English  |  正體中文  |  简体中文  |  Items with full text/Total items : 54371/62179 (87%)
Visitors : 8730072      Online Users : 105
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTHU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
  • Adv. Search
    HomeLoginUploadHelpAboutAdminister Goto mobile version
    National Tsing Hua University Institutional Repository > 生命科學院  > 分子與細胞生物研究所 > 博碩士論文  >  B 型肝炎大表面蛋白調控腫瘤抑制蛋白p53 之作用機制


    Please use this identifier to cite or link to this item: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/86842


    Title: B 型肝炎大表面蛋白調控腫瘤抑制蛋白p53 之作用機制
    Authors: 陳韋岑
    Chen, Wei-Chen
    Description: GH02102080543
    碩士
    分子與細胞生物研究所
    Date: 2015
    Keywords: 肝細胞癌 B型肝炎病毒 腫瘤抑制蛋白p53
    HCC Hepatitis B virus p53
    Abstract: 肝癌為全世界致死率第二高之癌症。約70-80%之肝癌屬於肝細胞癌 (Hepatocellular carcinoma, HCC) 並且其中近六成與慢性B型肝炎病毒感染有關,而B型肝炎病毒之大表面蛋白 (HBV large surface antigen, LHBs) 則被視為促使肝細胞癌發生之致癌蛋白。在本研究中,我們發現LHBs的對於腫瘤抑制蛋白p53的表現有負調控之作用。此負調控肇因於降低腫瘤抑制蛋白p53之穩定性並同時促進其負調控因子Mdm2之表現。我們也發現在帶有LHBs之肝細胞中,p53的負調控現象會伴隨著較高DNA損傷以及減低細胞對與DNA損傷之反應,且在此細胞中進一步誘導DNA損傷並無法活化腫瘤抑制因子p53以及其下游分子p21。而LHBs的表現也造成了細胞出現多核 (multinucleation) 之情形,顯示負調控p53使LHBs細胞無法維持其正確之染色體倍數。利用Nutlin-3干擾p53-Mdm2之間交互作用可恢復細胞中p53表現量但不具活性,反之抑制細胞中Sirtuins之去乙醯化活性可回復p53表現量及其生物功能。為了釐清LHBs如何調控p53蛋白之穩定性,我們鑑定出一屬於BAG蛋白質家族之伴護子調節蛋白,Bag2,能與LHBs結合而影響其原本做為p53伴護子之功能。實驗結果顯示在LHBs細胞中大量表現Bag2可恢復部分p53的表現。總結上述結果,LHBs利用兩種不同機制來弱化腫瘤抑制因子p53之功能,分別為藉由與Bag2結合來影響其保護p53之功能以及將p53去乙醯化使p53失去生物活性。這些發現對於LHBs如何誘發肝癌的致病機轉提供了新的機轉。
    Liver cancer is the second frequent cause of cancer death worldwide. About 70-80% of liver cancer belongs to hepatocellular carcinoma (HCC) and nearly 60% of HCC are associated chronic hepatitis B virus (HBV) infection. HBV large surface antigen (LHBs) has been considered as a potential oncoprotein in hepatocarcinogenesis. In this study, we found that the presence of LHBs down-regulates tumor suppressor p53 in hepatocytes. This down-regulation is associated with decreased stability of p53 and increased Mdm2 expression. We also found that p53 down-regulation accompanies with intrinsic DNA damages and reduced of DNA damage response in hepatocytes. Chemical induced DNA damages fails to activate p53 and its downstream p21 in LHBs-expressing cells. Moreover, we detected a significant increase in multinucleation in LHBs-expressing cells, indicating a loss of ploidy control. The disruption of p53-Mdm2 interaction with Nutlin-3 is not sufficient to restore p53 expression in LHBs-expressing cells, whereas the inhibition of Sirtuin-mediated p53 deacetylation successfully rescues p53 expression and its biological function. To clarify how does LHBs regulates p53 stability, we identified BAG family molecular chaperone regulator 2 (Bag2), a binding partner of LHBs which acts as a chaperon protein of p53. Overexpression of Bag2 partially restored p53 expression level in LHBs-expressing cells. Together these results indicate that LHBs attenuates p53 functionality via two independent mechanisms, compete with p53 for binding to chaperon protein Bag2 and inactivate p53 by deacetylation. These findings therefore highlight the pathologic function of LHBs in HBV-mediated hepatocarcinogenesis.
    URI: http://nthur.lib.nthu.edu.tw/dspace/handle/987654321/86842
    Source: http://thesis.nthu.edu.tw/cgi-bin/gs/hugsweb.cgi?o=dnthucdr&i=sGH02102080543.id
    Appears in Collections:[分子與細胞生物研究所] 博碩士論文

    Files in This Item:

    File SizeFormat
    GH02102080543.pdf170KbAdobe PDF229View/Open


    在NTHUR中所有的資料項目都受到原著作權保護,僅提供學術研究及教育使用,敬請尊重著作權人之權益。若須利用於商業或營利,請先取得著作權人授權。
    若發現本網站收錄之內容有侵害著作權人權益之情事,請權利人通知本網站管理者(smluo@lib.nthu.edu.tw),管理者將立即採取移除該內容等補救措施。

    SFX Query

    與系統管理員聯絡

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback