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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 蔡錦華 | |
dc.contributor.author | Kai-Min Lin | en |
dc.contributor.author | 林楷敏 | zh_TW |
dc.date.accessioned | 2021-05-14T17:44:59Z | - |
dc.date.available | 2018-09-25 | |
dc.date.available | 2021-05-14T17:44:59Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-22 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4670 | - |
dc.description.abstract | EB病毒是第一個被發現與腫瘤高度相關的DNA病毒,可以作為研究病毒致癌分子機制的範本,對病毒如何調控細胞因子來幫助其感染、潛伏於宿主,甚至使宿主細胞癌化的研究,有很大的助益。近年的研究逐漸發現,EB病毒的致病機制,除了與其潛伏期有關,病毒的裂解複製期,亦能對EB病毒相關疾病的產生造成影響,惟EB病毒在宿主細胞內複製、進入裂解期的分子機制尚未完全明瞭。我們利用人類白血球濃厚液分離出的B細胞,感染EB病毒,發現細胞內一個鷹架蛋白IQGAP2的表現量增加。IQGAP2目前被認定為腫瘤抑制因子,所以在致癌EB病毒感染中會增加讓人好奇。除了病毒感染,當病毒進入裂解期時,IQGAP的表現量也會增加。我們接著發現EB病毒的裂解轉活化因子Rta會讓細胞內的IQGAP2增加。實驗結果顯示,Rta可能透過IQGAP2驅動子上的Rta反應元素來調控其轉錄。有趣的是,我們發現Rta會將IQGAP2蛋白帶入細胞核內,而Rta與IQGAP2在細胞核的複合體,會影響EB病毒裂解期蛋白的表現。Rta會和IQGAP2共同作用,並且調控EB病毒進入裂解期。最後,我們發現在EB病毒感染而不朽化的類淋巴母细胞中,IQGAP2能透過鈣黏蛋白E影響細胞之間的團聚。綜上所述,我們發現當EB病毒進入裂解期時,其裂解轉活化因子Rta會透過IQGAP2驅動子上的作用而使細胞核內的IQGAP2蛋白增加。這樣的一個Rta-IQGAP2複合體會在細胞核內調控Rp的活化。我們的發現找出一個新的參與EB病毒進入裂解期,使其進入複製期的調控因子,這些結果對我們了解EB病毒的生活史,有助於控制EB病毒的複製知相關研究。 | zh_TW |
dc.description.abstract | As the first defined human oncogenic virus, Epstein-Barr virus (EBV) provides a good model to investigate how pathogens “hijack” cellular factors to promote their infection, persistence and even tumorigenesis. Although prolonged latency is the key feature of EBV, growing evidence suggests that lytic replication is crucial to EBV pathogenesis, yet how the virus promotes lytic cycle is not fully elucidated. In our B cell EBV infection model, we found that IQGAP2, a scaffold protein recognized as a tumor suppressor, was up-regulated after EBV infection. EBV lytic activation also increases IQGAP2 expression. We then identified that EBV immediate-early transactivator Rta was responsible to this up-regulation, most likely through a putative Rta responsive element (RRE) on IQGAP2 promoter. Surprisingly, we demonstrated that Rta was able to recruit IQGAP2 to the nucleus. This nuclear complex may play a role in lytic activation since lytic protein expression decreased when IQGAP2 transcription was suppressed due to impaired Rta auto-activation. Furthermore, in LCLs, IQGAP2 mediate cell-to-cell adhesion through regulation of adhesion molecule E-cadherin. To sum up, we found that, upon lytic stimuli, Rta increased IQGAP2 expression and translocalized it to the nucleus. The Rta-IQGAP2 complex activated Rta promoter (Rp) and promote lytic progression. This novel finding shed lights on a new path to understanding the intricate mechanism of EBV lytic cycle. | en |
dc.description.provenance | Made available in DSpace on 2021-05-14T17:44:59Z (GMT). No. of bitstreams: 1 ntu-104-R02445114-1.pdf: 3803603 bytes, checksum: 08f6e195bc938eeca1e46c73c1cc3f4d (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 摘要…………………………………………………………………….I
Abstract………………………………………………………………..II Table of Contents……………………………………………………..III Introduction…………………………………………………………….1 1. Epstein-Barr virus…………………………………………………………….1 1.1 Discovery…………………………………………………………………..1 1.2 Classification, viral structure, and genome………………………...………1 1.3 Life cycle…………………………………………………………………..2 1.4 Regulation of lytic reactivation……………………………………………3 1.5 EBV-associated diseases……………………………………………..…….4 2 Rta………………………………………………………………………….…5 2.1 Structure……………………………………………………………………5 2.2 Transactivation ability……………………………………………………..5 2.3 Cellular effects…………………………….……………………………….6 3 IQGAP………………………………….…………………………………….7 3.1 IQGAP family………………….………………………………….