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系統識別號 U0026-0908201012381100
論文名稱(中文) 利用QNanoPX的方法結合蛋白質體學及生物資訊來解析與雌激素接受器應答序列相關的轉錄複合體
論文名稱(英文) Proteomics and Bioinformatic Analysis on the Transcriptional Complex of Estrogen Responsive Element using QNanoPX Approach
校院名稱 成功大學
系所名稱(中) 生物資訊研究所
系所名稱(英) Institute of Bioinformatics
學年度 98
學期 2
出版年 99
研究生(中文) 張翔凱
研究生(英文) Hsiang-Kai Chang
學號 z2697105
學位類別 碩士
語文別 英文
論文頁數 73頁
口試委員 指導教授-陳淑慧
口試委員-蔡美玲
口試委員-洪建中
口試委員-高宏宇
中文關鍵字 雌激素  雌激素接受器  雌激素接受器應答序列  金奈米粒子 
英文關鍵字 17β-estradiol  estrogen receptor  estrogen response element  AuNP 
學科別分類
中文摘要 在生理狀態下,雌激素主要透過與核內雌激素接受器(ER) α和β的結合進而去調控特定目標器官。在相關於雌激素基因訊息路徑,雌激素 17β-estradiol (E2) 可以活化游離的ER結合在雌激素接受器應答序列上,而此相似性極高序列為5’- GGTCAnnnTGACC - 3’ ,雌激素反應序列常出現於與雌激素相關反應基因的調控區雌激素接受器可藉由與雌激素接受器應答序列的結合調控其基因的表現。我們結合了生物資訊和訊息路徑進行分析由應用蛋白質複合體的定量奈米質譜學(QNanoPX)的雌激素接受器應答序列純化實驗所得的大量數據,分析結果顯示大部分會受到雌激素影響的蛋白都跟轉錄調控相關的,而且不只跟雌激素接受器相關,也跟另一轉錄因子c-Myc有相關,而這也指出在轉錄因子啟動區域中的應答序列之間是會相互影響的。而由西方點默法的數據指出在有E2的催化之下雌激素接受器α與c-Myc有著明確的相關性,而另一個雌激素接受器β卻沒有。為了減少兩個雌激素接受器帶來的複雜性,我們利用具有雌激素接受器 α專一性的催化劑 PPT去進行另一個結合蛋白質複合體的定量奈米質譜學的實驗。在系統性的研究下,PPT證實可以專一性的增加雌激素接受器α的表現但卻不會影響雌激素接受器β而且在3小時的PPT誘發下確實造成MCF-7細胞中雌激素接受器α最大量的轉移從細胞質移動到細胞核。我們遂以此結論並應用蛋白質複合體的定量奈米質譜學(QNanoPX)去鑑別雌激素接受器-雌激素接受器應答序列複合體中的構成要素以及在3小時PPT誘發下量的變化。在蛋白質體學的數據上顯示眾多目前清楚和不清楚的輔助啟動子像CBP/p300和CARM1都會出現在複合體中且它們的量都會因PPT誘發而增加。生物資訊分系上也顯示這些蛋白同時跟雌激素接受器α和c-Myc會有互相的作用。另外蛋白質體學的數據更顯示了輔助啟動子會比輔助抑制子的量更多存在雌激素接受器-雌激素接受器應答序列複合體中,而這也符合PPT能夠加強基因的轉錄是透過輔助啟動子補充的論據。在使用重組蛋白的實驗中,我們證實在雌激素接受器-雌激素接受器應答序列複合體中c-Myc能夠直接地結合雌激素接受器應答序列,讓雌激素接受器分子的表現增加,也由於雌激素接受器α分子的表現增加可以補充更多的c-Myc分子。因此我們提出一個假說c-Myc會包含在雌激素接受器-雌激素接受器應答序列複合體中而且能幫助補充更多能加強基因轉錄的輔助調節子。在未來,我們將利用更進一步的實驗顯示在雌激素轉錄的行為上c-Myc所扮演的功能性角色為何。
英文摘要 Physiological effects of estrogens are mediated by nuclear estrogen receptor (ER) α and β present in target organs. In genomics pathway, the 17β-estradiol (E2)-activated ER binds to estrogen responsive element (ERE), which is often found clustered as multiple copies of the consensus 5’- GGTCAnnnTGACC - 3’or related nonconsensus sequences along with binding sites for other transcription factors in the regulatory regions of responsive genes. Based on a combination of bioinformatic and pathway analysis on a large scale proteomics data of ERE pull down experiments using quantitative nanoproteomics for protein complex (QNanoPX) approach, most of the E2-affected proteins were found to be the transcriptional regulation of not only ER, but also c-Myc, indicating cross-interactions among transcription factors in the promoter region of the responsive element. Western blotting data indicated that the E2-induced expression pattern of c-Myc is positively correlated with ER but not ER. To minimize the complication of two isoforms, we conducted another QNanoPX experiment using ER specific agonist, 4-Propyl-[1H]-Pyrazole-1, 3, 5-triyl Trisphenol (PPT), for the treatment. Based on systematic studies, PPT (10‐6 M) was proved to specifically increase the expression of ER but not ER and 3-hour treatment was determined to cause the maxima translocation of ER from the cytosol to the nuclei of MCF-7 cells. We thus conducted QNanoPX experiment in identifying the components of ER-ERE complex and quantifying their change upon 3-hour PPT treatment. Proteomics data revealed many known and unknown co-activators such as CBP/p300 and CARM1 were involved in the complex and their amount was increased by PPT treatment. Bioinformatics analysis revealed most of these proteins could interact with both ER and c-Myc. Proteomics data also revealed that more co-activators were enriched in ER-ERE complex than co-repressors, consistent with the fact that PPT could enhance gene transcription by co-activator recruitment. Using recombinant proteins, we confirmed that c-Myc could directly bind to ERE and increasing ER molecules increases the recruited c-Myc molecules. Thus, we hypothesized that c-Myc is involved in ER-ERE complex and assists to recruit co-regulators in enhancing gene transcription. Further experiments will be conducted in the future to reveal the functional role of c-Myc in ER transcription action.

