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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李建國(Chien-Kuo Lee) | |
| dc.contributor.author | Hao-Kang Den | en |
| dc.contributor.author | 鄧皓亢 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:18:49Z | - |
| dc.date.copyright | 2010-09-09 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22482 | - |
| dc.description.abstract | 第一型干擾素是先天免疫對抗病毒感染時關鍵的細胞激素。而第一型干擾素的訊息傳導主要可以磷酸化 STAT1、STAT2、和 STAT3。磷酸化的 STAT1 與 STAT3 分別可以形成同質雙體與異質雙體，另外 STAT1、STAT2、與 IRF9 可以形成 ISGF3 複合物進而誘發下游基因的表現。STAT1 與 STAT3 同質雙體與異質雙體步有結合基因啓動子上 GAS 序列的能力,而 ISGF3 則俱有結合在 ISRE 的能力。透過分子生物學實驗已知 STAT1 與 STAT3 所結合的 GAS 序列大致相同，照理在干擾素的訊息傳導中 STAT1 與 STAT3 的角色應可以互換。利用基因剔除鼠的實驗發現 STAT1 剔除與 STAT3 剔除的表徵完全不同，暗示 STAT1 與 STAT3 可以分別誘發不同的基因。在之前的研究中我們已經證明 STAT3 可以調控 MDA5 ─個細胞內病毒感測器的表現,達到調控抗病毒反應的功能。在 ChIP 實驗中干擾素的刺激可在 STAT3 剔除細胞中使 ISFG3 結合到 MDA5 ISRE 的量增加，而補回 STAT3 的表現則抑制這種現象。這些證據暗示 STAT3 可以藉著影響轉錄複合物結合到起動子的方式來影響干擾素的反應。在此我們在 STAT1/STAT3 雙基因剔除的細胞株中利用反轉錄病毒感染的模式建立起下列四種細胞：STAT1 單獨表現、STAT3 單獨表現、STAT1/STAT3 雙基因表現，與空載體作為陰性對照組。藉由微陣列分析比較上述四種細胞經由干擾素刺激前後的基因表現模式,我們發現 STAT3 在調控基因表現中俱有獨特的角色。此外染色質免疫沉澱及基因序列分機證實 STAT3 可以結合在其目標基因啓動子上。功能性分析顯示 STAT3 藉由調控下游基因進而影響細胞遷移能力與抗病毒反應。本研究顯示 STAT3 在不依賴 STAT1 的條件下仍俱有獨立影響細胞功能─包含負調控抗病毒反應以及正調控細胞遷移的功能分析。 | zh_TW |
| dc.description.abstract | Type I IFN-stimulation leads to the phosphorylation of STAT1, STAT2, and STAT3. Activated STAT1 and STAT3 can form homodimer or heterodimer. Since STAT1 homodimer, STAT3 homodimer, and STAT1-STAT3 heterodimer can all bind to GAS elements in vitro, it is presumable that the role of STAT1 and STAT3, at least in the type I IFN signaling, is interchangeable. However, genetic studies using knockout mice have revealed that the phenotypes of STAT1KO and STAT3KO mice are very different, suggesting that STAT1 and STAT3 regulate distinct sets of target genes. We have previously shown that in the absence of STAT3, mouse embryonic fibroblasts (MEFs) displayed enhanced expression of ISGs and increased antiviral response upon IFN stimulation and EMCV infection. Here I reported that STAT3 negatively regulated antiviral responses and stimulated type I IFN-dependent STAT1-independent gene expression. First I showed that an enhanced expression of MDA5, an IFN-inducible, cytosolic viral RNA sensor, contributed to the enhanced antiviral response in STAT3KO MEFs. Chromatin immunoprecipitation (ChIP) assays revealed that increased recruitment of ISGF3 on ISRE of MDA5 promoter in STAT3KO MEF following IFN stimulation. Restoration of STAT3 effectively reduced the otherwise increased enrichment of these promoter, suggesting that STAT3 may regulate IFN-induced transactivation by altering the binding or recruitment of ISGF3. Second, by comparing the expression profiles between EV-, STAT1-, STAT3-, and STAT1/STAT3-double-restored MEFs lacking both STAT1 and STAT3, we were able to identify genes dependent on STAT1, STAT3, or both. Chip-seq analysis confirmed that STAT3 bound to the promoters of its target genes. Functional analysis revealed that, by inducing its target genes, STAT3-independently regulated cell migration and antiviral responses. Overall, our results show a negative role of STAT3 in regulating of antiviral responses and a unique role of STAT3 in mediating STAT1-independent gene expression in response to type I IFN. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:18:49Z (GMT). No. of bitstreams: 1 ntu-99-R97449005-1.pdf: 1938457 bytes, checksum: cd3e7ba5bb0dc3063c74923947d92b7b (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 致謝 1
