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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
| dc.contributor.author | Hsiang-Tsan Hsieh | en |
| dc.contributor.author | 謝祥燦 | zh_TW |
| dc.date.accessioned | 2021-06-13T02:14:32Z | - |
| dc.date.available | 2009-06-23 | |
| dc.date.copyright | 2007-06-23 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-05-08 | |
| dc.identifier.citation | Amir, R., Ciechanover, A. and Cohen, S. (2001) [The ubiquitin-proteasome system: the relationship between protein degradation and human diseases]. Harefuah, 140, 1172-1176, 1229.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30753 | - |
| dc.description.abstract | 肝受體同源體-1 (liver receptor homolog, LRH-1) 為轉錄因子，屬於核受體NR5A家族的一員，主要表現在由內胚層分化而成的肝腸組織及卵巢。mLRH-1可以促進人類類固醇生成基因CYP11A1啟動子的轉錄作用，當mLRH-1的羧基端轉錄活性作用區 (activation function-2, AF-2) 被除去之後，mLRH-1即喪失其對人類CYP11A1啟動子的轉錄活性。我們發現mLRH-1促進CYP11A1啟動子的轉錄作用會受到PIASy所抑制，且具有劑量依存性。PIASy蛋白質具有兩個可能的抑制區RD1與RD2，去除RD1使得PIASy無法抑制mLRH-1轉錄活性，而刪除RD2則沒有影響，因此PIASy可能藉由RD1來抑制mLRH-1轉錄之進行。給予組蛋白去乙醯酶抑制劑，或是共同轉染組蛋白去乙醯酶 (histone deaceylase) 皆不影響PIASy對mLRH-1的抑制能力，說明了PIASy並非經由招募組蛋白去乙醯酶來抑制mLRH-1轉錄活性。將PIASy與mLRH-1分別接上螢光蛋白轉染至細胞，我們觀察到mLRH-1在細胞核中分布不因PIASy的存在而改變，說明PIASy不是藉由改變mLRH-1在細胞核中分布位置來影響mLRH-1的轉錄作用。GST pull down的實驗則顯示PIASy的胺基酸158-510片段與mLRH-1有直接的交互作用。
我們將不同片段的mLRH-1接上螢光蛋白，分析其在細胞表現之分布，由結果推測其nuclear localization signal (NLS) 可能位於mLRH-1胺基酸序列117-167以及169-193兩處。另外，給予蛋白酶體 (proteasome) 抑制劑MG-132會增加mLRH-1在細胞的蛋白質總量，表示mLRH-1可能經由蛋白酶體降解路徑分解，但此路徑可能與泛素化修飾作用無關。去除羧基端後，會提高mLRH-1的蛋白質總量，且其蛋白質總量不再因MG-132作用而增加，說明了羧基端可能參與了蛋白酶體降解路徑。 | zh_TW |
| dc.description.abstract | Liver receptor homolog-1 (LRH-1) is a transcription factor and belongs to nuclear receptor 5A subfamily. LRH-1 is mainly expressed the tissues of endodermal origin, such as liver and intestine and also in the ovary. Our previous studies indicated that mLRH-1 stimulated the activity of the human steroidogenic gene CYP11A1 promoter. When the C-terminal activation function-2 (AF-2) was truncated, mLRH-1 lost the ability to induce the transcriptional activity of CYP11A1 promoter. We found that PIASy could repress mLRH-1-mediated CYP11A1 activity in a dosage dependent manner. It is indicated that PIASy contains two transcriptional repression domains, RD1 and RD2. Deletion of the RD1, but not RD2, failed to repress mLRH-1 transcriptional activity, indicating that RD1 is essential for PIASy-mediated inhibition of mLRH-1. Treatment with histone deaceylase (HDAC) inhibitors or overexpression of HDAC did not influence the repression activity of PIASy. It is suggested that HDAC recruitment is not essential for PIASy-mediated repression of mLRH-1. In addition, the distribution of mLRH-1 in the nucleus was not changed by cotransfection with PIASy. GST pull down assay showed that residues 158-510 of PIASy are responsible for interacting with mLRH-1.