……….7 3.2 IQGAP1…………………………………………………..……………..…9 3.3 IQGAP2…………………………………………………………………..10 3.4 IQGAP3…………………………………………………………………..11 3.5 Interaction of IQGAP1 with viruses……………………………....……11 4 Study aim…………………………………………………………..……….11 Materials and Methods……………………………………..…………13 1 Materials……………………………………………………...……………..13 1.1 Cell lines……………………………………………………………….…13 1.2 Competent cells…………………………………………………………..14 1.3 DNA plasmids…………………………………………………………….14 1.4 Primers……………………………………………………………………16 1.5 Antibodies………………………………………………………...………16 1.6 Chemicals and reagents…………………………..……………………17 1.7 Kits….……………………………………………………...…………….20 1.8 Buffers……………………………………………………...…………….20 2 Methods……………………………………………………………………..24 2.1 Cell culture………………………………………………………………24 2.2 Polymerase chain reaction (PCR)……………………………………….25 2.3 Plasmid construct………………………………………………………..25 2.4 Transformation…………………………………………………………..26 2.5 Plasmid preparation………………………………………..……………26 2.5.1 QIAGEN plasmid midi kit………………………………………….26 2.5.2 Presto mini plasmid kit……………………………………………..27 2.6 NTRII transfection……………..…………………………….…………28 2.7 Lentivirus packaging and infection…………………………….……….28 2.8 Electroporation………………………………………………….………28 2.9 RNA extraction………………………………………………….………29 2.10 Reverse transcription………………………………………………..…29 2.11 Real-time quantitative polymerase chain reaction (Q-PCR)……….….30 2.12 Protein extraction………………………………………………………30 2.13 Protein concentration measurement……………………………………30 2.14 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)………………………………………………………………………31 2.15 Western Blot………………………….………………………………..31 2.16 Human primary B cell purification…………………………………….32 2.17 Lymphoblastoid cell line (LCL) establishment………………………..33 2.18 Indirect immunofluorescent assay…………………………...………...33 2.19 Subcellular fractionation…………………………………..…………..33 2.20 Co-immunoprecipitation (Co-IP)………………….…………………..34 2.21 Luciferase reporter assay………………………………………………34 2.22 Cell proliferation rate determination…………………………………..35 2.23 Chromatin immunoprecipitation assay (ChIP)……………….………..35 Results……………………………………………...…………………38 1. EBV infection and reactivation increased the expression of IQGAP2…….38 2. Rta increased IQGAP2 expression with both of its DNA-binding and transactivation domains………………………………………..……….….40 3. Rta increased IQGAP2 expression though direct binding to the promoter….41 4. Rta recruited IQGAP2 to the nucleus………………………………….…..41 5. IQGAP2 was required for lytic replication since it participated in Rp auto-activation……………………………………………………………….…..43 6. IQGAP2 mediated cell-to-cell adhesion in LCLs through E-cadherin…….44 Discussion………………..……………………………………………45 1. Hypothesis……………………………………………………………..…..45 2. Direct transcription activation of Rta ……………………………….…….45 3. Association of IQGAP2 with Rta in gene expression regulation………….46 4. Nuclear function of IQGAP2………………………………………………47 5. Diverse functions of IQGAP family in EBV infection…………………….49 6. The role of IQGAP2 in EBV-associated disease progression……….……..50 Figures…………………………………………...……………………51 Figure 1. Schematic diagrams reveal binding factors on Epstein-Barr virus Zta and Rta promoters…………………………………………………………….……..51 Figure 2. A diagram represents the structure of EBV Rta protein………………52 Figure 3. Schematic representation of human IQGAP family………………..…53 Figure 4. Expression kinetics of IQGAP2 mRNA and protein in human primary B cell along the course of EBV-induced LCL transformation were analyzed by Q-PCR. ………………………………………………………………….…..……..54 Figure 5. mRNA and protein expression of IQGAP family in human primary B cells and paired EBV-transformed LCLs were revealed…………….