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博碩士論文 etd-0421115-100738 詳細資訊
Title page for etd-0421115-100738
論文名稱
Title
Gfi1 蛋白相撲化位置之研究
Investigation of the SUMOylation sites of Gfi1
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
119
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2015-06-08
繳交日期
Date of Submission
2015-08-19
關鍵字
Keywords
共位、相撲蛋白交互作用區域、試管內相撲化反應、相撲蛋白、生長因子非依賴性蛋白1
SIM, Colocalization, In vitro SUMOylation, SUMO, Gfi1
統計
Statistics
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中文摘要
轉錄抑制因子「生長因子非依賴性蛋白1」(Gfi1) 調節許多生物功能,例如顆粒球的生長、 T 細胞的分化,依賴巨噬細胞細胞素的產生,及內耳毛細胞的發育。此蛋白的 C 端含有六個 C2H2 型鋅手指 (zinc-finger),它的 N 端含有一段 20 個胺基酸,稱為 SNAG 的區域。Gfi1 C 端 C2H2 型鋅手指的存在使它成為一個可結合 DNA 的轉錄因子。Gfi1 上的第三、四、五個鋅手指可結合至重要的 DNA 保留性辨識序列 taAATCac(t/a)gca 上。另外,第一、二、六個鋅手指為此蛋白與其他蛋白質相互結合區域。相撲蛋白 (小的泛素相關修飾蛋白,SUMO) 有許多生物功能,包括對轉錄因子的調控。透過生物資訊方法的分析,我們發現 Gfi1 蛋白質序列上有四個重要位置含有相撲蛋白進行修飾 (相撲化反應SUMOylation) 的保留序列 (ΨKXE)。因此本研究便對 Gfi1 蛋白質上的相撲蛋白修飾位置進行探討。透過對保留序列的突變以及試管內相撲化反應來辨識 Gfi1 蛋白上相撲蛋白修飾的位置;並以螢光顯微鏡分析 Gfi1 蛋白和 SUMO 蛋白是否出現於細胞中的相同位置來探討它們間的相互作用。結果顯示,部份的Gfi1 蛋白和 SUMO 蛋白會共同出現於細胞中的相同位置,且 Gfi1 為 SUMO 修飾的目標蛋白。
Abstract
The transcriptional repressor Growth Factor Independence 1 (Gfi1) regulates many biological functions, such as development of granulocytes, T-cell differentiation, macrophage-dependent cytokine production and the development of inner ear hair cells. It contains six C-terminal C2H2-type zinc-finger domains and a characteristic stretch of 20 amino acids, called the SNAG-domain, at its N-terminus. The presence of C2H2 zinc fingers suggested a function for Gfi1 as a DNA binding transcription factor. Zinc fingers 3–5 of Gfi1 are necessary for binding to its cognate consensus DNA recognition sequence taAATCac(t/a)gca, and zinc fingers 1, 2 and 6 have a role in interaction with other proteins. The small ubiquitin-related modifier (SUMO) has many roles in cellular biology including regulation of transcription factors. We found that there are four major SUMOylation predicted sites (ΨKXE) in Gfi-1 protein analyzed with bioinformatics. The SUMOylation site of the Gfi-1 protein was therefore investigated in the present studies. To identify the SUMOylation sites of Gfi1, mutants were used in in vitro SUMOylation assay. Fluorescence microscopy assay was used to investigate the interaction between Gfi1 and SUMO. Results suggest that Gfi1 and SUMO are colocalized partially and Gfi1 is a target protein for SUMO modification.
目次 Table of Contents
論文審定書...........................................i
論文公開授權書....................................ii
誌謝....................................................iii
摘要....................................................iv
Abstract..............................................v
縮寫表.................................................vi
壹、緒論..............................................1
一、Growth factor independence 1.........1
1.1 Gfi1 及同源蛋白質結構..................2
1.2 Gfi1/Senseless/Pag-3 ...................3
1.3 Gfi1 之活化表現 ...........................3
1.4 Gfi1 之生理功能 ...........................4
1.5 Gfi1 目標......................................5
1.6 Gfi1 調節顆粒性細胞......................5
1.7 Gfi1 調節 T 細胞生長、活化以及分化...........6
1.8 Gfi1 調節 B 細胞生長、活化以及分化...........6
1.9 Gfi1 之臨床診斷 ........................................8
二、 Small ubiquitin-related modifiers, SUMOs....9
2.1 SUMO......................................................9
2.2 SUMO 同型體及結構..................................9
2.3 SUMOylation..............................................10
2.4 調控蛋白質運輸..........................................13
2.5 調控核體組成.............................................13
2.6 調控粒線體分裂...........................................14
2.7 調節轉錄因子..............................................14
2.8 抑制 ubiquitin 降解.......................................14
2.9 調控細胞循環...............................................15
2.10 SUMO interacting Motifs...............................16
貳、研究目的........................................................18
參、實驗方法與材料...............................................20
一、 E.coli expression plasmids製備.......................20
二、 PCR 反應......................................................20
三、 DNA Cloning..................................................22
四、 Site-Directed Mutagenesis..............................26
五、 PCR overlapping extension mutagenesis.........29
六、 蛋白質表現、純化及保存................................30
七、 In vitro SUMOylation assay............................35
八、 蛋白質電泳與西方墨點法................................36
九、 細胞培養.......................................................40
十、 基因轉殖 (tranfection).....................................42
十一、免疫細胞化學法 (Immunocytochemistry, ICC) 44
十二、His pull down assay.....................................46
肆、結果...............................................................48
一、 試管中 Gfi1 蛋白的 SUMOylation (In vitro SUMOylation of Gfi1 protein)..48
二、 細胞中 Gfi1 蛋白與 SUMO 蛋白的相互作用 (In vivo interation between Gfi1 and SUMOs)....................................................................................................56
三、 Gfi1 蛋白 SUMOylation site 之辨識 (Identification of the Gfi1 SUMOylation site) ................................................................................................................60
四、 試管中 Gfi1 蛋白之 Pull down asssy (In vitro Pull down assay of Gfi1 protein).66
伍、討論...................................................................................................68
陸、未來工作.............................................................................................71
柒、參考文獻.............................................................................................72
捌、附錄....................................................................................................81
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