG132，會部分抑制LRH-1對RNF138蛋白質的影響。這些結果顯示，LRH-1可能會促進RNF138經由蛋白酶體路徑而降解。
GST pull down的分析顯示，LRH-1以DNA binding domain (DBD) 與RFN138的N端進行交互作用。有研究指出，核受器的DBD可能具有潛在的RING finger結構。我們以點突變破壞LRH-1位於DBD的潛在環狀結構 (loop)，這些突變在失去轉錄活性的情況下，仍能使RNF138蛋白質量下降，說明LRH-1的DBD可能不具有E3連接酶活性，且調控RNF138蛋白質量的作用與其轉錄活性無關。位了確認LRH-1調控RNF138蛋白質量的重要區段，建構出不同的LRH-1片段，發現單獨的LBD片段能降低RNF138蛋白質的量。綜合結果顯示，LRH-1會降低RNF138蛋白質的穩定性，而此作用與其轉錄活性無關，反而是LBD在LRH-1的功能中扮演重要角色。 | zh_TW |
| dc.description.abstract | Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor, is predominantly expressed in the liver, intestine, pancrease and ovaries. LRH-1 regulates the expression of genes involved in development, metabolism, steroidogenesis and cancinogenesis. We found that LRH-1 reduced the protein level of RNF138 (RING finger protein), and they had interaction in vitro. By protein turnover assay, we found that LRH-1 decreased RNF138 protein stability. In addition, LRH-1 mediated RNF138 protien levels were inhibited by the proteasome inhibitor MG132. These results indicates that LRH-1 may promote RNF138 degradation through proteasome pathway.
The GST pull-down experiments showed that LRH-1 interacted with RNF138 N-terminus by DNA binding domain (DBD). It has been reported that the DBD of nuclear receptors has potential RING finger structure. We destroyed the potential loop structure in DBD of LRH-1 by site mutagenesis. These mutants lose the transcriptional activity, but still could reduce RNF138 protein level. It suggested that LRH-1 DBD may not have E3 ligase activity and LRH-1-mediated RNF138 protein reduction was independent of its transactivity. To identify the region responsible for LRH-1 function, a series of LRH-1 truncation constructs were generated. We found that the ligand binding domain (LBD) alone could reduce RNF138 protein level. Together, these results suggested that LRH-1 can reduce RNF138 protein stability that is independent of LRH-1 transcriptional activity and LBD plays an important role in LRH-1-mediated function. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T02:36:49Z (GMT). No. of bitstreams: 1 ntu-104-R02441003-1.pdf: 1735096 bytes, checksum: 541e6ab1c047dd67e25908dda34275bf (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 目錄
致謝 I 目錄 II 表次 IV 圖次 IV 中文摘要 V Abstract VI 第一章 序論 1 一、 LRH-1簡介 1 1. LRH-1之生理功能 1 2. LRH-1之蛋白質結構 2 二、 泛素 (ubiquitin)-蛋白酶體 (proteasome)系統 3 1. 泛素修飾之作用機轉 3 2. 泛素之鍵結種類與功能 4 三、 RNF138簡介 5 1. RNF138之蛋白質結構 5 2. RNF138之生理功能 5 四、 Wnt signaling 6 五、 研究目的 8 第二章 材料與方法 9 一、 細胞培養 9 二、 質體 9 三、 暫時性轉染法 (Transient transfection) 16 四、 西方墨點法 (Western blot) 分析 17 五、 冷光酶活性分析 (Luciferase assay) 19 六、 GST沉澱法 (GST pull down) 19 七、 蛋白質半衰期測定 (protein half-life) 測定 20 第三章 結果 22 一、 LRH-1影響RNF138蛋白質的量 22 二、 LRH-1影響RNF138蛋白質降解 22 三、 RNF138受LRH-1調控的重要區段分析 23 四、 LRH-1與RNF138蛋白質之間的交互作用 23 五、 LRH-1調控RNF138蛋白質量的重要區段分析 24 第四章 討論 26 一、 LRH-1降低RNF138蛋白質穩定性的路徑 26 二、 LRH-1 DBD的潛在性RING finger結構 27 三、 DBD與LBD對於LRH-1調控RNF138蛋白質量所扮演的角色 28 參考文獻 30 表次 表一、LRH-1片段對RNF138蛋白質的影響 36 圖次 圖一、LRH-1降低RNF138蛋白質量 37 圖二、LRH-1降低RNF138蛋白質量具有劑量依賴性 38 圖三、LRH-1使RNF138蛋白質穩定性降低 39 圖四、LRH-1使RNF138蛋白質降解路徑分析 40 圖五、LRH-1對不同片段RNF138蛋白質量的影響 41 圖六、LRH-1對RNF138 K158R蛋白質量的影響 42 圖七、LRH-1與不同片段RNF138蛋白質之間的交互作用 43 圖八、不同片段LRH-1與RNF138蛋白質之間的交互作用 44 圖九、LRH-1與RNF138蛋白質之間的交互作用 45 圖十、LRH-1點突變對RNF138蛋白質量的影響 46 圖十一、LRH-1的轉錄活性分析 47 圖十二、LRH-1片段對RNF138蛋白量的影響 48 圖十三、LRH-1單一片段對RNF138蛋白量的影響 49 圖十四、LRH-1促進RNF138蛋白質降解機制假設模型 50 | |
| dc.language.iso | zh-TW | |
| dc.subject | RNF138 | zh_TW |
| dc.subject | LRH-1 | zh_TW |
| dc.subject | 泛素-蛋白?體路徑 | zh_TW |
| dc.subject | LRH-1 | zh_TW |
| dc.subject | RNF138 | zh_TW |
| dc.subject | 泛素-蛋白?體路徑 | zh_TW |
| dc.subject | RNF138 | en |
| dc.subject | LRH-1 | en |
| dc.subject | Ubiquitin-proteasome pathway | en |
| dc.subject | RNF138 | en |
| dc.subject | LRH-1 | en |
| dc.subject | Ubiquitin-proteasome pathway | en |
| dc.title | LRH-1調控RNF138蛋白質穩定性 | zh_TW |
| dc.title | Liver receptor homolog-1 regulates RING finger protein 138 protein stability | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳瑞華,湯志永,徐立中 | |
| dc.subject.keyword | LRH-1,RNF138,泛素-蛋白?體路徑, | zh_TW |
| dc.subject.keyword | LRH-1,RNF138,Ubiquitin-proteasome pathway, | en |
| dc.relation.page | 50 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-07-27 | |
| 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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