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乙型肝炎病毒X蛋白升高的MSL2调节乙型肝炎病毒通过诱导APOBEC

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发表于 2017-10-22 16:24 |显示全部帖子
Hepatitis B virus X protein–elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis

    Yuen Gao1,†, Jinyan Feng1,†, Guang Yang1, Shuqin Zhang1, Yunxia Liu1, Yanan Bu1, Mingming Sun1, Man Zhao1, Fuquan Chen1, Weiying Zhang1, Lihong Ye2,* andXiaodong Zhang1,*

Version of Record online: 11 OCT 2017

DOI: 10.1002/hep.29316

© 2017 by the American Association for the Study of Liver Diseases.

Issue
Hepatology


Volume 66, Issue 5, pages 1413–1429, November 2017
Article has an altmetric score of 1

    1    State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, China
    2    State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, China

    †    These authors contributed equally to this work.

Email: Lihong Ye ([email protected]), Xiaodong Zhang ([email protected])

*ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Xiaodong Zhang, M.D., Ph.D.
Nankai University
94 Weijin Road
Tianjin 300071
P. R. China
E-mail: [email protected]
or
Lihong Ye, M.D., Ph.D.
Nankai University
94 Weijin Road
Tianjin 300071
P. R. China
E-mail: [email protected]

    Potential conflict of interest: Nothing to report.

    Supported in part by the National Basic Research Program of China (973 Program, grant nos. 2015CB553703 and 2015CB553905), the National Natural Science Foundation of China (grant nos. 31670769 and 31470756), and the Project of Prevention and Treatment of Key Infectious Diseases (grant no. 2014ZX0002002-005).



Chronic hepatitis B virus (HBV) infection is a leading cause in the occurrence of hepatitis B, liver cirrhosis, and liver cancer, in which nuclear HBV covalently closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence, plays crucial roles. In the present study, we explored the hypothesis that HBV X protein (HBx)-elevated male-specific lethal 2 (MSL2) activated HBV replication by modulating cccDNA in hepatoma cells, leading to hepatocarcinogenesis. Immunohistochemical analysis revealed that the expression of MSL2 was positively associated with that of HBV and was increased in the liver tissues of HBV-transgenic mice and clinical HCC patients. Interestingly, microarray profiling identified that MSL2 was associated with those genes responding to the virus. Mechanistically, MSL2 could maintain HBV cccDNA stability through degradation of APOBEC3B by ubiquitylation in hepatoma cells. Above all, HBx accounted for the up-regulation of MSL2 in stably HBx-transfected hepatoma cell lines and liver tissues of HBx-transgenic mice. Luciferase reporter gene assays revealed that the promoter region of MSL2 regulated by HBx was located at nucleotide −1317/−1167 containing FoxA1 binding element. Chromatin immunoprecipitation assay validated that HBx could enhance the binding property of FoxA1 to MSL2 promoter region. HBx up-regulated MSL2 by activating YAP/FoxA1 signaling. Functionally, silencing MSL2 was able to block the growth of hepatoma cells in vitro and in vivo. Conclusion: HBx-elevated MSL2 modulates HBV cccDNA in hepatoma cells to promote hepatocarcinogenesis, forming a positive feedback loop of HBx/MSL2/cccDNA/HBV. Our finding uncovers insights into the mechanism by which MSL2 as a promotion factor in host cells selectively activates extrachromosomal DNA. (Hepatology 2017;66:1413–1429).

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才高八斗

发表于 2017-10-22 16:24 |显示全部帖子
乙型肝炎病毒X蛋白升高的MSL2调节乙型肝炎病毒通过诱导APOBEC3B降解来增加肝癌发生共价闭合环状DNA

    袁高1,†金金凤1,光阳1,张舒琴1,云夏刘1,延安布1,明明孙1,赵钊1陈福英1张丽红2 *张晓东1 *

在线记录版:2017年10月11日

DOI:10.1002 / hep.29316

©2017美国肝病研究协会。

问题
肝病


第66卷,第5期,第1413-1429页,2017年11月
文章的高分为1分

    1南开大学生命科学学院药物化学生物学国家重点实验室,天津市,中国
    2中国天津市南开大学生命科学学院生物化学系药物化学生物学国家重点实验室

    † 这些作者同等贡献这项工作。

电子邮箱:lihong Ye([email protected]),张晓东([email protected]

*地址相关性并重申要求:
张晓东博士
南开大学
维金路94号
天津300071
中国
电子邮件:[email protected]
要么
李丽红博士
南开大学
维金路94号
天津300071
中国
电子邮件:[email protected]

    潜在的利益冲突:没有报告。

    中国国家自然科学基金(拨款号:31670769和31470756)和中国国家基础研究计划(973计划,授权号:2015CB553703和2015CB553905)部分支持,重点传染病预防与治疗项目(授权号:2014ZX0002002-005)。



慢性乙型肝炎病毒(HBV)感染是乙型肝炎,肝硬化和肝癌发生的主要原因,其中核HBV共价闭合环状DNA(cccDNA),模板病毒转录并维持病毒持久性的基因组形式,扮演重要的角色。在本研究中,我们探讨了HBV X蛋白(HBx)升高的男性特异性致死2(MSL2)通过调节肝癌细胞中的cccDNA而激活HBV复制的假说,导致肝癌发生。免疫组织化学分析显示,HBV转基因小鼠和临床HCC患者的肝组织中MSL2的表达与HBV阳性表达呈正相关。有趣的是,微阵列分析发现MSL2与响应病毒的基因相关。机制上,MSL2可以通过肝癌细胞中的泛素化降解APOBEC3B来维持HBV cccDNA的稳定性。最重要的是,HBx在稳定的HBx转染的肝癌细胞系和HBx转基因小鼠的肝组织中占MSL2的上调。荧光素酶报告基因测定显示,HBx调控的MSL2启动子区位于含有FoxA1结合元件的核苷酸-1317 / -1167。染色质免疫沉淀测定验证了HBx可以增强FoxA1与MSL2启动子区域的结合特性。 HBx通过激活YAP / FoxA1信号上调MSL2。功能上,沉默MSL2能够在体外和体内阻断肝癌细胞的生长。结论:HBx升高的MSL2调节肝癌细胞中的HBV cccDNA,促进肝癌发生,形成HBx / MSL2 / cccDNA / HBV阳性反馈回路。我们的发现揭示了MSL2作为宿主细胞促进因子选择性激活染色体外DNA的机制的见解。 (Hepatology 2017; 66:1413-1429)。

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发表于 2017-10-23 09:50 |显示全部帖子
文章发表之后的后续工作是怎么安排的?

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发表于 2017-10-23 10:12 |显示全部帖子
回复 windu 的帖子

说实话,这种纯实验性文章,一年几十篇,看着就激动,最后大部分无疾而终

离开药物起码还有五年以上,临床又是五年

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才高八斗

发表于 2017-10-23 10:44 |显示全部帖子
回复 windu 的帖子

这是基础研究,提高对HBV病毒X蛋白的了解.
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