……...……56 Figure 6. mRNA expression of IQGAP2 in EBV-infected, anti-CD40 / IL-4 stimulated, LPS-stimulated human or poly I:C-stimulated B cells was measured with Q-PCR. ………………………….……………………………………..…..58 Figure 7. Reactivation of EBV in Akata+ increased the expression of IQGAP2.59 Figure 8. Reactivation of EBV in NA cells increased the expression of IQGAP2.60 Figure 9. EBV Rta increased IQGAP2 protein expression………………...……61 Figure 10. Rta upregulated IQGAP2 promoter activity in 293T and TW01 cells.62 Figure 11. Rta with C-terminal deletion or N terminal deletion could not induce IQGAP2 protein expression in TW01 cells…………………………………….63 Figure 12. IQGAP2 promoter luciferase reporter assay with different Rta-GFP proteins…………………………………………………………………………64 Figure 13. Luciferase activity assay with different 5’-deleted IQGAP2 reporter plasmids revealed the important promoter region…………………...………….65 Figure 14. Knockdown of Sp1 did not affect Rta-induced IQGAP2 promoter activation………………………………….……………………………………..66 Figure 15. Rta binds to IQGAP2 promoter. …………………………………….67 Figure 16. Nuclear expression of IQGAP2 was associated with Rta expression.68 Figure 17. Subcelluar localization of transfected and induced IQGAP2 in relation with Rta was analyzed with confocal microscopy………………………………69 Figure 18. Subcelluar localization of IQGAP2 in human CD19+ B lymphocytes and EBV-immortalized LCL was analyzed with confocal microscopy………….70 Figure 19. Interaction of IQGAP2 and Rta was analyzed with co-immuniprecipitation……………………………………………………………..72 Figure 20. Knockdown of IQGAP2 affected spontaneous lytic progression in LCLs……………………………………………………….…..………………..73 Figure 21. Knockdown of IQGAP2 impaired TPA/SB-induced lytic progression in NA cells……………………………………………….………….…………..74 Figure 22. Knockdown of IQGAP2 impacted Rta autoregulation in 293T cells..75 Figure 23. Knockdown of IQGAP2 did not affect Rta-induced Zp or pBLLF1 activation in 293T cells………………………………………………….………76 Figure 24. Knockdown of IQGAP2 altered LCL clumping morphology……….77 Figure 25. Knockdown of IQGAP2 did not affect LCL proliferation…………..78 Figure 26. Knockdown of IQGAP2 decreased E-cadherin in LCLs……...…….79 Figure 27. Hypothesis Model………………………………………………...…80 Figure 28. Rta activates lytic promoters through different pathways………..….81 Tables…………………………………………………………………82 Table 1. Primers used for plasmid constructs (pGL3-pIQGAP2 and promoter serial deletion)……………………………………………..……………………82 Table 2 Primers used for polymerase chain reactions………………….………..83 Table 3. shRNA sequence for gene knockdown lentiviruses…………….……...84 Table 5. Dilution fold for antibodies…………………………………………….85 Appendixes……………………………………………………..……..87 Appendix I. Expression of IQGAPs in B cells and EBV-infected B cells was analyzed with cDNA microarray……………….……………………………….87 Appendix II. Expression of IQGAPs was analyzed when TW01 cells were transfected with EBV viral genes…………………….…………………………88 References…………………………………………………………….89 | |
dc.language.iso | en | |
dc.title | 探討鷹架蛋白IQGAP2在EB病毒感染中所扮演之角色 | zh_TW |
dc.title | The roles of scaffold protein IQGAP2 in Epstein-Barr virus infection | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林素芳,林素珍 | |
dc.subject.keyword | EB病毒,Rta (BRLF1),鷹架蛋白,IQGAP2,裂解期, | zh_TW |
dc.subject.keyword | Epstein-Barr virus (EBV),Rta (BRLF1),IQ-motif containing GTPase activating-like protein 2 (IQGAP2),lytic replication, | en |
dc.relation.page | 100 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2015-07-22 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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