scholarly journals Hepatitis B Virus X Protein Enhances Transcriptional Activity of Hypoxia-inducible Factor-1α through Activation of Mitogen-activated Protein Kinase Pathway

2003 ◽  
Vol 278 (40) ◽  
pp. 39076-39084 ◽  
Author(s):  
Young-Gun Yoo ◽  
Seung Hyun Oh ◽  
Eun Sook Park ◽  
Hyeseong Cho ◽  
Naery Lee ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Protein Kinase ◽  
Hepatitis B ◽  
Transcriptional Activity ◽  
Hypoxia Inducible Factor ◽  
Mitogen Activated Protein Kinase ◽  
X Protein ◽  
B Virus ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

scholarly journals Hepatitis B Virus X Protein Activates the p38 Mitogen-Activated Protein Kinase Pathway in Dedifferentiated Hepatocytes

2002 ◽  
Vol 76 (19) ◽  
pp. 9763-9772 ◽  
Author(s):  
Chi Tarn ◽  
Lin Zou ◽  
Ronald L. Hullinger ◽  
Ourania M. Andrisani
Keyword(s):  
Hepatitis B Virus ◽  
Protein Kinase ◽  
Hepatitis B ◽  
Cell Line ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
X Protein ◽  
Pathway Activation ◽  
B Virus ◽  
Mitogen Activated Protein

ABSTRACT Hepatitis B virus X protein (pX) is implicated in hepatocarcinogenesis by an unknown mechanism. Employing a cellular model linked to pX-mediated transformation, we investigated the role of the previously reported Stat3 activation by pX in hepatocyte transformation. Our model is composed of a differentiated hepatocyte (AML12) 3pX-1 cell line that undergoes pX-dependent transformation and a dedifferentiated hepatocyte (AML12) 4pX-1 cell line that does not exhibit transformation by pX. We report that pX-dependent Stat3 activation occurs only in non-pX-transforming 4pX-1 cells and conclude that Stat3 activation is not linked to pX-mediated transformation. Maximum Stat3 transactivation requires Ser727 phosphorylation, mediated by mitogenic pathway activation. Employing dominant negative mutants and inhibitors of mitogenic pathways, we demonstrate that maximum, pX-dependent Stat3 transactivation is inhibited by the p38 mitogen-activated protein kinase (MAPK)-specific inhibitor SB 203580. Using transient-transreporter and in vitro kinase assays, we demonstrate for the first time that pX activates the p38 MAPK pathway only in 4pX-1 cells. pX-mediated Stat3 and p38 MAPK activation is Ca2+ and c-Src dependent, in agreement with the established cellular action of pX. Importantly, pX-dependent activation of p38 MAPK inactivates Cdc25C by phosphorylation of Ser216, thus initiating activation of the G2/M checkpoint, resulting in 4pX-1 cell growth retardation. Interestingly, pX expression in the less differentiated hepatocyte 4pX-1 cells activates signaling pathways known to be active in regenerating hepatocytes. These results suggest that pX expression in the infected liver effects distinct mitogenic pathway activation in less differentiated versus differentiated hepatocytes.

scholarly journals An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
So-Young Kim ◽  
Hong Kim ◽  
Sang-Won Kim ◽  
Na-Rae Lee ◽  
Chae-Min Yi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Protein Kinase ◽  
Hepatitis B ◽  
P38 Mapk ◽  
Sodium Taurocholate ◽  
Therapeutic Strategies ◽  
Host Factors ◽  
Mitogen Activated Protein Kinase ◽  
B Virus ◽  
Mitogen Activated Protein

ABSTRACT Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.

scholarly journals Hepatitis B Virus Core Protein Sensitizes Hepatocytes to Tumor Necrosis Factor-Induced Apoptosis by Suppression of the Phosphorylation of Mitogen-Activated Protein Kinase Kinase 7

