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Pathogenesis of hepatitis B virus infection: The effect of the HBx protein from HBV on cell survival and death.

機(jī)譯：乙型肝炎病毒感染的發(fā)病機(jī)制：HBV中的HBx蛋白對(duì)細(xì)胞存活和死亡的影響。

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Human hepatitis B virus (HBV) is one of several agents causing infectious hepatitis, which can lead to the development of liver cirrhosis and hepatocellular carcinoma (HCC). HBV-related HCC is among the top 10 most frequent cancers throughout the world. More than 400 million people worldwide are chronically infected with this virus. Currently, no effective treatment is available for those with established HBV infections, despite the recent development of a recombinant vaccine for protecting previously unexposed individuals. The exact molecular events involved in HBV-related liver carcinogenesis remain to be elucidated. A viral protein, the HBx protein from HBV has been implicated in the liver carcinogenesis after HBV infection. The work presented in this thesis explores the mechanism of HBx's involvement in liver cancer, focusing on its effect on apoptosis and its interaction with cellular signaling pathways. Experiments demonstrated that cell apoptosis caused by anti-Fas antibodies and serum deprivation can be blocked by the expression of the HBx protein. However, fibroblasts that are SEK1 deficient still undergo Fas-mediated apoptosis whether or not the viral protein is present. Under low serum condition, cells treated with PI3-K inhibitor lose the survival advantage provided by the HBx protein. Therefore, it is suggested that interactions with SEK1-dependent pathway and PI3K-dependent pathway are responsible for the effect of the HBx protein on Fas-mediated apoptosis and serum-starvation-mediated apoptosis, respectively. Experiments further demonstrated that the HBx protein interacts with SEK1-dependent SAPK and PI3K-PKB signaling pathway and enhances the SAPK and PKB activities, which contribute to the protective effects of the HBx protein on cells under specific apoptotic stimuli. Lastly, interaction of the HBx protein with the components in the apoptotic pathway was also studied. Results show that the HBx protein targets the apoptotic pathway, perhaps mainly by locating on the mitochondria and cooperating with an anti-apoptotic molecule Bcl-XL. Generally, data presented in this thesis indicates that the HBx protein can be involved in the multiple regulatory steps in survival and death signaling. HBx protein is thus suggested to be a multifunctional viral regulator strongly implicated in hepatocarcinogenesis.
機(jī)譯：人乙型肝炎病毒（HBV）是引起傳染性肝炎的幾種藥物之一，可導(dǎo)致肝硬化和肝細(xì)胞癌（HCC）的發(fā)展。 HBV相關(guān)的HCC是全球十大最常見的癌癥之一。全世界有超過4億人長(zhǎng)期感染這種病毒。當(dāng)前，盡管最近開發(fā)了用于保護(hù)先前未接觸個(gè)體的重組疫苗，但對(duì)于已確診的HBV感染者，尚無有效的治療方法。尚需闡明與HBV相關(guān)的肝癌發(fā)生有關(guān)的確切分子事件。 HBV感染后，一種病毒蛋白，即來自HBV的HBx蛋白與肝癌發(fā)生有關(guān)。本文提出的工作探討了HBx參與肝癌的機(jī)制，重點(diǎn)研究了其對(duì)細(xì)胞凋亡的影響及其與細(xì)胞信號(hào)通路的相互作用。實(shí)驗(yàn)證明，抗-Fas抗體引起的細(xì)胞凋亡和血清剝奪可以被HBx蛋白的表達(dá)所阻斷。但是，無論是否存在病毒蛋白，SEK1缺陷的成纖維細(xì)胞仍會(huì)經(jīng)歷Fas介導(dǎo)的凋亡。在低血清條件下，用PI3-K抑制劑處理的細(xì)胞失去了HBx蛋白提供的生存優(yōu)勢(shì)。因此，建議與SEK1依賴性途徑和PI3K依賴性途徑的相互作用分別負(fù)責(zé)HBx蛋白對(duì)Fas介導(dǎo)的凋亡和血清饑餓介導(dǎo)的凋亡的影響。實(shí)驗(yàn)進(jìn)一步證明，HBx蛋白與SEK1依賴的SAPK和PI3K-PKB信號(hào)通路相互作用，并增強(qiáng)SAPK和PKB活性，這有助于HBx蛋白在特定凋亡刺激下對(duì)細(xì)胞的保護(hù)作用。最后，還研究了HBx蛋白與細(xì)胞凋亡途徑中成分的相互作用。結(jié)果表明，HBx蛋白靶向凋亡途徑，可能主要是位于線粒體上并與抗凋亡分子Bcl-X L 協(xié)同作用。通常，本論文提供的數(shù)據(jù)表明HBx蛋白可能參與生存和死亡信號(hào)的多個(gè)調(diào)控步驟。因此，HBx蛋白被認(rèn)為是與肝癌發(fā)生密切相關(guān)的多功能病毒調(diào)節(jié)劑。

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  • 作者

    Diao, Jingyu.;

  • 作者單位

    University of Toronto (Canada).;

  • 授予單位 University of Toronto (Canada).;
  • 學(xué)科 Biology Molecular.; Biophysics Medical.
  • 學(xué)位 Ph.D.
  • 年度 2002
  • 頁碼 232 p.
  • 總頁數(shù) 232
  • 原文格式 PDF
  • 正文語種 eng
  • 中圖分類 分子遺傳學(xué);生物物理學(xué);
  • 關(guān)鍵詞

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