Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein HBx requires MTA1 coregulator.

ABSTRACT The hepatitis B virus (HBV) X protein (HBx) is a multifunctional regulator of cellular signal transduction and transcription pathways and has a critical role in HBV replication. Much of the cytoplasmic signal transduction activity associated with HBx expression and its stimulation of viral replication is attributable to HBx-induced activation of calcium signaling pathways involving Pyk2 and Src tyrosine kinases. To further characterize upstream signal transduction pathways that are required for HBx activity, including activation of Src and mitogen-activated protein kinase (MAPK) cascades, we determined whether focal adhesion kinase (FAK), a known regulator of Src family kinases and the other member of the Pyk2/FAK kinase family, is activated by HBx. We report that HBx activates FAK and that FAK activation is important for multiple HBx functions. Dominant inhibiting forms of FAK blocked HBx activation of Src kinases and downstream signal transduction, HBx stimulation of NF-κB and AP-1-dependent transcription, and HBV DNA replication. We also demonstrate that HBx-induced activation of FAK is dependent on cellular calcium signaling, which is modulated by HBx. Moreover, prolonged expression of HBx increases both FAK activity and its level of expression. FAK activation may play a role in cellular transformation and cancer progression. HBx stimulation of FAK activity and abundance may also be relevant as a potential cofactor in HBV-associated hepatocellular carcinoma.

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Interaction between STAT-3 and HNF-3 Leads to the Activation of Liver-Specific Hepatitis B Virus Enhancer 1 Function

Journal of Virology ◽

10.1128/jvi.76.6.2721-2729.2002 ◽

2002 ◽

Vol 76 (6) ◽

pp. 2721-2729 ◽

Cited By ~ 51

Author(s):

Gulam Waris ◽

Aleem Siddiqui

Keyword(s):

Gene Expression ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Transcriptional Control ◽

Viral Gene Expression ◽

Cooperative Interaction ◽

Viral Gene ◽

Mobility Shift ◽

B Virus ◽

Stimulation Of

ABSTRACT The signal transducer and activator of transcription 3 (STAT-3), a member of the STAT family of proteins, binds to a large number of transcriptional control elements and regulates gene expression in response to cytokines. While it binds to its cognate nucleotide sequences, it has been recently shown to directly interact with other transcriptional factors in the absence of DNA. We report here one such novel interaction between STAT-3 and hepatocyte nuclear factor 3 (HNF-3) in the absence of DNA. We have identified a STAT-3 binding site within the core domain of hepatitis B virus (HBV) enhancer 1. The HBV enhancer 1 DNA-STAT-3 protein interaction is shown to be stimulated by interleukin-6 (IL-6) and epidermal growth factor, which leads to an overall stimulation of HBV enhancer 1 function and viral gene expression. Using mobility shift assays and transient transfection schemes, we demonstrate a cooperative interaction between HNF-3 and STAT-3 in mediating the cytokine-mediated HBV enhancer function. Cytokine stimulation of HBV gene expression represents an important regulatory scheme of direct relevance to liver disease pathogenesis associated with HBV infection.

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Hepatitis B virus transactivator protein X interacts with the TATA-binding protein.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.92.4.1003 ◽

1995 ◽

Vol 92 (4) ◽

pp. 1003-1007 ◽

Cited By ~ 121

Author(s):

I. Qadri ◽

H. F. Maguire ◽

A. Siddiqui

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Binding Protein ◽

Tata Binding Protein ◽

B Virus ◽

Protein X ◽

Transactivator Protein

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Nitric Oxide Inhibits Hepatitis B Virus Replication in the Livers of Transgenic Mice

Journal of Experimental Medicine ◽

10.1084/jem.191.7.1247 ◽

2000 ◽

Vol 191 (7) ◽

pp. 1247-1252 ◽

Cited By ~ 88

Author(s):

Luca G. Guidotti ◽

Heike McClary ◽

Jacquelyn Moorhead Loudis ◽

Francis V. Chisari

Keyword(s):

Nitric Oxide ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Antiviral Activity ◽

Transgenic Mice ◽

Hbv Replication ◽

Polycytidylic Acid ◽

B Virus ◽

Ifn Γ ◽

Deficient Mice

We have previously identified two antiviral cytokines (interferon [IFN]-γ and IFN-α/β) that downregulate hepatitis B virus (HBV) replication in the liver of transgenic mice. The cytokine-inducible downstream events that inhibit HBV replication have not been identified. One possible factor is nitric oxide (NO), a pleiotropic free radical with antiviral activity that is produced in the liver by the inducible NO synthase (iNOS). To examine the role of NO in our model, we crossed transgenic mice that replicate HBV with mice that lack a functional iNOS. Importantly, iNOS-deficient mice were almost completely resistant to the noncytopathic inhibitory effect of HBV-specific cytotoxic T lymphocytes on viral replication, an effect that we have shown previously to depend on the intrahepatic induction of IFN-γ. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-α/β induced by either polyinosinic-polycytidylic acid complex or by lymphocytic choriomeningitis virus (LCMV) infection. These results indicate that NO mediates the antiviral activity of IFN-γ, whereas the antiviral activity of IFN-α/β is NO independent. We also compared the relative sensitivity of LCMV to control by NO in these animals. Interestingly, LCMV replicated to higher levels in the liver of iNOS-deficient mice than control mice, indicating that NO controls LCMV replication in the liver, as well as HBV.

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