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研究生:王志宏
研究生(外文):Chih-Hung Wang
論文名稱:mLRH-1結構功能之探討:PIASy作用區、Hinge結構區及核定位訊號
論文名稱(外文):Structure-function relationship of mLRH-1 : PIASy interaction region, hinge and NLS domains
指導教授:胡孟君胡孟君引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:55
中文關鍵詞:抑制機制基因調控核定位訊號交互作用
外文關鍵詞:LRH-1PIASyinteractionNLS
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肝受器同源體-1 (Liver receptor homolog-1 ; LRH-1) 為核受器 NR5A 家族的成員之一,由於目前仍然未發現其配體,因此稱之為孤兒核受器。LRH-1 主要表現於肝腸組織與卵巢。已知 LRH-1 具有調控類固醇生成基因的能力,本實驗室先前已證實 mLRH-1 可以促進類固醇生成基因 CYP11A1 啟動子的轉錄活性,並發現此作用明顯地會被 PIASy 所抑制,本論文即探討 PIASy 抑制mLRH-1 轉錄活性的分子機制。為了找出 mLRH-1 與 PIASy 交互作用區域,我們建構了不同片段的 Gal4-mLRH-1以及 VP16-PIASy 融合蛋白,並利用哺乳類雙雜交系統進行分析。結果發現 mLRH-1 是利用 C 端胺基酸 193-560 與 PIASy 作用;而PIASy 則是利用 C 端胺基酸 331-510 片段與 mLRH-1 作用。已知蛋白分子可能會藉由干擾輔活化因子與轉錄因子的交互作用而達到抑制轉錄因子的效應。為了了解 PIASy 是否經由這種機制影響 mLRH-1 對CYP11A1 啟動子的轉錄作用,我們取了 LRH-1 的輔活化因子 SRC-1 與 β-catenin,以及與 PIASy 有交互作用的 TBP 蛋白作測試。結果發現只有 SRC-1 可部分回復 PIASy 對 mLRH-1 的抑制作用,因而推論 PIASy 可能會干擾 SRC-1 與 mLRH-1 的結合而影響 mLRH-1 的轉錄能力。此外,我們還發現 β-catenin 與 TBP 本身都會抑制 mLRH-1 對CYP11A1啟動子的轉錄能力。
本實驗室先前研究指出 mLRH-1 有兩段胺基酸序列 (117-168及169-193) 具有 NLS (Nuclear localization signal) 的特性,可將 GFP 綠色螢光蛋白引導至細胞核中。當我們將此兩片段分別從mLRH-1上剔除後進行免疫螢光染色分析,結果顯示刪除任何一片段,其在細胞中的分布與全長 mLRH-1 相似,只存在於細胞核中。若同時將這兩片段剔除後,mLRH-1則會均勻分散至細胞質與細胞核中。這說明 mLRH-1 具有兩個 NLS 片段,只要有一個 NLS即可使 mLRH-1 專一表現於細胞核中。
Liver receptor homolog-1 (LRH-1) is a transcription factor and belongs to nuclear receptor 5A subfamily. LRH-1 is mainly expressed in liver、intestine and in ovary. LRH-1 has been shown to enhance the tanscriptional activity of several steriodogenic promoters including CYP11A1. Our previous studies indicated that PIASy markedly inhibited the mLRH-1-stimulated activity of the human CYP11A1 promoter. This study investigates the molecular mechanism of the expression of PIASy on mLRH-1-mediated transcription. A series of fusion proteins of Gal4-mLRH-1 and VP16-PIASy were constructed. Mammalian two-hybrid assay demostrates the protein-protein interaction between mLRH-1 and PIASy. In addition, the C-terminal residues 193-560 of mLRH-1 and C-terminal of PIASy are invovled in this interaction. We futher tested whether PIASy inhibits mLRH-1 transactivity by interfering the interaction between mLRH-1 and coactivators. We found that SRC-1 can partially rescued the PIASy inhibition of mLRH-1 transactivity. Furthermore, mammalian two-hybrid assay recealed that PIASy reduced the interaction between mLRH-1 and SRC-1.It suggests that PIASy may function as a repressor of mLRH-1 by interfering the action of SRC-1. In addition, we found that both β-catenin and TBP can inhibit the mLRH-1 sitimulated CYP11A1 promoter activity.

Our previous studied indicated that the DNA binding domain of mLRH-1 may contain two nuclear localization signaling peptides (117-168 and 169-193). In this study, we examined the location of mutated by immunocytochemistry. Deletion of residues 116-169 or 169-193 has no effect on nuclear localization of mLRH-1. However, removal of residues 116-193 results in a evenly distribution of mLRH-1 in nucleus and cytoplasm. It suggested that either 116-169 or 169-193 is sufficient for nuclear localization of mLRH-1.
圖次 VI
中文摘要 VII
英文摘要 VIII
第一章 序論 1
一、LRH-1 之簡介 1
1. LRH-1 在生理上的功能 1
2. LRH-1 之結構 2
3. LRH-1 的輔調控因子 2
a. LRH-1 的輔活化子 (coactivator) 3
b. LRH-1 的輔抑制子 (corepressor) 3
4. LRH-1的轉錄後修飾作用 4
二、PIASy 的簡介 5
1. PIASy 的結構 5
2. PIASy 為一種輔調控因子 6
三、核定位訊號 (Nuclear-localization signal ; NLS) 7
四、研究動機 8
第二章 材料與方法 10
一、細胞培養 10
二、質體建構 10
三、暫時性轉染法 (Transient transfection) 16
四、Luciferase 活性測定 16
五、西方墨點法 (Western blotting) 17
六、細胞免疫螢光染色法 (Immunocytochemistry) 18
七、DAPI染色法 18
八、反轉錄-聚合酶鏈鎖反應 18
九、免疫沉澱法 (Immunoprecipitation) 19
第三章 結果 21
一、 mLRH-1 與 PIASy 在細胞內具有交互作用 21
1. PIASy與mLRH-1交互作用的區域 21
2. mLRH-1與PIASy交互作用的區域 22
3. mLRH-1 與 PIASy 形成蛋白質複合體 22
二、 mLRH-1 的轉錄活性受 PIASy 抑制之機制探討 23
1. PIASy 抑制 mLRH-1 的轉錄機制是否與TBP有關? 23
2. PIASy 抑制 mLRH-1 的轉錄機制是否與 β-catenin 有關? 24
3. PIASy 抑制 mLRH-1 的轉錄機制是否與 SRC-1 有關? 25
三、 Hinge region 對於 mLRH-1 本身轉錄活性之特性探討 26
1. mLRH-1 的 hinge region 可能具有 repression domain 26
2. Hinge region 去除會增加 mLRH-1 蛋白質的表現量 26
3. Hinge region 去除後無法有效提升 mLRH-1 對於CYP11A1 驅動子的轉錄活性 27
四、 mLRH-1 的 DBD 含有兩個潛在的 NLS 片段 27
第四章 討論 29
一、PIASy 與 mLRH-1 的交互作用 29
二、PIASy 抑制 mLRH-1 轉錄活性之機制 30
三、Hinge region 在調控 mLRH-1 轉錄活性上所扮演的角色 31
四、mLRH-1 的 NLS 32
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