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???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
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dc.contributor.advisor | 蔡明道 | |
dc.contributor.author | Tong-You Wade Wei | en |
dc.contributor.author | 魏同佑 | zh_TW |
dc.date.accessioned | 2021-06-15T12:39:50Z | - |
dc.date.available | 2021-08-03 | |
dc.date.copyright | 2016-08-03 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-07-28 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50416 | - |
dc.description.abstract | NF-κB控制著各方面的免疫反應,並調控著细胞的存活,增殖,和分化。由於其功能的多樣性,NF-κB的失調已經被發現與許多疾病有關連。我們先前的研究指出,TIFA蛋白質的的多聚化現象需要第九號蘇胺酸殘基的磷酸化, 進而活化NF-κB訊息調控路徑。此外,我們我們發現有與PI3K-Akt信號傳遞途徑相關的激酶參與磷酸化第九號蘇胺酸殘基。
在這項研究中,我們找到了上游能夠對TIFA蛋白質第九號蘇胺酸磷酸化的磷酸化激酶Aurora A, 在急性骨髓性白血病中,我們也證實前人所提出的Aurora A激酶活化NF-κB訊息傳遞路徑是由於TIFA蛋白質所調控的。 我們發現TIFA蛋白質表現量在急性骨髓性白血病中與Aurora A及NF-κB所調控的腫瘤存活因子的表現量有高度正相關性,且與病人的預後表現呈現負相關。我們進一步發現,抑制活體急性骨髓性白血病細胞中的TIFA表現量能夠擾亂白血病細胞激素的分泌,顯著地提昇化學治療的敏感度,並且提高人類急性骨髓性白血病細胞在裸鼠模式中的清除率。這些結果共同顯示,TIFA可以支持的AML的發展,並且標靶TIFA可以提高治療AML的效果。 我們也發現TIFA蛋白在肝癌細胞株與肝癌病人細胞中過度表達。而且越高的TIFA表現量,患者的無疾病存活期越短。這可能與TIFA調控上皮間質轉化的訊息傳遞作為肝癌腫瘤侵襲和轉移的分子機制有關。我們也發現了抑制TIFA可以特別地降低肝癌細胞株的細胞活性,提高化學治療毒性,並抑制其移動和侵襲的能力。這些結果顯示TIFA在未來將是一個嶄新的肝癌化學治療標把。 另一方面,在血管內皮細胞面臨促氧化和炎性刺激時,先天免疫反應主要主要是受到類鐸受體調控的NF-κB的訊息調控路徑所活化。我們發現TIFA在內皮細胞中是一個新穎的NLRP3炎性體啟動(訊息一)與活化(訊息二)的調控者。氧化和發炎的壓力例如剪切應力與氧化修飾的低密度脂蛋白皆會誘導並活化TIFA。 在訊息一中的炎性細胞激素和炎性體組成成分的轉錄活性中,TIFA的誘導被認為是必需的。 此外,Akt增加TIFA蛋白質第九號蘇胺酸的磷酸化並促使NLRP3炎性體組裝,可視為訊息二的炎性體活化。這些結果顯示TIFA透過訊息一以及訊息二來啟動與活化NLRP3炎性體,使其在內皮先天免疫反應扮演一個關鍵的調節者。 此研究所發現的機制提供了重要的轉譯意義,尤其是在哺乳動物細胞中的炎性反應。我們所得到的整體的結果不僅對腫瘤壞死因子到NF-κB的訊息傳遞有了詳細的解釋,並且在免疫疾病和癌症的治療中提供了潛在的治療靶標。 | zh_TW |
dc.description.abstract | Nuclear factor-κB (NF-κB) controls various aspects of immune responses and regulates cell survival, proliferation, and differentiation. In light of its functional diversity, dysregulation of NF-κB has been linked to a variety of diseases. Our previous study demonstrated that Thr9 phosphorylation-dependent oligomerization of TRAF-interacting protein with a FHA domain (TIFA) triggers the activation of NF-κB. In addition, we investigated the involvement of the kinase in PI3K-Akt signaling pathway is response for the Thr9 phosphorylation.
