國家衛生研究院 NHRI:Item 3990099045/11647
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    題名: Pre-S-2 mutant surface antigen of hepatitis B virus induces retinoblastoma hyper-phosphorylation through interaction with JAB1 protein in endoplasmic reticulum: A novel mechanism for HBV-induced hepatocellular carcinoma
    作者: Hsieh, YH;Tsai, JH;Wang, HC;Su, IJ;Huang, W
    貢獻者: National Institute of Infectious Diseases and Vaccinology
    摘要: Chronic HBV infection is a major global cause of hepatocellular carcinoma (HCC). HBV encodes three types of surface proteins that are different in sizes. Two major types of deletion mutants in HBS gene have been identified, and designated pre-S1 and pre-S2 mutant large HBsAg. The pre-S mutants large HBsAg accumulate in hepatocytes and reveal ground-glass hepatocytes (GGH), which are often seen in patients with chronic HBV infection. Hepatocytes expressing the pre-S2 mutant large HBsAg cluster into groups and exhibit clonal expansion and growth advantage. This suggests that pre-S2 mutant large HBsAg may participate in HBV-related HCC. Previously, we found the pre-S mutant large HBS proteins accumulated in endoplasmic reticulum (ER) and induced oxidative stress and oxidative DNA damage in vitro and in vivo. In this study, we found retinoblastoma (RB) was hyper-phosphorylated in the HuH-7 hepatoma cells expressing pre-S2 mutant large HBsAg, but not in those expressing wild-type or pre-S1 mutant large HBsAg. The RB hyper-phosphorylation induced by the pre-S2 mutant large HBsAg is acted by CDK-2 and causes dissociation of RB-E2F1 complex. This is an ER stress-dependent manner, as the ER stress inhibitors nearly completely abolished it. Cyclin A, associated with CDK-2, was also found to be up-regulated by the pre-S2 mutant large HBsAg, resulting in cell cycle progression even in presence of oxidative stress. In order to identify the molecule(s) directly targeted by the pre-S2 mutant large HBsAg, the yeast-two hybrid assays were employed to identify the proteins that interact with pre-S2 mutant large HBsAg. The Jun activation domain-binding protein 1 (JAB1), a subunit of the COP9 signalosome complex, was found to interact with pre-S2 mutant large HBsAg but not with wild type or pre-S1 mutant large HBsAg. Through its direct binding to JAB1, the pre-S2 mutant large HBsAg disrupts association of JAB1 with IRE1 (in ER) or MIF (in cytosol) and releases JAB1 from the complexes. The free JAB1 has been reported to interact with p27Kip1 and promote its degradation. By western blot analysis, the p27Kip1 was found to be down-regulated in the cells expressing pre-S2 mutant large HBsAg. In transgenic mice carrying the pre-S2 mutant large HBsAg but not wild-type large HBsAg, the RB hyperphorylation and CDK-2 activation were also observed, indicating that the pre-S2 mutant large HBsAg causes RB hyperphosphorylation by CDK-2/cyclin A in vitro and in vivo. In summary, the pre-S2 mutant large HBsAg directly associates with JAB1, inducing RB hyper-phosphorylation and ultimately genomic instability and HCC.
    日期: 2006-04
    關聯: Cancer Research. 2006 Apr;66(8, Suppl.):603-604.
    Link to: http://cancerres.aacrjournals.org/content/66/8_Supplement/603.4
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000454606200527
    顯示於類別:[蘇益仁(2002-2015)] 會議論文/會議摘要

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