2014 ◽  
Vol 89 (4) ◽  
pp. 2041-2051 ◽  
Author(s):  
Baosen Jia ◽  
Minggao Guo ◽  
Gaiyun Li ◽  
Demin Yu ◽  
Xinxin Zhang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Protein Kinase ◽  
Hepatitis B ◽  
Mitogen Activated Protein Kinase ◽  
Virus Core ◽  
Tnf Α ◽  
B Virus ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACTHepatitis B, which caused by hepatitis B virus (HBV) infection, remains a major health threat worldwide. Hepatic injury and regeneration from chronic inflammation are the main driving factors of liver fibrosis and cirrhosis in chronic hepatitis B. Proinflammatory tumor necrosis factor alpha (TNF-α) has been implicated as a major inducer of liver cell death during viral hepatitis. Here, we report that in hepatoma cell lines and in primary mouse and human hepatocytes, expression of hepatitis B virus core (HBc) protein made cells susceptible to TNF-α-induced apoptosis. We found by tandem affinity purification and mass spectrometry that receptor of activated protein kinase C 1 (RACK1) interacted with HBc. RACK1 was recently reported as a scaffold protein that facilitates the phosphorylation of mitogen-activated protein kinase kinase 7 (MKK7) by its upstream activators. Our study showed that HBc abrogated the interaction between MKK7 and RACK1 by competitively binding to RACK1, thereby downregulating TNF-α-induced phosphorylation of MKK7 and the activation of c-Jun N-terminal kinase (JNK). In line with this finding, specific knockdown of MKK7 increased the sensitivity of hepatocytes to TNF-α-induced apoptosis, while overexpression of RACK1 counteracted the proapoptotic activity of HBc. Capsid particle formation was not obligatory for HBc proapoptotic activity, as analyzed using an assembly-defective HBc mutant. In conclusion, the expression of HBc sensitized hepatocytes to TNF-α-induced apoptosis by disrupting the interaction between MKK7 and RACK1. Our study is thus the first indication of the pathogenic effects of HBc in liver injury during hepatitis B.IMPORTANCEOur study revealed a previously unappreciated role of HBc in TNF-α-mediated apoptosis. The proapoptotic activity of HBc is important for understanding hepatitis B pathogenesis. In particular, HBV variants associated with severe hepatitis may upregulate apoptosis of hepatocytes through enhanced HBc expression. Our study also found that MKK7 is centrally involved in TNF-α-induced hepatocyte apoptosis and revealed a multifaceted role for JNK signaling in this process.

scholarly journals Hepatitis B Virus X Protein Induces Perinuclear Mitochondrial Clustering in Microtubule- and Dynein-Dependent Manners

2006 ◽  
Vol 81 (4) ◽  
pp. 1714-1726 ◽  
Author(s):  
Sujeong Kim ◽  
Hye-Young Kim ◽  
Seungmin Lee ◽  
Sung Woo Kim ◽  
Seonghyang Sohn ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nuclear Periphery ◽  
Mitogen Activated Protein Kinase ◽  
Transport Systems ◽  
Dependent Manner ◽  
Atpase Inhibitor ◽  
X Protein ◽  
Hbv Replication ◽  
B Virus

ABSTRACT The hepatitis B virus (HBV) X protein (HBx) is thought to play a key role in HBV replication and the development of liver cancer. It became apparent that HBx induces mitochondrial clustering at the nuclear periphery, but the molecular basis for mitochondrial clustering is not understood. Since mitochondria move along the cytoskeleton as a cargo of motor proteins, we hypothesized that mitochondrial clustering induced by HBx occurs by an altered intracellular motility. Here, we demonstrated that the treatment of HBx-expressing cells with a microtubule-disrupting drug (nocodazole) abrogated mitochondrial clustering, while the removal of nocodazole restored clustering within 30 to 60 min, indicating that mitochondrial transport is occurring in a microtubule-dependent manner. The addition of a cytochalasin D-disrupting actin filament, however, did not measurably affect mitochondrial clustering. Mitochondrial clustering was further studied by observations of HBV-related hepatoma cells and HBV-replicating cells. Importantly, the abrogation of the dynein activity in HBx-expressing cells by microinjection of a neutralizing anti-dynein intermediate-chain antibody, dynamitin overexpression, or the addition of a dynein ATPase inhibitor significantly suppressed the mitochondrial clustering. In addition, HBx induced the activation of the p38 mitogen-activated protein kinase (MAPK) and inhibition of the p38 kinase activity by SB203580-attenuated HBx-induced mitochondrial clustering. Taken together, HBx activation of the p38 MAPK contributed to the increase in the microtubule-dependent dynein activity. The data suggest that HBx plays a novel regulatory role in subcellular transport systems, perhaps facilitating the process of maturation and/or assembly of progeny particles during HBV replication. Furthermore, mitochondrion aggregation induced by HBx may represent a cellular process that underlies disease progression during chronic viral infection.

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