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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
dc.contributor.author | Chih-Chang Chou | en |
dc.contributor.author | 周志璋 | zh_TW |
dc.date.accessioned | 2021-06-15T11:52:32Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-11 | |
dc.identifier.citation | Acconcia, F., S. Sigismund and S. Polo (2009). 'Ubiquitin in trafficking: the network at work.' Exp Cell Res 315(9): 1610-1618.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49851 | - |
dc.description.abstract | 第一部分:上皮生長因子受體的新穎調控機制
人類癌症是由許多複雜的綜合因素導致,發生的其中一個重要因素是導因於上皮生長因子受體下游所傳遞的訊息路徑未受到正確的調控,有越來越多的研究證據指出,上皮生長因子受體在細胞中的運輸模式對於其下游訊息傳遞路徑的調控具有相當重要的影響。在我們的研究中證實,起先在受損的神經元當中發現的一個E3 ubiquitin ligase稱為ZNRF1 ,也參與在上皮生長因子受體的運輸以及下游訊息傳遞路徑的調控當中。在兩個分別有表現內生性野生型以及突變型(L858R)上皮生長因子受體的非小細胞肺癌細胞株當中剔除ZNRF1的蛋白質表現,皆會導致上皮生長因子受體累積在細胞內體當中,阻止受器傳遞進入溶小體的運輸過程,最終抑制了受器的降解,並大幅提高了其下游的訊息傳遞路徑強度,其中包含AKT以及ERK的活化程度都有大幅的提升。透過免疫螢光染色以及生物化學的方法,我們發現ZNRF1分布在細胞中的內體以及溶小體當中,並與上皮生長因子受體之間有交互作用。除此之外,在ZNRF1剔除的情況下亦會導致上皮生長因子受體面對上皮生長因子刺激之後所產生的泛素修飾程度下降。蛋白質體的分析也顯示ZNRF1調控了上皮生長因子受體面對上皮生長因子刺激之後所形成的蛋白質複合體。我們也意外地發現,剔除ZNRF1會抑制細胞與腫瘤的生長。綜合以上結果,我們發現了由ZNRF1所參與的上皮生長因子受體之新穎調控機制,ZNRF1調控了上皮生長因子受體的泛素化修飾作用、細胞內的運輸、降解作用以及最終的訊息傳遞。 第二部分:第三型與第四型類鐸受體的新穎調控機制 生物個體面臨病原菌的侵襲時,經由先天性免疫系統所產生的細胞發炎激素對於個體抵抗病原菌扮演著不可或缺的角色。先天性免疫系統中的第四型類鐸受體會辨認來自葛蘭氏陰性菌細胞壁的主要成分脂多糖,進而引發MyD88訊息傳遞路徑來產生細胞發炎激素以及TRIF訊息傳遞路徑來產生第一型干擾素。近期的研究指出,經由活化第四型類鐸受體產生的細胞發炎激素也同時需要TRIF訊息傳遞路徑的參與,顯示著兩個訊息傳遞路中之間有交互作用存。但目前還不清楚TRIF訊息傳遞路徑是如何調控第四型類鐸受體活化後產生細胞發炎激素的過程。在這個研究當中,我們證實在細胞發炎激素的產生過程中也需要TRIF訊息傳遞路徑下游的一個蛋白質稱為TBK1的參與。在免疫細胞當中剔除TBK1不只抑制了第一型干擾素的產生,也使得細胞發炎激素包含第六型介白素以及第十二型介白素的產生大幅減少。然而,經由脂多糖所活化的MyD88訊息傳遞路徑,包含IKK的活化、MAPKs的活化、IκBα的降解以及NF-κB p65的入核,皆未受到TBK1剔除的影響。令人意外的是,對於p65轉錄活性相當重要的Ser536位點,在TBK1剔除的情況下其磷酸化程度大幅的下降,我們也發現p65在結合到第六型介白素以及第十二型介白素的促進子區域上的程度有下降的情況。這些結果顯示,細胞受到脂多糖刺激之後,第四型類鐸受體可經由TRIF訊息傳遞路徑下游的TBK1蛋白質來完成與MyD88訊息傳遞路徑協同調控細胞發炎激素的產生。另一方面,我們也發現在免疫細胞當中,polyI:C的刺激會活化第三型類鐸受體,進而導致TBK1蛋白質在Lys694位點產生SUMOylation的修飾作用,顯示著此修飾作用可能參與在生物個體抵抗病毒感染的過程中。 | zh_TW |
dc.description.abstract | Part I: The novel regulation mechanism of epidermal growth factor receptor signaling
Aberrant regulation of epidermal growth factor receptor (EGFR) resulted in dysregulated mitogenic signaling has been associated with many human cancers. There are growing evidences indicating that EGFR trafficking plays an important role in signaling transduction and tumorigenesis. Here, we demonstrate that ZNRF1, an E3 ubiquitin ligase, which was originally identified in injured neurons, controls EGFR endosomal trafficking and downstream signaling. Depletion of ZNRF1 protein leads to the accumulation of EGFR in endosomes and blocks EGFR sorting into lysosomes in wild type or mutated EGFR (L858R) expressing non-small-cell-lung cancer (NSCLC) cell line. Loss of lysosomal sorting inhibits EGFR degradation and greatly enhances EGFR downstream signaling, including AKT and ERK activation in respond to low and high dose of EGF concentration. Immunofluorescene staining and biochemical studies demonstrate that ZNRF1 localizes to endosomes and associate with EGFR in an EGF-independent manner. Furthermore, ZNRF1 depletion results in significant downregulation of EGF-induced EGFR ubiquitination, particularly the K63-linkage. Proteomic analysis also reveals that loss of ZNRF1 alters the composition of EGFR interactome in respond to EGF. Surprisingly, depletion of ZNRF1 inhibit anchorage-independent cell growth and decreases tumor growth in a xenograft