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

Chronic infection with hepatitis B virus (HBV) in humans is strongly linked to the development of hepatocellular carcinoma (HCC). Activation of growth-regulatory genes may play a crucial role in carcinogenesis. Proto-oncogene expression has been shown to be higher in HCC tissue with integrated HBV DNA than in the normal liver. Earlier, we showed that the 3' end of the HBV major surface gene (S) (426-855 nucleotides of the S region) is a transactivator of the X promoter-enhancer regulatory element in co-transfection experiments. This region expresses a truncated carboxy terminal S protein extending from amino acid residues 102 to 226. In this study, the truncated S protein (trc-S) was examined for its enhancing activity on several viral and cellular regulatory elements. The results indicate that trc-S activates rous sarcoma virus long terminal repeat (LTR), human T-lymphotropic virus 2 LTR, human immunodeficiency virus 1 LTR, and the c-jun and c-fos promoters. Electrophoretic mobility shift assays carried out to investigate its DNA-binding properties established that trc-S binds to HBV X promoter and oligonucleotides representing binding sites for the AP1 and TFIID transcription factors. The specificity of this interaction was confirmed by using competition experiments and supershift assays. These experiments suggest that trc-S is a transactivator of several cellular and viral promoters and that this activity is mediated by direct interaction with DNA.
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PMID:Hepatitis B virus surface (S) transactivator with DNA-binding properties. 1074 25

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

The hepatitis B virus (HBV) X protein (HBx) is a transactivator encoded by mammalian hepadnaviruses, and is thought to stimulate transcription by interacting with one or more host cell factors. Numerous cellular proteins have been reported to interact with HBx including a component of the nucleotide excision repair complex called ultraviolet damaged DNA binding (UV-DDB, or DDB1) protein. Recent studies have identified a role for DDB1 in transcription, raising the possibility that HBx may acquire its broad transcriptional properties by interacting with DDB1. A panel of HBx mutant proteins, some of which no longer bind to DDB1, was used to test this hypothesis. Plasmid DNAs encoding HBx wildtype and mutant derivatives were transfected into HepG2 cells, and their ability to transactivate a cotransfected reporter plasmid tested. Results from the transactivation assays in HepG2 cells were then compared with data obtained from HBx-DDB1 binding studies performed in yeast. Several HBx mutant proteins unable to bind DDB1 remained competent for transactivation, indicating that HBx binding to DDB1 is not required for HBx transactivation of the ETS1 promoter. It remains possible that a subset of HBx transactivation function targets an as yet undefined DDB1-specific pathway.
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PMID:Dissociation of DDB1-binding and transactivation properties of the hepatitis B virus X protein. 1093 Jun 65

The hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) were coexpressed from a synthetic bidirectional promoter with the tetracycline-inactivated transactivator (tTA). The function of this autoregulative system was evaluated following either transfer into established cell lines or intramuscular and intradermal injection of high or low doses of DNA into mice. We measured in vitro antigen expression and in vivo the induction of specific humoral and cellular immune responses. Successful regulation of antigen expression was observed in cultured cells. DNA vaccination with these constructs efficiently primed hepatitis B virus (HBV) specific immunity. However, immunogenic concentrations of the antigens were expressed even in the absence of the transactivator, indicating that low expression level is sufficient to prime an immune response. The bidirectional promoter allows coexpression of either both HBV antigens or a HBV antigen and enhanced green fluorescent protein leading to efficient priming of stable immunity against both antigens. This study demonstrates the potential of synthetic polyvalent plasmids in DNA vaccination.
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PMID:Polyvalent DNA vaccines with bidirectional promoters. 1114 Mar 75

The hepatitis B virus HBx protein is a promiscuous transactivator implicated in the development of hepatocellular carcinoma. The ectopic expression of HBx fails to transform both primary and immortalized rodent cells, but rather induces apoptosis. Furthermore, most transgenic mice harboring HBx do not develop liver tumors. Thus, it remains unclear whether and how HBx contributes to oncogenesis. Here, we show that HBx collaborates with activated H-ras to transform immortalized rodent cells. Indeed, REF52 cells transfected by both HBx and activated H-ras were morphologically transformed and were able to grow in soft agar. Remarkably, nude mice injected with REF52 cells transfected by both HBx and activated H-ras developed tumors, whereas the mice injected with REF52 cells transfected by either gene alone did not. Thus, we concluded that HBx could contribute to neoplastic transformation of cells in collaboration with other oncogenes, such as H-ras, that renders cells to overcome the HBx-mediated apoptosis. Further, we found that HBx mediated apoptosis was suppressed by activated H-ras through activation of the phosphatidylinositol-3 kinase and Akt pathway. Data presented here firmly established the oncogenic potential of HBx during multistage carcinogenesis. Oncogene (2001) 20, 16 - 23.
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PMID:Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. 1124 1

Hepatitis B virus X (HBx) protein is known as an oncogenic transactivator, E2F1 as a positive regulator of the cell cycle, and pRb as a tumor suppressor. Here, we investigated the functional interactions of these proteins on the human Rb promoter. Interestingly, HBx transactivated the Rb promoter cooperatively with E2F1 in HepG2 cells but not in HeLa cells, in which the functions of p53 and pRb are inactive. Combinatorial cotransfection analyses in HepG2 cells showed that HBx overcame the inhibition of E2F1 activity by pRb but not that by p53. Domain analysis showed that aa 47-70 and aa 117-133 of HBx are important for this effect. These results suggest that HBx could inhibit the pRb tumor suppressor and increase E2F1 activity. Our data support the oncogenic potential of HBx, which may cause HBV-infected cells to grow continuously in the development of hepatocellular carcinoma.
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PMID:Hepatitis B viral X protein overcomes inhibition of E2F1 activity by pRb on the human Rb gene promoter. 1124 64

