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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 繆希椿 | |
| dc.contributor.author | Chen-Yen Lai | en |
| dc.contributor.author | 賴正晏 | zh_TW |
| dc.date.accessioned | 2021-06-16T23:39:40Z | - |
| dc.date.available | 2017-09-18 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-25 | |
| dc.identifier.citation | Anderson,M.S. and Bluestone,J.A. (2005). The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23, 447-485.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65380 | - |
| dc.description.abstract | Maf家族蛋白質參與多種重要的生物反應，包括腫瘤生成過程和水晶體發育及分化。在Maf家族蛋白質的成員之c-Maf在免疫系統中扮演多樣又重要的角色。它被發現能轉錄活化介白質四的表現，而在初代T細胞中異位過度表現c-Maf會使T細胞趨往分化為第二型輔助性T細胞。然而我們對於c-Maf的轉譯後修飾研究所知甚少。而本研究首次發現在第二型輔助性T細胞中，c-Maf能分別在第21號、第92號、第131號酪胺酸位置被磷酸化。另外我們的研究顯示在這三個位置磷酸化對於c-Maf結合到介白質四的啟動子進而促使第二型輔助性T細胞分泌介白質四是重要的。我們使用第一型糖尿病的模式動物NOD小鼠做活體外分化第二型輔助性T細胞實驗，結果顯示NOD小鼠中第二型輔助性T細胞的c-Maf酪胺酸磷酸化程度與介白質四基因的表現成正相關，而與NOD小鼠發病嚴重程度成負相關。此外，對於能將c-Maf進行酪胺酸磷酸化的激脢研究有更進一步的探討。總結來說，本研究釐清c-Maf的酪胺酸磷酸化修飾現象以及此修飾對於介白質四基因的影響。 | zh_TW |
| dc.description.abstract | Maf proteins are involved in a variety of biological processes such as oncogenesis, lens development and differentiation. One of Maf protein family members, c-Maf, plays central and diverse roles in immune system. It was found that c-Maf transactivates IL-4 promoter, and ectopic expression of c-Maf skews primary T cell response towards the TH2 pathway. However, the modulation of c-Maf activity through post-translation modification remains unclear. Here, we show for the first time that c-Maf undergoes tyrosine phosphorylation at Tyr21, Tyr92 and Tyr131 residues in TH2 cells. Furthermore, tyrosine phosphorylation at these three residues is critical for the recruitment of c-Maf to IL-4 promoter and IL-4 production in TH2 cells. Importantly, the level of c-Maf tyrosine phosphorylation positively correlates with IL-4 expression by skewed TH2 cells and its level negatively associates with the severity of disease in NOD mice. The possible kinases responsible for phosphorylating c-Maf is further investigated. Taken together, this study sheds new light on the modification of c-Maf by tyrosine phosphorylation and its effect on downstream gene target Il4 | en |
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| dc.description.tableofcontents | Tables of contents
中文摘要 ii Abstract iii Chapter I Introduction 1 1.1 The differentiation of T helper cells 1 1.1.1 TH1 differentiation 1 1.1.2 TH2 differentiation 2 1.1.3 TH17 differentiation 3 1.2 The function of c-Maf 5 1.2.1 The overview of Maf family 5 1.2.2 The diverse function of c-Maf 6 1.3 An overview of kinase and phosphatase in immune cells 7 1.3.1 Phosphorylation by PTK in immune cell responses 7 1.3.2 Dephosphorylation by PTP 10 1.4 The versatile role of tyrosine-phosphorylated proteins in immune cells 13 1.5 The role of post-translational modification in Maf family 14 1.6 Rationale and significance 15 Chapter II Materials and Methods 16 2.1 Materials 16 2.1.1 Mice 16 2.1.2 Cells 16 2.1.3 Antibodies 16 2.1.4 Primers 17 2.2 Methods 18 2.2.1 Generation of c-Maf mutants 18 2.2.2 Cell transfection 18 2.2.3 Immunoprecipitation and Western Blotting 19 2.2.4 Luciferase assay 20 2.2.5 In vitro TH cells differentiation 20 2.2.6 Quantitative real-time PCR 21 2.2.7 Retrovirus infection 21 2.2.8 Measurement of IL-4 production in primary T cells 22 2.2.9 Confocal microscopy 22 2.2.10 CIP alkaline phosphatase treatment 23 2.2.11 Preparation of recombinant GST c-Maf 23 2.2.12 In vitro kinase assay 23 2.2.13 Cytosolic and nuclear extract separation 24 2.2.14 EMSA 24 2.2.15 CFSE proliferation assay 25 Chapter III Results 26 3.1 Tyrosine residues of c-Maf can be phosphorylated in TH2 clone and primary TH2 cells. 26 3.2 The dominant tyrosine residues of c-Maf for phosphorylation are located at Tyr21, Tyr92 and Tyr131. 27 3.3 Optimal c-Maf-dependent IL-4 expression requires tyrosine phosphorylation at Tyr21/92/131 29 3.4 The subcellular localization of c-Maf is not affected by its tyrosine phosphorylation status 30 3.5 Tyrosine phosphorylation of c-Maf facilitates its binding to IL-4 promoter 31 3.6 The level of tyrosine phosphorylation of c-Maf correlates positively with IL-4 production but negatively with disease activity in NOD mice 31 3.7 The degree of proliferation and differentiation in TH2 cells from NOD mice that had developed glycosuria and age-matched healthy NOD mice are comparable. 33 3.8 The putative tyrosine kinase for phosphorylating c-Maf 34 3.9 The IL-4 transactivity is enhanced by kinase induced-phospho-c-Maf 36 Chapter IV Discussion 38 4.1 TH2 specific transcription factor, c-Maf, is phosphorylated at multiple tyrosine residues. 38 4.2 The IL-4 transactivity of c-Maf is regulated by phosphorylation and SUMOylation. 40 4.3 One of tyrosine kinases that can phosphorylate c-Maf 41 4.4 Negative correlation between the level of c-Maf phosphorylation and severity of diabetes in NOD mice 44 Figures and Tables 46 References 90 Appendix 100 | |
| dc.language.iso | en | |
| dc.subject | 介白質四 | zh_TW |
| dc.subject | 輔助型T細胞 | zh_TW |
| dc.subject | 酪胺酸磷酸化 | zh_TW |
| dc.subject | 介白素四 | zh_TW |
| dc.subject | c-Maf | en |
| dc.subject | tyrosine phosphorylation | en |
| dc.subject | IL-4 | en |
| dc.subject | Th2 | en |
| dc.title | 酪胺酸磷酸化修飾之c-Maf強化轉錄介白質四的生成 | zh_TW |
| dc.title | Tyrosine phosphorylation of c-Maf enhances the expression of IL-4 gene | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 賴明宗,司徒惠康,張智芬,顏裕庭 | |
| dc.subject.keyword | 酪胺酸磷酸化,介白質四,介白素四,輔助型T細胞, | zh_TW |
| dc.subject.keyword | c-Maf,tyrosine phosphorylation,IL-4,Th2, | en |
| dc.relation.page | 100 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-101-1.pdf 未授權公開取用 | 1.49 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。