Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hepatitis B virus X protein (HBx) is suggested to regulate transcription by stimulation of intracellular signalling pathways. We have analysed the effects of HBx on activation of the MAP kinase (Erk) and JNK/SAPK signalling pathways and confirm a stimulation of the Erk/MAP kinase in quiescent cells. However, a substantial Erk-independent activation of AP-1, and phosphorylation of c-Jun (serine-63), but not Erk-2, was induced by HBx in dividing, serum-maintained cells. These data suggest that HBx promiscuously activates Erk and JNK responsive pathways and that its overall effect on signalling may be influenced by external mitogenic stimuli.
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PMID:Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein. 982 Jan 49

Insulin stimulates cellular oncogenic activators such as c-jun, c-fos, and c-myc; and hepatitis B virus (HBV) X, a viral transactivator, is known to induce liver cancer in transgenic mice. In this respect, the effect of insulin on the expression of HBx protein was investigated in HepG2 cells. Insulin-stimulated transcription from the HBV X promoter in a dose-dependent manner was assessed by chloramphenicol acetyltransferase (CAT) assay. A mutation preventing AP-1 binding to the E element abolished the activation of the HBV X promoter by insulin. In addition, insulin stimulated the minimal thymidine kinase (tk) gene promoter activity through both the HBV E element and the consensus AP-1 binding site in HepG2 cells. An electrophoretic mobility shift assay (EMSA) using insulin-treated HepG2 nuclear extracts showed that insulin actually enhanced the binding of nuclear proteins to the HBV E element as well as to the consensus AP-1 binding site. Both HBV E and AP-1 oligonucleotides were effective competitors for this binding. These results showed that insulin elevated the expression of HBx protein through the AP-1 binding site of HBV EnI. We suggest that insulin can augment the role of HBx in the development of hepatocellular carcinoma (HCC) in HBV-infected liver, probably through interaction with other cellular oncogenes.
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PMID:Insulin activates the hepatitis B virus X gene through the activating protein-1 binding site in HepG2 cells. 983 4

In addition to causing acute and chronic hepatitis, hepatitis B virus (HBV) is considered to be a major cliological factor in the development of human hepatocellular carcinoma (HCC). Epidemiological studies have demonstrated an approximately 10-fold increase in the relative risk of HCC among HBV carried compared to noncarriers. Almost all HBV-associated HCCs studied so far harbor chromosomally integrated HBV DNA. Integrated viral DNA can encode two types of transcriptional activators, the HBx protein and the PreS2 activators [the large surface proteins (LHBs) and truncated middle surface proteins (MHBs)]. The activator function of the PreS2 activators is based on the cytoplasmic orientation of the PreS2 domain. The PreS2 domain is PKC-dependent phosphorylated. Moreover, the PreS2 domain binds of PKC alpha/beta and triggers a PKC-dependent activation of the c-Raf-1/MAP2-kinase signal transduction cascade, resulting in an activation of transcription factors such as AP-1 and NF-kB. Furthermore, by activation of this signaling cascade, the PreS2 activators cause an increased proliferation rate of hepatocytes. According to the two-step model of carcinogenesis (initiation/promotion), the PreS2 activators could exert a tumour-promoter-like function by activation of the PKC/c-Raf-1/MAP2-kinase signaling cascade: cells harboring critical mutations (initiation) may be positively selected (promotion). Such a multistep process may account for the long latency period in HCC development, but it also leads to the hypothesis that each tumor reflects an individual case.
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PMID:The PreS2 activators of the hepatitis B virus: activators of tumour promoter pathways. 1002 12

