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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 葉秀慧 | |
dc.contributor.author | Ching-Ju Chang | en |
dc.contributor.author | 張靜如 | zh_TW |
dc.date.accessioned | 2021-06-12T17:58:39Z | - |
dc.date.available | 2018-12-31 | |
dc.date.copyright | 2008-02-20 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-01-29 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/27233 | - |
dc.description.abstract | 肝癌(Hepatocellular cacinoma)為台灣最常見的惡性腫瘤,在造成肝癌的危險因子中又以B型肝炎病毒(HBV)的感染最為重要,但HBV導致癌症發生過程可能的分子機轉到目前仍不清楚,而HBV引起的肝癌病例有個顯著的特徵是在性別上的偏好性,男性的罹病率相較於女性約高三~七倍左右。本實驗室先前研究中就已發現HBx具有正向調控男性荷爾蒙受體(androgen receptor)對帶有ARE(androgen-response element)基因的轉錄活性,而這可能是HBV相關肝癌好發於男性的可能機制。
在探討HBx促進男性荷爾蒙受體轉錄活化分子機制的研究中,我們著重在調控AR轉錄活性重要的兩步驟:AR N/C interaction及AR NTD活性。我們發現HBx可透過這兩個步驟來促進AR轉錄活性,分別藉由調控細胞中c-Src與GSK-3β的活性,我們首先證實了c-Src kinase活性在HBx促進AR NTD活性過程中扮演重要的角色,所以本研究接著想進一步探討HBx造成AR N/C interaction增加的機制為何。過去分別有文獻指出HBx可活化Erk kinase使GSK-3β活性受到抑制,且於prostate cancer cell中GSK-3β具有抑制AR N/C interaction的功能,因此我們假設於肝細胞中HBx或許可透過抑制GSK-3β的活性來造成AR N/C interaction的上升。這部分的研究成果大致簡述如下: (1)我們利用mammalian two-hybrid assay的方法證實了GSK-3β確實於肝細胞中在AR N/C interaction調控中扮演負調控的角色。 (2)在HepG2細胞株中,HBx的表現並不足以抑制GSK-3β,必須在AR與HBx的協同作用下,經AR ligand刺激下GSK-3β活性才受到抑制,GSK-3β活性遭抑制後AR N/C interaction就會增加,進而轉錄活化promoter帶有ARE的基因。 (3)針對GSK-3β調控的下游分子中最關鍵的β-catenin,我們進一步探討GSK-3β調控AR N/C interaction機制裡是否β-catenin有參與,實驗結果說明了GSK-3β並非藉由抑制β-catenin的活性來調控AR N/C interaction。 (4)最後,我們在分別證實了AR N/C interaction與AR NTD活性各自有GSK-3β與c-Src調控之後,想釐清這兩個步驟影響AR轉錄活性的程度,結果發現到HBx活化AR的轉錄活性主要就是藉由AR N/C interaction及AR NTD活性兩步驟加以調控,因此確立了GSK-3β與c-Src在HBx活化AR轉錄活性過程中的重要樞紐性質。 另一方面,被認為與HCC形成有關的抑癌基因p53,過去也有研究指出AR具有負調控AR N/C interaction的功能,所以我們假設p53在HBx促進AR轉錄活性增加的過程中,可能也是重要的負調控者。關於這部份的研究成果則簡述如下: (1) p53可透過抑制AR N/C interaction及AR NTD活性在HBx促進AR轉錄活性增加過程中扮演負調控者的角色。 (2) R249S突變的p53會失去抑制AR轉錄活性的功能。 (3)我們證實了GSK-3β的活性對於p53調控AR N/C interaction是重要的,但p53抑制AR轉錄活性不僅只倚賴GSK-3β的調控路徑。 在本研究中,我們證實了AR N/C interaction與AR NTD活性兩步驟是主要決定HBx 促進AR轉錄活性的關鍵,也針對AR N/C interaction的兩個負調控者GSK-3β及p53做了較深入的探討,希望藉由對HBx促進AR轉錄活化的負調控機制的了解,知曉如何阻礙細胞癌化的過程,而本研究結果可做為將來HBV相關男性肝癌治療上的參考。 | zh_TW |