摘要 2 Abstract 3 Table of Contents 5 Chapter I Introduction 10 Part 1 Background 10 1.1 Interferons and interferon receptors 10 1.2 IFN receptors and their intracellular partners 11 1.3 STATs activation and dimerization 12 1.4 Activated STATs and their cellular partners 13 1.5 IFN-induced antiviral effecters 13 1.6 IFN-induced antiviral sensors 14 1.7 Identification of global binding sites of STAT 15 Part II Rationales and objectives 17 Part I: STAT3 as a negative regulator of ISG expression 19 Part II: STAT3 as a positive regulator of ISG expression 19 Significance 20 Chapter II Materials and methods 21 2.1 Cells 21 2.2 Retroviral transduction 21 2.3 Generation of STAT1/STAT3 DKO MEFs and restoration of STAT1 and/or STAT3 back into STAT1/STAT3 DKO MEFs. 22 2.2 Promoter analysis 22 2.3 RT-QPCR 23 2.4 MDA5 knockdown by lentiviral shRNA 25 2.5 Western blot 26 2.6 In vitro antiviral state assay 26 2.7 Cell viability assay 27 2.8 ChIP assays 27 2.9 Wound healing assay 29 2.10 Microarray analysis 29 2.11 ChIP-seq analysis 30 Chapter III Results 31 Part I: STAT3 as a negative regulator of ISG expression 31 3.1. Enhanced expression of intracellular viral sensors in STAT3KO MEFs 31 3.2 MDA5 knockdown reverses the enhanced antiviral state of STAT3KO MEFs 32 3.3 STAT3 suppresses type I IFN-mediated ISRE promoter activity 33 Part II: STAT3 as a positive regulator of ISG expression 35 3.4 STAT1-independent STAT3-dependent ISG expression 35 3.5 Identifying direct target genes of STAT3 37 3.6 The role of STAT3 in STAT1-independent regulation of cell migration and antiviral responses 39 3.7 Conclusions 40 Chapter III Discussion 43 Figures 47 Figure 1. Enhanced IFNα-mediated gene induction in STAT3KO MEFs. 48 Figure 2. Knockdown efficiency of five MDA5 shRNA. 49 Figure 3. MDA5 expression in control or MDA5 knockdown MEFs. 50 Figure 4. MDA5 knockdown reverses the enhanced antiviral responses of STAT3KO MEF. 51 Figure 5. STAT3 suppresses the recruitment of transcription complex ISGF3 and GAF to ISRE and GAS, respectively. 53 Figure 6. STAT expression and activation in WT, and STAT1/STAT3-double knockout MEFs restored with EV, STAT1, STAT3, and STAT1/STAT3. 54 Figure 7. Expression of STAT1-dependent ISG in WT, EV-restored, STAT1-restored, STAT3-restored, and STAT1/STAT3 double restored MEFs. 55 Figure 8. Expression of STAT3-dependent ISG in WT, EV-restored, STAT1-restored, STAT3-restored, and STAT1/STAT3-double restored MEFs. 56 Figure 9. Normalization of microarray data. 57 Figure 10. Relations of different microarray samples. 58 Figure 11. Increased basal expression by STAT1, STAT3, or double-restoration of STAT1/STAT3 before and after IFN stimulation. 60 Figure 12. Increased ISG expression in WT, EV-restored, STAT1-restored, STAT3-restored, and STAT1/STAT3 double restored MEFs. 61 Figure 13. Parallel comparison between RT-QPCR and microarray results. 64 Figure. 14. Distribution of the STAT3-binding sites (BS). 65 Figure. 15. STAT3 binding sites on various gene promoters. 67 Figure 16. IFN-stimulated STAT3-dependent wound healing. 69 Figure 17. STAT3-mediated suppression of antiviral responses. 70 References 71 | |
| dc.language.iso | en | |
| dc.subject | 干擾素 | zh_TW |
| dc.subject | 抗病毒反應 | zh_TW |
| dc.subject | 基因調控 | zh_TW |
| dc.subject | 染色質免疫沉澱 | zh_TW |
| dc.subject | 訊息傳遞 | zh_TW |
| dc.subject | MDA5 | en |
| dc.subject | Interferon | en |
| dc.subject | STAT1 | en |
| dc.subject | STAT2 | en |
| dc.subject | STAT3 | en |
| dc.subject | antiviral responses | en |
| dc.title | 分析 STAT3 在抗病毒反應中的角色以及 STAT3 的目標基因 | zh_TW |
| dc.title | The role of STAT3 in antiviral response and characterization of STAT3
target genes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王學偉(Hsei-Wei Wang),陳美如(Mei-Ju Chen) | |
| dc.subject.keyword | 干擾素,抗病毒反應,訊息傳遞,染色質免疫沉澱,基因調控, | zh_TW |
| dc.subject.keyword | Interferon,STAT1,STAT2,STAT3,antiviral responses,MDA5, | en |
| dc.relation.page | 78 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2010-07-26 | |
| 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 | |
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