We cloned and characterized the woodchuck tumor necrosis factor (TNF) and lymphotoxin-alpha, -beta (LT-alpha, -beta) cDNAs, genes and proteins to facilitate study of the functions of these cytokines during the course of woodchuck hepatitis virus (WHV) infection. Woodchuck cDNA and genomic DNA libraries were screened with woodchuck-specific DNA probes to isolate the cDNA and gene clones for TNF, LT-alpha and LT-beta. The cDNAs for woodchuck TNF, LT-alpha and LT-beta code for proteins of 233, 205 and 310 amino acids respectively. The polypeptide encoded by each gene among woodchucks, humans and mice can differ: the human TNF, LT-alpha and LT-beta genes encode polypeptides of 233, 205 and 244 amino acids respectively, whereas the mouse TNF, LT-alpha and LT-beta genes encode polypeptides of 235, 202 and 306 amino acids respectively. In the woodchuck, there are four exons for TNF, four exons for LT-alpha and three exons for LT-beta. The RNA splicing patterns for TNF, LT-alpha and LT-beta genes are identical among woodchucks, humans and mice, except that the human LT-beta gene contains four exons. The woodchuck TNF gene promoter contains consensus sequences for binding of AP-1, AP-2, C/EBPbeta, CRE, Egr-1, Ets, NF-AT, NF-kappaB and SP-1 transcription factors. LT-alpha has AP-2, Ets, NF-kappaB, SP-1 and STAT binding sites, and LT-beta has Egr-1/SP-1, Ets and NF-kappaB binding sites. The bacterially expressed woodchuck TNF and LT-alpha proteins exhibited cytotoxic activities on both mouse L929B and woodchuck A2 cells in the presence of actinomycin D. The specific activities of TNF and LT-alpha were 2.62x10(8) units/mg and 2.22x10(3) units/mg respectively for L929B cells, and 1.05x10(9) units/mg and 3.56x10(4) units/mg respectively for A2 cells. However, only woodchuck TNF showed cytotoxic activity on human HepG2 cells, with a specific activity of 6.55x10(7) units/mg in the presence of actinomycin D. The data obtained from this study will be useful to future investigations of the TNF and LT antitumor and anti-viral activities, and their therapeutic potential in the woodchuck model for human hepatitis B virus (HBV).
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PMID:Woodchuck lymphotoxin-alpha, -beta and tumor necrosis factor genes: structure, characterization and biological activity. 1072 23

Hepatitis B virus (HBV) has a unique fourth open reading frame coding for a 16.5-kDa protein known as hepatitis B virus X protein (HBX). The importance of HBX in the life cycle of HBV has been well established, but the underlying molecular function of HBX remains controversial. We previously identified a proteasome subunit PSMA7 that interacts specifically with HBX in the Saccharomyces cerevisiae two-hybrid system. Here we demonstrate that PSMC1, an ATPase-like subunit of the 19 S proteasome component, also interacts with HBX and PSMA7. Analysis of the interacting domains among PSMA7, PSMC1, and HBX by deletion and site-directed mutagenesis suggested a mutually competitive structural relationship among these polypeptides. The competitive nature of these interactions is further demonstrated using a modified yeast two-hybrid dissociator system. The crucial HBX sequences involved in interaction with PSMA7 and PSMC1 are important for its function as a transcriptional coactivator. HBX, while functioning as a coactivator of AP-1 and acidic activator VP-16 in mammalian cells, had no effect on the transactivation function of their functional orthologs GCN4 and Gal4 in yeast. Overexpression of PSMC1 seemed to suppress the expression of various reporters in mammalian cells; this effect, however, was overcome by coexpression of HBX. In addition, HBX expression inhibited the cellular turnover of c-Jun and ubiquitin-Arg-beta-galactosidase, two well known substrates of the ubiquitin-proteasome pathway. Thus, interaction of HBX with the proteasome complex in metazoan cells may underlie the functional basis of proteasome as a cellular target of HBX.
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PMID:Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex. 1074 18

To elucidate the molecular mechanisms involved in the action of common carcinogens, which can act as important cofactors in modulating hepatitis B virus-mediated hepatocellular carcinogenesis, we have investigated the influence of aflatoxin B(1) (AFB), a potent liver carcinogen, as well as benzo[a]pyrene (BP) and 4-aminobiphenyl (4-ABP), carcinogens in cigarette smoke, on the induction of various transcription factors in human hepatoblastoma HepG2 cells. DNA electrophoretic mobility shift assays were performed with nuclear extracts from HepG2 cells treated with 10 micromol/L AFB, 40 micromol/L BP, or 300 micromol/L 4-ABP for 6 and 24 hours. Eight- and 6-fold increases in nuclear transcription factor kappaB (NF-kappaB), and 5- and 10-fold increases in activated protein (AP-1) transcription factor were observed with 24 hours AFB and BP treatments, respectively, whereas 4-ABP treatment resulted in an approximately 4-fold induction of both NF-kappaB and AP-1. Moreover, 4-ABP gave the strongest NF-kappaB activation in 6 hours of treatment. Four- and 10-fold activation of stress protein was detected by a consensus heat shock factor (HSF) sequence binding probe, with AFB and BP treatments, respectively. DNA adducts were observed by immunoassays in HepG2 cells treated with AFB and BP but not with 4-ABP. Increased human hepatitis B virus (HBV) surface antigen (HBsAg) synthesis was detected in AFB- and BP-treated HepG2 cells following transfection with recircularized HBV DNA. These data suggest that certain carcinogen-induced transcription factors may influence viral carcinogenesis and initiate hepatocellular carcinomas (HCC).
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PMID:Effects of carcinogen-induced transcription factors on the activation of hepatitis B virus expression in human hepatoblastoma HepG2 cells and its implication on hepatocellular carcinomas. 1091 44