dc.description.provenance | Made available in DSpace on 2021-06-12T17:58:39Z (GMT). No. of bitstreams: 1 ntu-97-R94445132-1.pdf: 1481969 bytes, checksum: bca9e910ffad987855de85be32d418f5 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………… i
中文摘要…………………………………………………………………………...… ii 英文摘要…………………………………………………………………………….. iv 序論…………………………………………………………………..…………….. 1 B型肝炎病毒與B型肝炎的發生 ………………………………………...… 1 B型肝炎與肝癌(HCC)形成之關係 ………………………………………… 1 B型肝炎病毒引起之肝癌有性別偏好性 …………………………………... 3 B型肝炎病毒X蛋白質(HBx)的功能與轉活化能力 ………………………. 3 HBx引發肝癌發生之動物模式研究 ……………………………………….. 5 男性荷爾蒙受體與肝癌形成的相關性 …………………………………….. 6 男性荷爾蒙受體之結構與功能 …………………………………………….. 7 男性荷爾蒙受體N端與C端間的交互作用及其調控 …………………….. 8 GSK-3β kinase特性及其調控方式 ………………………………………... 10 GSK-3β與肝癌發展過程的關係 ………………………………………….. 11 p53與肝癌發展過程的關係 …………………………………………….… 12 p53與GSK-3β之間可互相活化 …………………………………………. 13 研究目的 ………………………………………………………………………… 15 材料與方法 ……………………………………………………………………… 17 結果 …………………………………………………………………………….... 24 第一部份:探討GSK-3β在HBx促進AR轉錄活性過程中的角色 1. 探討HBx是否會經由影響AR NTD活化及AR N/C interaction兩步 驟促進AR的轉錄活性 ………..…………………………………..... 24 2. 探討GSK-3β是否可以調控HBx所促進的AR N/C interaction步驟... 25 3. 探討GSK-3β的活性在肝癌細胞株中是否會受HBx或是AR與HBx 協同活化的訊息傳導路徑所影響 ………………………...………… 26 4. 探討GSK-3β影響AR N/C interaction的可能機制 ………….……. 28 5. 探討AR轉錄活性的調控是否主要經由GSK-3β及c-Src分別調控 AR N/C interaction及AR NTD的活性 ………..……..……………… 30 6. 探討結合針對AR N/C interaction與AR NTD活性調節者的抑制劑, 對AR轉錄活性的影響 …………………..……………………....….. 32 第二部份:探討p53在HBx促進AR轉錄活性過程中的角色 1. 探討p53是否調控AR的轉錄活性,而R249S突變是否造成此調控 功能喪失 ……..………………………………………….………….... 34 2. 探討p53調控AR轉錄活性是否與影響AR N/C interaction有關 ….. 35 3. 探討p53是否調控AR NTD的活性 ………………………………… 37 4. 探討p53調控AR轉錄活性的可能機制 ……………………….…… 38 討論 …………………………………………………………………………........ 39 參考文獻 ………………………………………………………………..…..…… 47 圖附錄 ………………………………………………………………………….... 59 | |
dc.language.iso | zh-TW | |
dc.title | B型肝炎病毒X蛋白質所促進男性荷爾蒙轉錄活性機制中GSK-3β與p53負向調控角色之研究 | zh_TW |
dc.title | Mechanism of HBx-enhanced AR transactivation:GSK-3β and p53 as two negative regulators | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳培哲,施修明 | |
dc.subject.keyword | 男性荷爾蒙受體,B型肝炎病毒, | zh_TW |
dc.subject.keyword | AR,HBx,GSK-3β,p53, | en |
dc.relation.page | 76 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-01-29 | |
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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