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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張 鑫(Shin C. Chang) | |
dc.contributor.author | Shih-Shan Huang | en |
dc.contributor.author | 黃詩珊 | zh_TW |
dc.date.accessioned | 2021-06-16T05:10:59Z | - |
dc.date.available | 2019-10-09 | |
dc.date.copyright | 2014-10-09 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/55927 | - |
dc.description.abstract | C型肝炎病毒感染後,大部分病人會發展為慢性感染,甚至進一步引發肝癌。已知C型肝炎病毒非結構性蛋白質NS5A會和許多蛋白質結合,進而影響宿主細胞內的訊息傳遞以及基因的表現。研究證明,NS5A蛋白質具有PKR蛋白質結合位,可和PKR蛋白質形成異質雙聚體並抑制PKR蛋白質的磷酸化活性。本實驗室發現NS5A會透過負調控PKR訊息傳遞使轉錄因子Sp-1表現量下降,進而導致受Sp-1調控之目標基因表現量下降。同時,在小鼠系統中以流體力學為基礎之體內轉染法進行NS5A基因轉染,並挑選出成功表現NS5A蛋白質的細胞進行cDNA微陣列系統分析,也發現在C型肝炎病毒NS5A蛋白質表現時,趨化素CXCL2的mRNA表現量明顯下降,此現象在表現C型肝炎病毒複製子的細胞株中同樣可以偵測到。在本研究中,進一步探討非結構性蛋白質NS5A如何調控趨化素CXCL2表現。首先,相較於沒有表現NS5A的細胞,表現NS5A之穩定細胞株中的CXCL2 mRNA表現量明顯下降。接著,藉由一系列含有不同長度CXCL2啟動子之報導質體分析CXCL2啟動子的轉錄活性。發現在沒有NS5A蛋白質表現的情況下,相較於CXCL2(-1050/+18)和CXCL2(-429/+18),CXCL2(-82/+18)啟動子活性明顯下降。而在轉錄調控區核苷酸序列第-429~-82區間含有三個Sp-1、兩個GATA-1以及一個CREB結合位,推測可能在CXCL2啟動子基礎活性的正調控上扮演重要功能。因此進一步進行內部序列刪除及結合位定點突變,並同時分析NS5A蛋白質是否會透過這些結合位影響CXCL2啟動子活性。結果發現在沒有NS5A表現的細胞中,突變Sp1-127結合位使CXCL2啟動子活性明顯下降,推測Sp1-127結合位對於CXCL2啟動子基礎活性很重要。另一方面,在NS5A蛋白質表現的情況下,對於CXCL2啟動子活性呈現負調控現象,相較於CXCL2(-1050/+18)和CXCL2(-82/+18),NS5A蛋白質對於CXCL2(-429/+18)啟動子活性有更高的抑制作用,推測NS5A蛋白質對於負調控CXCL2啟動子的作用範圍主要在核苷酸序列第-429~-82區間。進一步分析發現NS5A蛋白質對突變單一Sp1-127結合位及刪除含有三個Sp-1結合位的-428~-78 DNA片段之CXCL2啟動子活性的抑制程度與不表現NS5A之控制組間差異性小,但卻明顯抑制NF-κB結合位突變的CXCL2啟動子活性,推測NS5A是透過Sp1-127以外的結合位使CXCL2啟動子活性下降。以PKR結合位突變之NS5A蛋白質分析NS5A蛋白質負調控CXCL2之啟動子活性的可能機制,結果顯示NS5A可能透過抑制PKR訊息傳遞影響Sp-1表現量,進而導致CXCL2之啟動子活性下降;而ERK訊息傳遞是否也參與在CXCL2啟動子活性調控則有待進一步研究。 | zh_TW |
dc.description.abstract | Hepatitis C virus (HCV) often causes persistent infection and viral-associated hepatocellular carcinoma. The nonstructural protein NS5A of HCV has been known to interact with cellular proteins and affects their downstream signaling pathways and the expression of target genes. The NS5A protein contains PKR binding site that forms heterodimer with PKR and down-regulates PKR activity. Our laboratory previously demonstrated that NS5A negatively regulates Sp-1 expression via inhibiting PKR signaling. By performming hydrodynamics-based in vivo transfection for introducing NS5A gene to a mouse system followed by cDNA microarray analysis with mouse hepatocytes that successfully expressed NS5A protein, our laboratory identified the down-regulation of the mRNA level of chemokine CXCL2 under the expression of NS5A protein. The effect was also observed in an HCV replicon cell system. In this study, down-regulation of CXCL2 mRNA expression was observed in stable cell lines expressing NS5A protein. Transcriptional regulation of the promoter activity of CXCL2 was analyzed by introducing reporter plasmids containing various lengths of the CXCL2 promoter into culture cells for luciferase activity assay. In the absence of NS5A protein, CXCL2(-82/+18) promoter activity was significantly reduced as compared with those of CXCL2(-1050/+18) and CXCL2(-429/+18) promoters. Within the domain from nucleotides -429 to -82, there are three Sp-1, two GATA-1, and one CREB binding sites. Further study indicated that Sp1-127 binding site is important for the promoter activity of CXCL2. The domain from nucleotides -429 to -82 is also involved in the NS5A-mediated down-regulation of CXCL2 promoter activity. Nevertheless, different Sp-1 binding sites are likely to be involved. The results from a study using an NS5A protein in which the PKR binding site has been mutated, suggested that NS5A may down-regulate CXCL2 promoter activity by down-regulating Sp-1 expression via PKR pathway. The possibility of ERK involvement in the regulation of CXCL2 promoter activity needs to be further elucidated. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T05:10:59Z (GMT). No. of bitstreams: 1 ntu-103-R01445113-1.pdf: 1443004 bytes, checksum: 7a43516a4fbb2caf0c93ef01ddd244e0 (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 摘要 i
Abstract iii 英文縮寫對照表 v 目錄 vii 圖表目錄 ix 第一章、 緒論 1 1.1 C型肝炎病毒的發現 1 1.2 C型肝炎流行病學與治療現況 2 1.3 C型肝炎病毒基因體結構與蛋白質 3 1.4 非結構性蛋白質NS5A的特性 6 1.5 趨化素CXCL2的功能 10 1.6 研究目的 12 第二章、 材料與方法 13 2.1 材料 13 2.1.1 藥品 13 2.1.2 酵素 14 2.1.3 抗體 15 2.1.4 細胞培養液與轉染試劑 15 2.1.5 細胞株 15 2.1.6 質體 16 2.1.6.1 實驗室提供的質體 16 2.1.6.2 建構的質體 17 2.1.7 套組試劑 20 2.1.8 其他材料 20 2.2 方法 20 2.2.1 萃取細胞RNA 20 2.2.2 反轉錄聚合酶反應 (Reverse transcriptase reaction) 21 2.2.3 即時聚合酶鏈鎖反應 (Real-time polymerase chain reaction, Real-time PCR) 21 2.2.4 聚合酶鏈鎖反應 (Polymerase chain reaction, PCR) 22 2.2.5 細菌轉型 (Transformation) 22 2.2.6 DNA轉染 (DNA transfection) 22 2.2.7 細胞全蛋白質收取 22 2.2.8 蛋白質定量 23 2.2.9 正十二烷硫酸鈉─聚丙醯胺板膠電泳 (SDS-polyacrylamide gel electrophoresis, SDS-PAGE) 23 2.2.10 西方墨點法 (Western blot analysis) 24 2.2.11 螢火蟲冷光酶分析 (Luciferase assay) 25 第三章、 實驗結果 26 3.1 NS5A蛋白質抑制CXCL2 mRNA的表現 26 3.2 CXCL2啟動子活性分析 26 3.3 NS5A蛋白質對CXCL2啟動子活性的影響 27 3.4 NS5A-PKR訊息傳遞路徑對CXCL2啟動子活性的影響 28 3.5 NS5A對Sp-1以及NF-κB結合位的影響 29 第四章、 討論 31 第五章、 圖表 34 第六章、 參考文獻 43 附錄 51 | |
dc.language.iso | zh-TW | |
dc.title | C型肝炎病毒非結構性蛋白質NS5A對CXCL2之轉錄調控 | zh_TW |
dc.title | Transcriptional Regulation of CXCL2 by the NS5A Protein of Hepatitis C Virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 廖 楓(Fang Liao),楊宏志(Hung-Chih Yang) | |
dc.subject.keyword | C型肝炎病毒,非結構性蛋白質5A,趨化素,轉錄調控, | zh_TW |
dc.subject.keyword | HCV,NS5A,CXCL2, | en |
dc.relation.page | 57 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-19 | |
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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