In this study, we identified that Aurora A is an essential kinase for the Thr9 phosphorylation of TIFA, and that TIFA functionally mediates the Aurora A-driven NF-κB survival pathway in acute myeloid leukemia (AML). We found that TIFA protein is overexpressed concurrently with Aurora A and NF-κB signaling factors in de novo AML patients relative to healthy individuals, which is also correlated with the poor prognosis of patients. In addition, TIFA inhibition perturbs leukemic cytokine secretion, significantly enhances chemotoxicity, and potentiates the clearance of leukemic myeloblasts in a xenograft model. These results collectively demonstrate that TIFA may support AML progression, and that targeting TIFA can enhance therapeutic efficacies in the treatment of AML. In accord, we showed that TIFA protein is also overexpressed in hepatocellular carcinoma (HCC) lines and patient cells relative to normal ones. Higher TIFA expression showed significantly shorter disease free survival (DFS) than those with lower TIFA expression in HCC patients. This may correlate with TIFA directed epithelial-mesenchymal transition (EMT) signaling as the molecular mechanism underlying tumor invasion and metastasis in HCC. We also found that silencing of TIFA specifically reduces viability, enhances the chemotoxicity, and retards the migration and invasion abilities of HCC lines. These results may propose TIFA as a novel therapeutic target in the treatment of HCC. On the other hand, toll-like receptor-mediated NF-κB activation is a major innate immune response in vascular endothelial cells (ECs) in response to pro-oxidative and inflammatory stimuli. We identified TIFA as a novel regulator of both priming (Signal 1) and activating (Signal 2) signals of NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in ECs. Oxidative and inflammatory stresses such as atheroprone flow and oxidized-LDL induce and activate TIFA. Induction of TIFA is required for the transcriptional activation of inflammatory cytokines and inflammasome components which is considered Signal 1. Additionally, Akt-enhanced phosphorylation of TIFA Thr9 promotes the assembly of NLRP3 inflammasome which is considered Signal 2 of inflammasome activation. The results suggest that TIFA is a crucial mediator in the endothelial innate immune response by potentiating and amplifying NLRP3 inflammasome via augmenting Signal 1 and 2. This newly defined mechanism has important translational implications, particularly toward the inflammatory responses in mammalian cells. The overall results obtained in this study are expected to not only decipher the detailed molecular mechanism within TNF and NF-κB axis, but also provide a potential therapeutic target in the treatment of immune disorders and cancers. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T12:39:50Z (GMT). No. of bitstreams: 1 ntu-105-D99b46010-1.pdf: 25879208 bytes, checksum: f6c3e4606f8486a3c3cd305af436f759 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 國立臺灣大學博士學位論文 口試委員會審定書 iii
Acknowledgments v 中文摘要 ix Abstract xi Abbreviations xiii Contents xxi Chapter 1. Introduction and Research Background 1 1.1 Inflammation and diseases 1 1.1.1 Inflammation and pathophysiology of cancer 1 1.1.1.1 Chronic inflammation related to tumor formation 2 1.1.1.2 Inflammatory tumor microenvironment 3 1.1.2 Acute myeloid leukemia 6 1.1.2.1 Autoimmune diseases and the risk of myeloid leukemia 6 1.1.2.2 Cytokines and chemokines in AML 7 1.1.3 Hepatocellular carcinoma (HCC) 9 1.1.3.1 Inflammation and HCC 9 1.1.3.2 Molecular mechanisms of HCC progression 10 1.1.3.3 EMT in HCC 12 1.1.4 Inflammation and cardiovascular diseases (CVDs) 13 1.1.4.1 Role of the inflammatory process in CVDs 15 1.1.4.2 Shear stress and risk factors in CVDs 16 1.2 Inflammation and innate immunity 18 1.2.1 Innate and adaptive immunity 18 1.2.1.1 Innate immunity 18 1.2.1.2 Toll-like receptors, tumor necrosis factor, and interleukin-1 signaling in the innate immunity 19 1.2.1.3 Adaptive immunity 22 1.2.2 DAMPs and PAMPs 22 1.2.2.1 DAMPs 22 