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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蔡明道(Ming-Daw Tsai) | |
| dc.contributor.author | Chia-Chi Huang | en |
| dc.contributor.author | 黃家琦 | zh_TW |
| dc.date.accessioned | 2021-05-17T09:15:09Z | - |
| dc.date.available | 2017-08-16 | |
| dc.date.available | 2021-05-17T09:15:09Z | - |
| dc.date.copyright | 2012-08-16 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-08-13 | |
| dc.identifier.citation | 1. Adhikari, A., M. Xu, and Z. J. Chen. 2007. Ubiquitin-mediated activation of TAK1 and IKK. Oncogene 26:3214-26.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/6603 | - |
| dc.description.abstract | FHA (forkhead-associated) 是一種新發現的結構域，它可以專一性地結合磷酸化蘇氨酸，並藉此調控細胞內許多重要的機制。TIFA是所有已知人類蛋白質包含FHA結構域中最小的一個。先前的文獻已經發現在細胞中大量表現外源性TIFA會激活轉錄因子NF-kappaB，不過TIFA如何參與並調控這訊息傳導仍需要更深入的探討。在此研究中, 我們在TIFA上發現了一個蘇氨酸(第九個氨基酸)有被磷酸化修飾，並證實這個磷酸化蘇氨酸會與TIFA的FHA結構域結合。此交互作用會促進TIFA蛋白質間的聚合並激活下游的NF-kappaB。生化分析的結果顯示在緩衝溶液中，未磷酸化的TIFA是以二聚體的形式存在著，意味著TIFA FHA結構域和第九磷酸化蘇氨酸(pT9)間的結合是TIFA二聚體與二聚體間的交互作用。此外，我們也發現抑制內源性TIFA會削弱細胞激素TNF-alpha引發的訊息傳遞及其功能。根據這些結果，我們認為TIFA FHA-pT9的交互作用是TNF-alpha刺激後活化NF-kappaB傳導途徑中未知的新環節，而此TIFA二聚體分子間藉由FHA-pT9結合形成聚合體的機制，將是FHA結構域研究中另一個全新的範例。 | zh_TW |
| dc.description.abstract | The forkhead-associated (FHA) domain recognizes phosphothreonine (pT) with high specificity and functional diversity. TIFA (TRAF-interacting protein with a FHA domain) is the smallest FHA-containing human protein. Its over-expression was previously suggested to provoke NF-kappaB activation, yet its exact roles in this signaling pathway and the underlying molecular mechanism remain unclear. Here we identify a novel phosphorylated threonine site, threonine 9 (pT9), on TIFA and show that this phosphorylation site binds with the FHA domain of TIFA, leading to TIFA oligomerization and TIFA-mediated NF-kappaB activation. Detailed analysis indicated that unphosphorylated TIFA exists as an intrinsic dimer, and that the FHA-pT9 binding occurs between different dimers of TIFA. In addition, silencing of endogenous TIFA resulted in attenuation of TNF-alpha-mediated downstream signaling. We therefore propose that the TIFA FHA-pT9 binding provides a previously unidentified link between TNF-alpha stimulation and NF-kappaB activation. The intermolecular FHA-pT9 binding between dimers also represents a new mechanism for the FHA domain. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-17T09:15:09Z (GMT). No. of bitstreams: 1 ntu-101-D94b46017-1.pdf: 9992558 bytes, checksum: 0bc4b03f68181dc730ddef26ad5c3d09 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | Table of Contents
口試委員會審定書.................................................................................i ACKNOWLEDGEMENT........................................................................ii 中文摘要.............................................................................................iv ENGLISH ABSTRACT...........................................................................v TABLE OF CONTENTS........................................................................vi FIGURE LIST......................................................................................viii TABLE LIST........................................................................................xi Chapter 1. INTRODUCTION ..................................................................1 1.1 FHA domain...................................................................................1 1.1.1 Conserved folding.........................................................................1 1.1.2 Ligand specificity..........................................................................2 1.1.3 Mechanisms of FHA function.........................................................3 1.2 TRAF-interacting protein with a FHA domain (TIFA)............................5 1.3 TNF receptor associated factors (TRAFs)..........................................7 1.4 TNF-alpha-mediated NF-kappaB activation.......................................10 1.5 Inflammatory signaling....................................................................11 1.6 Other proteins relevant to TIFA........................................................14 1.7 Significances................................................................................15 Chapter 2. RESULTS..........................................................................18 2.1 Identification of phosphorylation at Thr9 on TIFA...............................18 2.2 Phosphorylation status of pT9........................................................18 2.3 Search for potential kinase.............................................................20 2.4 Interaction of TIFA-FHA and TIFA-pT9..............................................21 2.5 Expression and purification of recombinant TIFA…………..................23 2.6 Recombinant TIFA exists as intrinsic dimer in solution….….….…......25 2.7 Crystallization of recombinant TIFA..................................................26 2.8 Oligomerization status of native TIFA...............................................30 2.9 TIFA-mediated activation of NF-kappa..............................................32 2.10 Extracellular stimulation augments TIFA protein amount..................33 2.11 Silencing of endogenous TIFA........................................................35 2.12 Interaction of TIFA and TRAF2.......................................................35 Chapter 3. DISCUSSION AND CONCLUDING REMARKS.......................39 Chapter 4. MATERIAL AND METHODS ................................................48 Chapter 5. FIGURES...........................................................................58 Chapter 6. TABLES............................................................................103 Chapter 7. REFERENCES..................................................................113 APPENDIX..........................................................................................xii Appendix I. List of Supplementary Figures.............................................xii Appendix II. List of Abbreviations..........................................................xiii | |
| dc.language.iso | en | |
| dc.title | TIFA磷酸蘇氨酸與其FHA結構域分子間交互作用與活化NF-kappaB的機制 | zh_TW |
| dc.title | Intermolecular binding between TIFA-FHA & TIFA-pT9 mediates TNF-alpha stimulation & NF-kappaB activation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王惠鈞(Andrew H.-J. Wang),梁博煌(Po-Huang Liang),陳光超(Guang-Chao Chen),何孟樵(Meng-Chiao Ho) | |
| dc.subject.keyword | FHA結構域,轉錄因子NF-kappaB,磷酸化蘇氨酸,TIFA,細胞激素TNF-alpha傳遞訊號機制, | zh_TW |
| dc.subject.keyword | FHA domain,NF-kappaB,phosphothreonine,TIFA,TNF-alpha-mediated signaling, | en |
| dc.relation.page | 150 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2012-08-13 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-101-1.pdf | 9.76 MB | Adobe PDF | 檢視/開啟 |
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