mouse model. Together, these findings demonstrate an important role for ZNRF1, and reveal a novel regulation mechanism in which ZNRF1 controls EGFR ubiquitination, endosomal trafficking and degradation, leading to termination of downstream signaling. Part II: The novel regulation mechanism of TLR3/4 signaling Production of pro-inflammatory cytokines is crucial for innate immune response against pathogen infections. Innate immune sensor TLR4 (Toll-like receptor 4) recognizes lipopolysaccharide (LPS), a major component of gram-negative bacteria cell wall, and then turns on the MyD88-dependent pathway to produce pro-inflammatory cytokines, and the TRIF-dependent pathway to generate Type I interferons (IFNs). Recent data had demonstrated that the TRIF-dependent pathway is also required for TLR4-triggered pro-inflammatory cytokine production, suggesting a crosstalk between these two pathways. However, it is unclear how the TRIF-dependent pathway modulates pro-inflammatory cytokine expression after TLR4 activation. In this study, we demonstrate that TBK1 (TANK-binding kinase 1), a kinase downstream of the TRIF-dependent pathway, is also required for pro-inflammatory cytokine productions. Loss of TBK1 not only inhibits the production of Type I IFNs, but also greatly suppresses the production of pro-inflammatory cytokines, including IL-6 (interlukin-6) and IL-12 p40 (interlukin-12 p40 subunit), However, LPS-induced MyD88-dependent signaling, including activation of IKK (IκB kinase) and MAPKs (Mitogen-activated protein kinases), IκBα (NF-κB inhibitor α) degradation and the nuclear translocation of NF-κB subunit p65, is intact. Surprisingly, phosphorylation of NF-κB p65 Ser536 residue, which is critical for its transactivation activity, is dramatically decreased, leading to impaired p65 recruitment to Il6 and Il12b promoters. These findings reveal that TBK1 is a downstream mediator of TRIF-dependent pathway for pro-inflammatory cytokine production upon LPS stimulation. In addition, we also demonstrate that polyI:C stimulation resulted in TBK1 SUMOylation at Lys694 residue in macrophages. SUMOylation of TBK1 induced by TLR3 activation suggests that SUMOylation might play a role in regulating antiviral activity of a host. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:52:32Z (GMT). No. of bitstreams: 1 ntu-105-F97448001-1.pdf: 8059443 bytes, checksum: 7020016dc795a5b0d25101444e78f131 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | Part I: The novel regulation mechanism of epidermal growth factor receptor signaling
摘要…………………………………………………………………………………….10 Abstract……………………………………………………………………………..….12 Introduction…………………………………………………………………………….14 The epithelial growth factor receptor (EGFR)………………………...……….…14 EGFR trafficking……………………………………………………..…...………16 The role of EGFR ubiquitination in receptor trafficking…………….…...………19 The association of EGFR trafficking and cancer progression………….…..…..…22 ZNRF1, a RING domain containing E3 ubiquitin ligase………………..……..…23 Specific aim……………………………………………………………...…..……25 Materials and Methods…………………………………………………………………26 Cell culture and plasmids……………………………………...…………….……26 Antibodies………………………………………..…………………………….…27 shRNA-mediated gene silencing, transfection, and lentiviral infection………..…28 Generation of ZNRF1 knockout cells using the CRISPR/Cas9 system………..…29 Quantitative RT-PCR (RT-qPCR) ……………………………………………...