1.2.2.2 PAMPs 23 1.2.3 NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome 25 1.2.3.1 Innate immunity and inflammasome assembly 25 1.2.3.2 The role of inflammasome in tumorigenesis 26 1.3 NF-κB signaling in the regulation of inflammation 28 1.3.1 NF-κB signaling pathway 28 1.3.1.1 NF-κB transcriptional activity 30 1.3.1.2 Canonical NF-κB pathway 31 1.3.1.3 Non-canonical NF-κB pathway 31 1.3.1.4 NF-κB and cancer 33 1.3.1.5 NF-κB and inflammatory diseases 34 1.3.2 TNF signaling and TRAFs 35 1.3.2.1 Tumor necrosis factor alpha (TNF-) 35 1.3.2.2 TNF- and inflammatory diseases 36 1.3.2.3 TRAF2 and TRAF6 37 1.4 Kinases involved in inflammation and tumorigenesis 41 1.4.1 Aurora A kinase 41 1.4.1.1 Aurora kinase family 41 1.4.1.2 Aurora A and mitotic regulation 42 1.4.1.3 Aurora A and tumorigenesis 43 1.4.2 Akt kinase 44 1.4.2.1 Akt kinase family 44 1.4.2.2 Akt1, shear stress, and tumorigenesis 45 1.5 TRAF-interacting protein with a forkhead-associated domain (FHA) domain (TIFA), a new player in NF-κB signaling 47 1.5.1 The relationship between TIFA and TRAFs 48 1.5.2 TIFA oligomerization and TRAF activation 48 1.5.3 TIFA oligomerization-dependent NF-κB activation 50 1.5.3.1 TNF-α-mediated NF-κB activation 50 1.5.3.2 TIFA oligomerization and NF-κB activation 51 Chapter 2. Phosphorylation of TIFA threonine 9 (Thr9) and its oligomerization 54 2.1 Summary 54 2.2 Introduction 54 2.3 Results 55 2.3.1 Glu5 and Ser53 are important to the TIFA self-association 55 2.3.2 The involvement of the kinases in TNF--dependent PI3K-Akt signaling pathway in Thr9 phosphorylation 57 2.3.3 Aurora A is the potent kinase for TIFA pT9 60 2.3.4 Protein degradation of TIFA is negatively regulated through Aurora A 63 2.4 Conclusion 69 2.5 Materials and Methods 71 2.5.1 Cell culture 71 2.5.2 Kinase inhibitors for treatments of cells 72 2.5.3 In vitro kinase assay 72 2.5.4 Co-immunoprecipitation assay 73 2.5.5 Western blotting 73 2.5.6 RNA interference 73 2.5.7 WST-1 cell viability assay 74 2.6 Supplementary Information 75 Chapter 3. TIFA Links Aurora A to NF-κB Survival Pathway to Support Chemoresistance in AML 92 3.1 Abstract 92 3.2 Introduction 93 3.3 Results 95 3.3.1 TIFA is involved in Aurora A kinase-dependent NF-κB signaling 95 3.3.2 TIFA is correlated with Aurora A, pro-survival factors, and poor prognosis of AML 100 3.3.3 TIFA silencing enhances chemotoxicity to AML 105 3.3.4 Targeting TIFA through dominant-negative inhibition 114 3.3.5 Targeting TIFA potentiates the clearance of leukemic myeloblasts 120 3.4 Conclusion 126 3.5 Materials and Methods 132 3.5.1 Antibodies 133 3.5.2 In vitro kinase assay 133 3.5.3 Immunoprecipitation 134 3.5.4 Immunofluorescence staining 134 3.5.5 Luciferase reporter assay 135 3.5.6 WST-1 cell viability assay 136 3.5.7 Analyses of apoptosis and flow cytometry 136 3.5.8 Patient samples 137 3.5.9 Isolation of human PBMCs 137 3.5.10 Immunocytochemical staining 138 3.5.11 Assessment of cytokine and chemokine secretion (cytokine array and ELISA) 138 3.5.12 Xenotransplantation of human leukemic cells, and in vivo chemo drug treatment 139 3.5.13 Statistical analysis 139 3.6 Supplementary Information 141 3.6.1 Supplementary methods 141 3.6.1.1 Cell culture and TNF-α stimulation 141 3.6.1.2 Chemotherapy drugs for treatments of cells 141 3.6.1.3 Plasmids and transient transfection 141 3.6.1.4 Preparation of retrovirus based stable lines 142 3.6.1.5 Transfection of siRNA 142 3.6.1.6 Western blot 143 3.6.1.7 Reverse transcription quantitative PCR (RT-qPCR) 144 3.6.2 Supplementary figures 145 3.6.3 Supplementary tables 170 Chapter 4. TIFA Modulates EMT in HCC 175 4.1 Summary 175 4.2 Introduction 175 4.3 Results 179 4.3.1 Aurora A specifically phosphorylates TIFA at Thr9 as the molecular basis of NF-κB activation 179 4.3.2 Targeting TIFA promotes chemotoxisity of HCC 187 4.3.3 TIFA modulates the formation of lamellipodia 191 4.3.4 TIFA directs EMT signaling as the molecular mechanism of tumor invasion and metastasis in HCC 192 4.3.5 TIFA is correlated with NF-κB p65 subunit, Snail, and poor prognosis