Hepatitis B virus X protein (HBx) is a multifunctional protein that exerts its effects primarily by acting as a transcriptional transactivator of viral and multiple host cell genes. HBx is thought to be essential for maintaining viral replication and has been implicated in the development of hepatocellular carcinoma in patients chronically infected with hepatitis B virus. Very little is known about its functional mechanisms and although interactions with several nuclear and cytoplasmic proteins have been demonstrated in vitro, there is no clear consensus as to where HBx localises in infected hepatocytes. In this study, the expression and intracellular distribution of HBx were examined in human liver biopsies using an anti-HBx rabbit polyclonal antiserum. HBx was detected in a high proportion (69%) of samples from patients with chronic HBV infection. Detection of HBx correlated with the absence of cirrhosis and the presence of serum e-antigen. HBx was detected predominantly in the cytoplasm; however, it was also found in the nuclei of up to 20% of positively stained hepatocytes, either exclusively nuclear or localised both in the nucleus and cytoplasm within the same cell. Furthermore, the intracellular distribution of HBx was analysed in transfected Huh-7 cells by confocal microscopy, using the monoclonal antibody 16F1. In these experiments, a substantial nuclear detection was confirmed in a significant proportion of HBx expressing cells. The data indicate a high functional significance of nuclear HBx, consistent with the concept that transactivation may involve interactions with nuclear proteins.
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PMID:Subcellular localisation of the X protein in HBV infected hepatocytes. 1146 25

The human hepatitis B virus X protein (HBx) is known as a dual-specificity transactivator stimulating the transcriptional machinery in the nucleus and signal transduction pathways in the cytoplasm. HBx-induced activation of mitogen-activated protein kinase (MAPK) signaling cascades is considered to play an important role in hepatitis B virus-mediated hepatocarcinogenesis. Herein, we have identified the regions of HBx that are crucial for activating such signaling cascades in vivo. A truncated mutant incorporating regions C-E (amino acids 58-140) was as effective as the full-length HBx in activating MAPKs and enhancing activator protein-1 binding activity. While deletion of region C (amino acids 58-84) or D (amino acids 85-119) led to a drastic loss of function, region E (amino acids 120-140) was dispensable for the activation of signaling cascades. Overall, these findings provide the first evidence for the requirement of domain 58-119 of HBx in transmitting mitogenic signals to the nucleus in vivo.
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PMID:An internal segment (residues 58-119) of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver. 1152 97

The hepatitis B virus (HBV) X protein (HBx) is a transcriptional transactivator that has been implicated in the development of HBV-related hepatocellular carcinoma. Mutations in the HBx open reading frame have been reported, but their general impact on the biological function of HBx remains unknown. To address this issue, we comparatively analyzed the structures and biological functions of HBx sequences isolated from sera and from tumor and nontumor tissues of patients with a HBV-related hepatocellular carcinoma. In addition to the HBx sequences derived from free HBV genomes, HBx from HBV integrants was also obtained from the tumor tissues by use of a HBx-Alu PCR-based approach. Sequence analysis showed that the HBx sequences derived from tumor tissues (6 of 7), particularly those isolated from HBV integrants (4 of 4), contained a deletion in the distal COOH-terminal region. Interestingly, most of the COOH-terminally truncated HBx sequences obtained from tumor tissues, in contrast to the full-length HBx isolated from the sera and nontumor tissues, lost their transcriptional activity and their inhibitory effects on cell proliferation and transformation. Importantly, although full-length HBx suppressed the focus formation induced by the cooperation of ras and myc oncogenes in primary rat embryo fibroblasts, COOH-terminally truncated HBx enhanced the transforming ability of ras and myc. Finally, by analyzing the artificial mutants, we were able to more precisely map the functional domains located at the COOH-terminal of HBx. Taken together, our results suggest a key role for the HBx COOH-terminal end in controlling cell proliferation, viability, and transformation. This study further supports the hypothesis that natural HBx mutants might be selected in tumor tissues and play a role in hepatocarcinogenesis by modifying the biological functions of HBx.
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PMID:Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. 1169 96

While the natural intact protein does not possess any transactivator function, C-terminal truncation of the middle hepatitis B surface (MHBs) protein yields a novel transactivator function. We have previously found that the truncated transactivator protein, MHBs(t167), is not secreted but retained within the secretory pathway. Here, we provide evidence that when full-length MHBs is coexpressed with the truncated MHBs(t167) protein, the secretion of the full-length protein is inhibited and both proteins accumulate within the cell. We further show that MHBs, forcibly retained in the cell by C-terminal fusion to the endoplasmic reticulum retention signal KDEL (MHBsKDEL), mimics the effects of MHBs(t167) in enhancing the nuclear-binding activity of transcription factors NFkappaB and AP-1, and activation of NFkappaB- and AP-1-dependent transcription of reporter genes. As is the case for MHBs(t167), MHBsKDEL-dependent activation of NFkappaB is inhibited by the antioxidant N-acetyl-L-cysteine indicating the involvement of reactive oxygen intermediates and suggesting a similar mechanism of activation. This study suggests that the intracellular retention and accumulation of the normally secreted MHBs leads to oxidative stress and activation of transcription. This may be an important but not exclusive mechanism in hepatocarcinogenesis.
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PMID:Intracellular accumulation of middle hepatitis B surface protein activates gene transcription. 1193 96


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