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研究生:陳泓志
研究生(外文):Hung-Chih Chen
論文名稱:決定金屬感應轉錄因子進核作用之因子的研究
論文名稱(外文):study on the factors determining nuclear translocation of metal-responsive transcription factor-1
指導教授:林立元林立元引用關係
指導教授(外文):Lih-Yuan Lin
學位類別:碩士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:99
中文關鍵詞:金屬感應轉錄因子鋅指區域進核作用進核信號
外文關鍵詞:MTF-1metal-responsive transcription factor-1zinc fingernuclear translocationimportin alphaNLS
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金屬感應轉錄因子為具六個C2H2類型鋅指結構之轉錄因子,它能調控金屬硫蛋白基因基礎表現以及受金屬刺激後之表現。目前已知若干逆境,如鋅離子,會促使金屬感應轉錄因子進入細胞核中而執行其功能,然引導其進核之進核信號與進核機制尚未明朗。在我們的實驗中,將不同金屬感應轉錄因子片段與綠螢光蛋白形成融合蛋白,並利用螢光顯微鏡觀察各片段於細胞內分佈之情形。金屬感應轉錄因子六個鋅指結構具有受鋅離子誘導進入細胞核之能力,其中單獨第四個鋅指結構便能進入細胞核中。利用GST pull-down assay,我們發現金屬感應轉錄因子能與各類型的importin α結合,且單獨第三或第四個鋅指結構便可和α1結合。此外,我們證實金屬感應轉錄因子第四個鋅指結構內,仳鄰構成鋅指結構之第一個組氨酸的兩個鹼性胺基酸殘基不但會影響金屬感應轉錄因子進核的作用,同時也影響其與importin α之結合能力。我們另外將金屬感應轉錄因子前端之典型進核信號與六個鋅指結構形成融合蛋白,並發現此融合蛋白進入細胞核之能力遠勝於單獨六個鋅指結構者。綜觀上述,我們推測調控金屬感應轉錄因子受鋅離子刺激進入細胞核之進核信號位於鋅指結構內,尤以第四個鋅指結構為要,其前端之典型進核信號能夠加強金屬感應轉錄因子進核之能力;且金屬感應轉錄因子之進核需要importin α協助才能完成。
Metal responsive transcription factor 1 (MTF-1) is a transcription factor that contains six C2H2 zinc fingers, and is essential for the basal and zinc-inducing expression of metallothionein. It was shown previously that the nuclear entry of MTF-1 could be induced by zinc. However, the region serving as nuclear localization signal (NLS) and nuclear import mechanism remain unclear. Here we generated a series of eGFP-tagged deletion mutants of MTF-1 and investigated the subcellular localization of these fusion proteins by fluorescence microscopy. We found that zinc finger domain of MTF-1 might contain an NLS. Using GST pull-down assay, we were able to demonstrate that MTF-1 binds to a variety of importin α families. Further analysis of the individual zinc finger showed that only zinc finger 3 and 4 bound importin α1. We also found that R246 and K247 adjacent to the first constituent His of MTF-1 zinc finger 4 are crucial for the nuclear transport of MTF-1 since mutation of these sites impaired the function of nuclear translocation of MTF-1 and its binding ability to importin α1. Furthermore, fusion protein of 6 zinc fingers with the classical NLS ahead of the zinc finger showed a better nuclear import than 6 zinc fingers alone. Overall, our results indicate that nuclear entry of MTF-1 after zinc induction is mediated by the NLS within the zinc finger domain. Among which, zinc finger 4 plays the most important role. Besides, the classical NLS adjacent to zinc finger domain enhances the nuclear translocation. Presence of either importin family is required for the translocation of MTF-1.