of HCC 195 4.3.6 TIFA protein is correlated with NF-κB and pro-survival factors in breast cancer 197 4.4 Conclusion 199 4.5 Materials and Methods 202 4.5.1 In vitro kinase assay 202 4.5.2 Identification of phosphorylated residues by mass spectrometry 202 4.5.3 Luciferase assay 203 4.5.4 Immunohistochemical staining 203 4.5.5 Preparation of cell extracts and Western blot analysis 204 4.5.6 Reverse transcription quantitative PCR (RT-qPCR) 205 4.5.7 Chemicals 205 4.5.8 Cell cultures and transfection 206 4.5.9 Transfection of siRNA 206 4.5.10 WST-1 assay 207 4.5.11 Analyses of apoptosis and flow cytometry 207 4.5.12 Immunofluorescence staining 207 4.5.13 Transwell-based cell migration and invasion assay 208 4.5.14 Preparation of retrovirus based stable lines 208 4.5.15 Statistical analysis 209 4.6 Supplementary Information 210 4.6.1 Supplementary figures 210 Chapter 5. TIFA Potentiates NLRP3 Inflammasome through Induction of Signal 1 and 2 214 5.1 Summary 214 5.2 Introduction 214 5.3 Results 216 5.3.1 Oxidative stress up-regulated TIFA protein 216 5.3.2 TIFA is involved in NLRP3 inflammasome activation 217 5.3.3 TIFA oligomerization is involved in of NLRP3 inflammasome activation 219 5.3.4 Akt is required for the Thr9 phosphorylation dependent oligomerization of TIFA 223 5.3.5 Aurora A is involved in the oxidative stress-induced TIFA Thr9 phosphorylation in ECs 232 5.3.6 Akt-TIFA modulates the activation of NLRP3 inflammasome 235 5.3.7 Akt is involved in TIFA induced NLRP3 inflammasome activation 238 5.4 Conclusion 244 5.5 Materials and Methods 246 5.5.1 Antibodies and reagents 246 5.5.2 Cell culture and shear stress experiments 247 5.5.3 RNAi transfection 247 5.5.4 Immunoblotting 248 5.5.5 In vitro kinase assay 248 5.5.6 Immunoprecipitation 249 5.5.7 Inflammasome reconstitution assay 249 5.5.8 Statistical analysis 249 5.6 Supplementary Information 251 5.6.1 Supplementary figures 251 Chapter 6. Potential rules of TIFA underlying immune modulations 258 6.1 TIFA regulates monocyte adhesion to ECs 258 6.1.1 Introduction 258 6.1.2 Results 259 6.2 TIFA is upregulated in CVDs 260 6.2.1 Introduction 260 6.2.2 Results 264 6.3 TIFA L83H attenuates the survival of memory B cells and IgG secretion 269 6.3.1 Introduction 269 6.3.2 Results 269 6.4 TIFA is required for CD69-S100A8/S100A9-dependent regulatory T cell (Treg) differentiation signaling 274 6.4.1 Introduction 274 6.4.2 Results 275 6.5 Conclusion 276 6.6 Materials and methods 278 6.6.1 Cell culture 278 6.6.2 Monocyte adhesion assay 278 6.6.3 Detection of the cytokine profile of macrophages 279 6.6.4 Isolation and maintenance of hPBMCs cells 279 6.6.5 Culture of patient-specific endothelial cells and SMCs 279 6.6.6 Preparation of cell extracts and Western blot analysis 280 Chapter 7. Discussion and Perspectives 281 7.1 The kinases for Thr9 phosphorylation of TIFA 281 7.2 TIFA-mediated cytokine secretion profile in AML 283 7.3 TIFA-regulated EMT in HCC 285 7.4 Aurora A and oxidative stress-induced NLRP3 inflammasome activation in ECs 286 7.5 TIFA self-association and PTM-related protein stability 287 7.6 TIFA, innate innunity, and CVDs 288 7.7 TIFA and adaptive immunity 290 7.8 Overall remarks 291 References 293 Appendix 346 | |
dc.language.iso | en | |
dc.title | TIFA調控發炎反應之病理生理機轉 | zh_TW |
dc.title | Pathophysiological Role of TIFA in the Regulation of Inflammation | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 陳鈴津,陳瑞華,蕭宏昇,周文堅 | |
dc.subject.keyword | NF-κB,TIFA,Aurora A,急性骨髓性白血病,肝癌,藥物抗性,上皮-間質轉化,Akt,NLRP3炎性體, | zh_TW |
dc.subject.keyword | NF-κB,TIFA,Aurora A,AML,HCC,chemoresistance,EMT,Akt,NLRP3 inflammasome, | en |
dc.relation.page | 463 | |
dc.identifier.doi | 10.6342/NTU201601470 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-07-28 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
Appears in Collections: | 生化科學研究所 |
Files in This Item:
File | Size | Format | |
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ntu-105-1.pdf Restricted Access | 25.27 MB | Adobe PDF |
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