To clarify the effects of hepatitis C virus (HCV) infection on hepatocytes, we analyzed and compared the induction of intracellular signals by HCV and hepatitis B virus (HBV) proteins. We examined the influence of 7 HCV (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and 4 HBV (precore, core, polymerase, and X) proteins on 5 well-defined intracellular signaling pathways associated with cell proliferation, differentiation, and apoptosis by use of a reporter assay. Viral protein-expression vectors were cotransfected into mammalian cells with reporter vectors having a luciferase gene driven by the following inducible cis-enhancer elements: the cyclic adenosine monophosphate response element, the serum response element (SRE), and the binding sites for nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1), and serum response factor (SRF). In addition, the activation of signals by HCV proteins was examined in a reporter plasmid having a natural interleukin-8 (IL-8) promoter upstream of a luciferase gene. Of 11 HCV and HBV proteins, HCV core had the strongest influence on intracellular signals, especially NF-kappaB-, AP-1-, and SRE-associated pathways. HCV core's activation level exceeded that of HBV X protein, a well-characterized transactivator of these signals. Moreover, HCV core activated the IL-8 promoter through NF-kappaB and AP-1. For the other proteins, HCV NS4B showed signal activation, but signals were activated at a lesser extent. The luciferase reporter assay, a recently introduced technique, helped in the elucidation of molecular events underlying the inflammatory and proliferation process in the liver induced by HCV.
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PMID:Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer. 1091 50

Hepatitis delta virus infection sometimes causes severe and fulminant hepatitis as a coinfection or superinfection along with the hepatitis B virus. To elucidate the underlying mechanism of injury caused by hepatitis delta virus, we examined whether two isoforms of the hepatitis delta antigen (HDAg) had any effect on five well defined intracellular signal transduction pathways: serum response factor (SRF)-, serum response element (SRE)-, nuclear factor kappaB-, activator protein 1-, and cyclic AMP response element-dependent pathways. Reporter assays revealed that large HDAg (LHDAg) activated the SRF- and SRE-dependent pathways. In contrast, small HDAg (SHDAg) did not activate any of five pathways. LHDAg enhanced the transcriptional ability of SRF without changing its DNA binding affinity in an electrophoretic mobility shift assay. In addition, LHDAg activated a rat SM22alpha promoter containing SRF binding site and a human c-fos promoter containing SRE. In conclusion, LHDAg, but not SHDAg, enhances SRF-associated transcriptions. Despite structural similarities between the two HDAgs, there are significant differences in their effects on intracellular signal transduction pathways. These results may provide clues that will aid in the clarification of functional differences between LHDAg and SHDAg and the pathogenesis of delta hepatitis.
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PMID:Large isoform of hepatitis delta antigen activates serum response factor-associated transcription. 1096 86

Hepatitis B virus produces chronic infections of the liver leading to cirrhosis and hepatocellular carcinoma. The X protein of hepatitis B virus (HBx) is a multifunctional protein that can interact with p53 but can also influence a variety of signal transduction pathways within the cell. In most instances this small viral protein favors cell survival and probably initiates hepatocarcinogenesis. HBx upregulates the activity of a number of transcription factors including NF-kappa B, AP-1, CREB, and TBP. However, the majority of HBx is localized to the cytoplasm where it interacts with and stimulates protein kinases such as protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. This small viral protein can localize to the mitochondrion. HBx may act as an adaptor or kinase activator to influence signal transduction pathways. This review will attempt to analyze the involvement of HBx in signal transduction pathways during hepatitis B viral infections and hepatocellular carcinoma development.
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PMID:X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. 1132 2

Here, based on the recent finding of HBx (X-gene product of hepatitis B virus) as the inducer of Jak1, we investigated the mechanism for the HBx-mediated host cell regulation and found that (i) HBx associates specifically with Jak1 in vivo; (ii) HBx itself forms a dimer which leads to juxtaposition of associated Jak1 and subsequent activation of the tyrosine kinase activity of Jak1; (iii) HBx-mediated activation of the promoters containing AP-1-, NF-kappaB-, SRE-, and SIE-sites is dependent on the activation of Jak1; (iv) Jak1, once activated by HBx, induces Ras activity through recruitment of Grb2 and induces tyrosine phosphorylation of Raf1, but not shc. These findings show that previously reported functions of HBx, such as activation of multiple signaling pathways and transcriptional activation are attributable to HBx-mediated Jak1 activation.
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PMID:Through induction of juxtaposition and tyrosine kinase activity of Jak1, X-gene product of hepatitis B virus stimulates Ras and the transcriptional activation through AP-1, NF-kappaB, and SRE enhancers. 1152 82


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