論文目次 Table of Contents
中文摘要 ………..…………………………………………………………………. Ⅰ
Abstract ……………………………………………………………………….. Ⅲ
誌謝 ............................................................................. Ⅴ
Table of Contents …………………………………………………………………Ⅵ
List of Figures ……………………….......................................................Ⅷ Abbreviations ……………………………………………………………Ⅹ

Chapter 1: Backgrounds and Introductions
1.Introduction of Estrogen Actions ………………………………………………….. 1
1.1 Estrogen signal transduction Pathways ……….…………………………………. 1
1.2 Estrogen Receptor and Estrogen ………………………………………………… 5
1.2.1 Structural fuctional domain of ER and ERβ……………………………….. 5
1.2.2 Ligand Binding Domain of Estrogen Receptor ………………………………... 6
1.2.3 DNA Binding Domain of Estrogen Receptor ………………………………….. 8
1.3 ER-ERE complex and transcription co-regulators ……………………………... 10

Chapter 2: Experimental Procedures
2.1 Materials ………………………………………………………………………... 14
2.2 Probe Fabrication ………………………………………………………………. 15
2.3 Cell Culture and Nuclear Extraction …………………………………………… 15
2.4 Affinity Purification Assay …………………………………………………….. 16
2.5 Western Blotting Analysis ……………………………………………………... 17
2.6 Trypsin Digestion and Dimethyl Labeling …………………………………….. 17
2.7 nanoLC/MS Analysis …………………………………………………………... 18
2.8 Bioinformatics ………………………………………………………………….. 19

Chapter 3: Results
3.1 E2 treatment in time course …………………………………………………….. 20
3.2 ER agonists and antagonists treatment …………………………………………. 23
3.3 QNanoPX Approach for large-scale proteomics ………………………………. 28
3.4 Bioinformatics Analysis of the ERE Protein Complex ………………………… 32

Chapter 4: Discussion
4.1 ERα and c‐Myc …………………………………………………………………. 35
4.2 ER-ERE complex and co-regulators …………………………………………… 36
4.3 LXXLL motif (NR-box) and estrogen action………………………………….. 37
4.4 Conclusions …………………………………………………………………….. 38

Acknowledgements …………….………………………………………39

References ……………………………………...…………………………………40

AppendixⅠ ……………………………………………………………………50

AppendixⅡ………………..………………………………………….…………51

Appendix Ⅲ ……………....…………………………………………………… 52

Appendix Ⅳ …..…………….…………..………………………………………53
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