…30 Immunoblotting……………………………………………..……………………31 Immunofluorescence………………………………………..……………….……31 Immunoprecipitation…………………………………………..……………….…32 Immunohistochemistry…………………………………………..……………..…33 EGFR internalization and EGFR recycling assay………………………..…….…33 Nuclear fractionation…………………………………………………..……….…35 The proximity ligation assay (PLA) ………………………………………..….…35 In vitro ubiquitination assay……………………………………………….…...…36 Cell proliferation assay……………………………………...……………….……36 The soft agar colony formation assay…………………………………………..…37 Xenograft mouse model……………………………………………….……..…...38 Statistical analysis………………………...………………………………………38 Result…………………………………………………………………………..………39 ZNRF1 controls EGFR degradation and signaling……………………..……...…39 ZNRF1 controls EGFR lysosomal sorting………………………..…………...…41 ZNRF1 associates with EGFR………………………………………..……..……44 ZNRF1 mediates EGFR ubiquitination……………………………………...……46 ZNRF1 and CBL cooperatively regulate EGFR ubiquitination and degradation…48 ZNRF1 modulates EGFR interactome……………………………..………….….50 ZNRF1 promotes cancer progression……………………………..………….…...52 Discussion………………………………………………………………………………56 Figure…………………………………………………………………………………...64 Figure 1. ZNRF1 controls EGFR degradation in respond to EGF stimulation…...64 Figure 2. ZNRF1 controlled EGFR degradation is observed in different cancer cell………………………………………………………………………….….…66 Figure 3. ZNRF1 controls EGFR signaling in respond to EGF stimulation….…67 Figure 4. ZNRF1 controls EGF-induced Src activation…………………….…....69 Figure 5. Depletion of ZNRF1 does not influence EGFR internalization…….…71 Figure 6. ZNRF1 controls EGFR endosomal trafficking………………………..72 Figure 7. ZNRF1 modulates EGFR nuclear translocation……………………....74 Figure 8. ZNRF1 associates with EGFR………………………………………...75 Figure 9. ZNRF1 associates with EGFR and localizes to early endosomes….…76 Figure 10. ZNRF1 RING domain interacts with EGFR TKD domain…….…….78 Figure 11. ZNRF1 regulates EGF-induced EGFR ubiquitination…………….…80 Figure 12. EGFR is directly ubiquitinated by ZNRF1…………………….…….82 Figure 13. Depletion of ZNRF1 does not affect the recruitment of CBL to EGFR in respond to EGF stimulation……………………………………….……………..83 Figure 14. ZNRF1 and CBL regulate EGF receptor ubiquitination and degradation………..…………………………………………………….…..…...85 Figure 15. ZNRF1 and CBL cooperatively regulate EGF receptor ubiquitination and degradation…………………………………………………………..………87 Figure 16. ZNRF1 does not affect the recruitment of Hrs to EGFR………..……89 Figure 17. Immunohistochemistry analysis of ZNRF1 in normal lung tissue and NSCLC……………………………………………………………………..…….90 Figure 18. ZNRF1 regulates cell proliferation…………………………….….….91 Figure 19. Depletion of ZNRF1 inhibits anchorage-independent growth…….….92 Figure 20. Depletion of ZNRF1 decreases tumor growth in vivo……………..…93 Table……………………………………………………………………………………95 Table 1. The molecules which fail to recruited EGFR signaling complex in EGF-induced ZNRF1-deficient A549 cell.………………………………………..…...95 Table 2. The proteins which are up-regulated in ZNRF1-deficient A549 cell…...97 Table 3. The proteins which are down-regulated in ZNRF1-deficient A549 cell.100 Part II: The novel regulation mechanism of TLR3/4 signaling 摘要…………………………………………………………………………………121 Abstract………………………………………………………………………………123 Introduction………………………………………………………………………...…125 Innate immunity………………………………………………………………….125 Toll-like receptors (TLRs) ………………………………………………………126 The MyD88-dependent signaling pathway…………………………………..