A series deletion of mLRH-1 was fused to fluorescent protein to analyze the subcellular distribution of these proteins. The results revealed that two nuclear localization signal (NLS) were located in the residues 117 to 167 and 169 to 193. Treatment of cells with proteasome inhibitor MG-132 clearly increased the protein levels, suggesting that mLRH-1 could be destroyed via proteasomal degradation pathway. Deletions of the C-terminal enhance the level of mLRH-1 protein expression. Treatment with MG-132 had no effect on the protein expression of C-terminal truncation mutants. The results indicated that the C-terminus of mLRH-1 was required for proteasomal degradation pathway. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T02:14:32Z (GMT). No. of bitstreams: 1 ntu-96-R93441005-1.pdf: 1104527 bytes, checksum: 736f09825249694635950bcc44f4fed7 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 目錄
誌謝 .............................................................................................................. Ⅰ 目錄 .............................................................................................................. Ⅲ 圖次 ……....................................................................................................... Ⅵ 中文摘要 ........................................................................................................ Ⅶ 英文摘要 ........................................................................................................ Ⅷ 第一章、序論 …............................................................................................ 1 一、LRH-1簡介 ………………………................................................. 1 1. LRH-1之結構 ………………....................................................... 1 2. LRH-1的轉譯後修飾作用 ………………...................................... 2 3. LRH-1的輔調控因子 ………………….......................................... 3 4. LRH-1之功能 ……………...……………..................................... 4 二、PIASy簡介 ……………………...................................................... 5 1. PIASy的結構 ................................................................................ 5 2. PIASy的功能 ………………...……….......................................... 6 三、泛素 (ubiquitin) –蛋白酶體 (proteasome) 系統 …….……............ 7 四、研究動機 …………….………....................................................... 7 第二章、材料與方法 ..................................................................................... 9 一、細胞培養 ........................................................................................ 9 二、質體建構 ………........................................................................... 9 三、暫時轉染法 (Transient transfection) …………………………… ... 13 四、Luciferase活性分析 ……..........................…................................. 13 五、DAPI染色法 ……………..…........................................................ 14 六、細胞萃取 …………......................................................................... 14 七、西方墨點法 (Western blotting) …………........................................ 14 八、Coomassie Brilliant Blue R-250染色 ………………….................... 15 九、誘導大腸桿菌表現重組蛋白 ……....................................................... 15 十、胞外轉錄轉譯作用 (In vitro transcription/translation) …….…......... 16 十一、GST pull down ........………….…………………………………..... 16 十二、藥品 ...................…………..……………………………………..... 16 第三章、結果 …………............................................................................... 17 一、mLRH-1的轉錄活性調控 ………………....................................... 17 1. mLRH-1轉錄活性依賴Activation Function-2區域 ........................ 17 2. PIASy抑制mLRH-1對人類CYP11A1基因啟動子的轉錄活性 ….. 17 3. PIASy抑制mLRH-1的轉錄活性作用具有劑量依存性 (dose-dependent) …………………………………….................... 17 4. PIASy的RD1區域對於PIASy抑制mLRH-1的轉錄活性具有 功能性 ………………………………………………………….... 18 5. PIASy抑制mLRH-1的轉錄活性與招募組蛋白去乙醯酶 (HDACs) 無關 ………………………………………………… ... 18 6. PIASy不影響mLRH-1於細胞核中的分布情形 ………................. 19 7. PIASy與mLRH-1有直接交互作用 ……………………................ 20 二、mLRH-1的特性 ……………………………………...................... 21 1. mLRH-1具有兩個nuclear localization signal (NLS) 分別位於 胺基酸序列117-168與169-193處 …….......................…........ 21 2. mLRH-1經由蛋白酶體 (proteasome) 降解 (degradation) ……...... 21 第四章、討論 ………….............................................................................. 23 一、PIASy抑制mLRH-1轉錄活性機制 ……………………............... 23 二、mLRH-1的NLS ….………………………………………............. 25 三、mLRH-1的AF-2 ……………………………………………… ... 26 四、mLRH-1的降解機制 ……………………………………............. 27 參考文獻 ....................….…......................................................................... 29 圖 .................................................................................................................. 38 | |
| dc.language.iso | zh-TW | |
| dc.subject | 肝受體同源體-1 | zh_TW |
| dc.subject | PIASy | en |
| dc.subject | LRH-1 | en |
| dc.title | LRH-1特性及其轉錄活性受PIASy調控之探討 | zh_TW |
| dc.title | Characterization of LRH-1 and its regulation of transcriptional activity by PIASy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 張淑芬(Shwu-Fen Chang),郭應誠(Ing-Cherng Guo),吳鈺琳(Yuh-Lin Wu) | |
| dc.subject.keyword | 肝受體同源體-1, | zh_TW |
| dc.subject.keyword | LRH-1,PIASy, | en |
| dc.relation.page | 50 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-05-08 | |
| 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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