目錄
摘要 i
Abstract ii
謝誌 iii
目錄 iv
圖表目錄 v
緒論 1
材料與方法 10
一、化學藥品及製備: 10
二、細胞培養: 10
三、大腸桿菌勝任細胞(Competent cells)製備: 11
四、轉型作用(Transformation): 11
五、質體構築: 12
六、轉殖作用 (Transfection): 13
七、螢光顯微鏡觀察: 15
八、In vitro nuclear import assay: 15
九、蛋白質表現及純化(Recombinant expression and purification): 17
十、蛋白質萃取: 18
十一、蛋白質的定量: 19
十二、GST pull-down assay: 20
十三、SDS-聚丙烯醯氨凝膠電泳 (SDS-PAGE): 20
結果 23
一、尋找MTF-1具有核定位訊號之區域: 23
二、尋找協助MTF-1進核之importin以及MTF-1和importin相結合之區域: 25
三、找出MTF-1 ZF1-6片段內所具有之NLS: 29
四、MTF-1 ZF4內之胺基酸序列影響MTF-1進核能力: 31
五、MTF-1具有Bipartite NLS: 34
討論 36
參考文獻 47
附表 56
附圖 58
附錄 96




圖表目錄
表一、選殖全長或片段MTF-1所使用之引子。 56
表二、定點突變所所使用之引子。 57
附圖 58
圖一、構築全長與片段MTF-1-eGFP融合蛋白。 58
圖二、原生株與classical NLS突變之全長MTF-1受鋅誘導後之細胞分佈。 59
圖三、FL MTF-1-eGFP與MTF-1 NLS-mut-eGFP融合蛋白受鋅誘導後之細胞分佈。 61
圖四、ATG-NLS-eGFP、ZF1-6-eGFP與After ZF-eGFP融合蛋白受鋅誘導後之細胞分佈。 64
圖五、FL MTF-1與importinα結合所需要之importinα量。 65
圖六、全長MTF-1與eGFP和不同importinα間之結合情況。 66
圖七、全長MTF-1加鋅處理後與不同importinα之結合情形。 67
圖八、利用In vitro nuclear transport assay觀察MTF-1與不同importinα間結合之狀況。 68
圖九、利用in vitro nuclear transport觀察MTF-1在不同刺激下進核之情形。 69
圖十、比較MTF-1 ATG-NLS、ZF1-6與After ZF等三個片段與importinα間之結合情況。 70
圖十一、MTF-1 ZF1-6-eGFP加鋅處理後與不同importinα之結合情形。 71
圖十二、比較MTF-1 ZF1-3與ZF4-6等片段與importinα間之結合情況。 72
圖十三、ZF1-6-eGFP、ZF1-3-eGFP與ZF4-6-eGFP融合蛋白受鋅誘導後之細胞分佈。 75
圖十四、ZF1-2-eGFP、ZF3-4-eGFP與ZF5-6-eGFP融合蛋白受鋅誘導後之細胞分佈。 78
圖十五、ZF1-2-eGFP、ZF3-4-eGFP與ZF5-6-eGFP融合蛋白受鋅誘導後之細胞分佈。 80
圖十六、比較MTF-1 ZF1-2、ZF3-4、ZF5-6、ZF3與ZF4等片段與importinα間之結合情況。 81
圖十七、比對MTF-1 zinc finger區域之氨基酸序列。 82
圖十八、ZF1-6-eGFP、ZF1-6 R246A-eGFP、ZF1-6 K247A-eGFP與ZF1-6 RK246AA-eGFP融合蛋白受鋅誘導後之細胞分佈。 85
圖十九、比較MTF-1 ZF1-6、ZF1-6 R246A、ZF1-6 K247A與ZF1-6 RK246AA等片段與importinα間之結合情況。 86
圖二十、ZF1-6-eGFP、ZF1-6 RK246AA-eGFP與ZF1-4 H252A-eGFP融合蛋白受鋅誘導後之細胞分佈。 89
圖二十一、全長MTF-1Z-eGFP、ZF1-6 -eGFP與NLS-ZF6-eGFP融合蛋白受鋅誘導後之細胞分佈。 92
圖二十二、全長MTF-1-eGFP、MTF-1 NLS-mut-eGFP 、MTF-1 RK246AA-eGFP與MTF-1 NLS dm-eGFP融合蛋白受鋅誘導後之細胞分佈。 95
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