….128 The TRIF-dependent signaling pathway……………………………………..….129 The TLR4 signaling pathway………………………………………….………..131 TANK-binding kinase 1 (TBK1) …………………………………….…………133 The SUMOylation machinery………………………………………….……….135 Specific Aim……………………………………………………………….……137 Materials and Methods……………………………………………………………..…138 Cell Culture and Plasmids……………………………………………………….138 Antibodies………………………………………………………………………139 shRNA-mediated gene silencing, transfection, and lentiviral infection…….….140 Quantitative RT-PCR (RT-qPCR)………………………………………….…….141 Enzyme-linked Immunosorbent Assay (ELISA)…………………………..……142 Immunoblotting…………………………………………………………………143 Immunoprecipitation…...……………………………………………………..…144 In vitro kinase assay…………………………………………………………..…144 Nuclear Fractionation……………………………………………………………145 Chromatin Immunoprecipitation (ChIP) ………………………………………..145 Luciferase reporter assay………………………………………………………..147 Statistical Analysis……………………………………………………………….148 Result……………………………………………………………………………….…149 TBK1 is required for LPS-induced pro-inflammatory cytokine production….....149 TBK1 deficiency does not affect IKK and MAPKs activation……………….....150 TBK1 is required for p65 recruitment to the promoter of NF-ĸB-regulated genes………………………………………………………………………..…...151 TBK1 is modified by SUMOylation at Lys694 residue…………………………153 Discussion………………………………………………………………………….…158 Figure………………………………………………………………………..………..164 Figure 1. TBK1 deficiency impairs LPS-induced pro-inflammatory cytokine mRNA expression………………………………………………………………164 Figure 2. Inhibition of TBK1 kinase activity impairs Il6 mRNA expression in respond to LPS in macrophage but not in MEF...………………………………166 Figure 3. TBK1 deficiency impairs LPS-induced production of pro-inflammatory cytokines.……………………………………………………………….………167 Figure 4. TBK1 deficiency does not impact LPS-induced activation of IKK and MAPKs and NF-B nuclear translocation..…………………………….………168 Figure 5. TBK1 associates with p65 and is required for its recruitment to Il-6 promoter………………………………………………………………….……..170 Figure 6. TBK1 is modified by SUMO1 at its Lys694 residue…………………172 Figure 7. TBK1 is modified by SUMOylation in polyI:C-stimulated macrophages.……………………………………………………………………173 Figure 8. TBK1 SUMOylation does not affect TBK1 dimerization and activation...………………………………………………………………………174 Supplementary Figure………………………………………………………...………176 Supplementary Figure 1. TBK1 phosphorylates p65 (480-550 a.a.) in respond to LPS……………………………………………………………………………176 Supplementary Figure 2. TBK1 is required for the recruitment of p65 to Il-12b promoter………………………………………………………………….……177 Supplementary Figure 3. The interaction of TBK1 and potential interaction candidates were verified by β–glycosidase reporter assay……………………178 Reference……………………………………………………………….…………..179 | |
dc.language.iso | en | |
dc.title | 上⽪⽣⾧因子受體以及類鐸受體之訊息傳遞路徑的新穎調控機制探討 | zh_TW |
dc.title | The novel regulation mechanism of EGF receptor signaling and TLR3/4 signaling | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 施修明(Hsiu-Ming Shih),吳君泰(Chun-Tai Wu),李建國(Chien-Kuo Li),莊宗顯(Tsung-Hsien Chuang) | |
dc.subject.keyword | 上皮生長因子受體,類鐸受體, | zh_TW |
dc.subject.keyword | EGFR,TLR, | en |
dc.relation.page | 196 | |
dc.identifier.doi | 10.6342/NTU201602308 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
顯示於系所單位: | 分子醫學研究所 |
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