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)

X protein of hepatitis B virus (HBV-X) is a transactivator to a wide variety of viral and cellular transcriptional regulatory elements. Since HBV-X does not act on a common cis-regulatory element of a wide variety of regulatory elements nor does it bind to DNA directly, it has been proposed that HBV-X acts indirectly through protein-protein interactions with other transcription factors or signal transducing pathway. In order to determine the functional domain of HBV-X, we have constructed and analyzed a number of deletion and site specific mutants. Our results showed that leucine zipper-like sequences were found in the C-terminal region of HBV-X and were very important for its transactivating activity. In the analysis of deletion mutants, seven conserved and strong basic amino acids (amino acids 135-141) were essential for the transactivating activity of HBV-X.
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PMID:Functional analysis of hepatitis B virus transactivator X: implication of the leucine zipper-like region and C-terminal seven conserved amino acids in functional regions. 826 29

Integrated hepatitis B virus DNA cloned from hepatitis B virus-associated hepatocellular carcinoma frequently contains 3'-truncated middle surface genes (preS2/St), which were recently found to have a transcriptional transactivator function. Because preS2/St, among others, is able to transactivate the promoters of the cellular oncogenes c-myc and c-fos, it has been speculated that integrated preS2/St genes might contribute to hepatitis B virus-associated liver carcinogenesis. In this study, we investigated the mechanism of target gene stimulation by preS2/St. It was found that deletion of a fragment containing the binding site for transcription factor AP-1 (Jun-Fos) substantially decreases inducibility of the human c-myc promoter by preS2/St. A subsequent investigation of AP-1 activation by preS2/St revealed the following: (a) insertion of multimeric AP-1 binding sites confers inducibility to an otherwise unstimulatable test promoter; (b) transactivation of AP-1 sites is dramatically increased when Jun and Fos are overexpressed by cotransfected expression plasmids; and (c) inhibitors of AP-1 activation also impair transactivation by preS2/St. Besides AP-1, preS2/St was also able to utilize the unrelated transcription factors NF-kappa B and AP-2 for transactivation, suggesting that the gene product of preS2/St acts indirectly through one or several general cellular pathways rather than as a bona fide transcription factor. Because AP-1 conveys induction of a large panel of tumor-relevant genes, its preS2/St-dependent activation implies a possible causative role in hepatitis B virus-associated hepatocarcinogenesis.
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PMID:The hepatitis B virus preS2/St transactivator utilizes AP-1 and other transcription factors for transactivation. 827 60

RFX1 is a transactivator of human hepatitis B virus enhancer I. We show here that RFX1 belongs to a previously unidentified family of DNA-binding proteins of which we have cloned three members, RFX1, RFX2, and RFX3, from humans and mice. Members of the RFX family constitute the nuclear complexes that have been referred to previously as enhancer factor C, EP, methylation-dependent DNA-binding protein, or rpL30 alpha. RFX proteins share five strongly conserved regions which include the two domains required for DNA binding and dimerization. They have very similar DNA-binding specificities and heterodimerize both in vitro and in vivo. mRNA levels for all three genes, particularly RFX2, are elevated in testis. In other cell lines and tissues, RFX mRNA levels are variable, particularly for RFX2 and RFX3. RFX proteins share several novel features, including new DNA-binding and dimerization motifs and a peculiar dependence on methylated CpG dinucleotides at certain sites.
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PMID:RFX1, a transactivator of hepatitis B virus enhancer I, belongs to a novel family of homodimeric and heterodimeric DNA-binding proteins. 828 3

The X gene product of hepatitis B virus (HBV) transactivates a wide variety of promoters, including four promoters on the HBV genome (Rossner, 1992, J. Med. Virol. 36, 101-117). We compared their transactivation efficiencies and investigated whether the spatial organization of the promoters with respect to other cis-acting elements might influence their activities. Eight reporter plasmid constructs containing the bacterial chloramphenicol acetyltransferase (CAT) gene were designed such that four had the isolated HBV promoters linked to the CAT gene. In the other four, the CAT gene was inserted downstream to each of the four promoters retained in context in the HBV genome. Cells of the human hepatoblastoma line HepG2 were transfected with each one of these reporters together with an effector plasmid, pRSVX, which allowed expression of X protein. All of these promoters could be stimulated by X protein by approximately 2- to 3.5-fold irrespective of their spatial context in the HBV genome. Mutational analysis of in-frame ATG codons in the X gene provides evidence that transactivator product(s) are produced by internal initiation of translation. Transfection of HepG2 cells with HBV genomes bearing a stop mutation in the X gene at codon 118 resulted in poor production of all viral components. Their syntheses were restored upon transfection of the wild-type X gene.
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PMID:Effect of X protein on transactivation of hepatitis B virus promoters and on viral replication. 833 16

The X protein of hepatitis B virus (HBV-X) can act as a transactivator of transcription but its mechanism of action remains obscure. We have analyzed HBV-X transactivation in several cell types using 13 unrelated viral and cellular promoters and found that transactivation is more or less apparent in most cell types and is promiscuous and unrelated to specific sequence motifs within the target promoters. In general, though, HBV-X appears to act on enhancer elements since HBV-X had no effect on a minimal promoter, whereas HBV-X was able to transactivate after insertion of an AP-1 minienhancer. Several lines of evidence exclude the possibility that HBV-X interacts directly with the AP-1 enhancer or its binding proteins and suggest that the proximal target of HBV-X is peripheral to the transcription complex. This hypothesis is supported by the observation that inhibition of serine/threonine kinases, which regulate AP-1 activity (phorbol ester down-regulation or staurosporine inhibition of protein kinase C and a dominant negative mutant of Raf-1), blocked the ability of HBV-X to transactivate without affecting basal promoter activity. Furthermore, basal transcription from the AP-1-dependent promoter was increased by overexpression of protein kinase C and Raf-1 but HBV-X was unable to further stimulate, indicating that these kinases act subsequently to HBV-X. These data suggest that transactivation by HBV-X is an indirect result of the activation of cellular serine/threonine kinases including protein kinase C and Raf-1. This mode of action implies that HBV-X may affect other cellular processes, besides transcription, that are regulated by these kinases.
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PMID:Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. 836 66

We have analyzed the structures, relative organization, and activities of binding sites for nuclear factors in the duck hepatitis B virus (duck HBV) enhancer. DNase I footprinting analysis and mobility shift assays demonstrate that this enhancer of 192 bp contains at least three binding sites for transcription factors: one for hepatocyte-adipocyte C/EBP, a second for the liver-specific transactivator hepatocyte nuclear factor 1 HNF-1, and a third for a factor, called F3, which binds to a DNA sequence bearing some resemblance to that for the ubiquitous factor EF-C. Analysis of transcriptional activity reveals that oligonucleotides corresponding to the individual binding sites, inserted upstream from a heterologous promoter, display very weak enhancer activity, whereas the enhancer encompassing these three sites displays very high activity. Analysis of duck HBV enhancer mutants indicates that the deletion of any of these sites leads to a modification of transcriptional enhancer activity. The hepatocyte nuclear factor 1 binding site is crucial, since an internal deletion of 14 bp abolishes the activity. The C/EBP site can act as repressor, and the F3 site is required for full activity. Comparative analysis reveals that the nuclear factors are similar to those bound to the human HBV enhancer but that the organization of their binding sites in the duck HBV enhancer is different.
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PMID:Binding of nuclear factors to functional domains of the duck hepatitis B virus enhancer. 837 57

The exact role of hepatitis B virus (HBV) in hepatocarcinogenesis is not known. We generated HBV x gene transgenic mice under the hypothesis that the viral transactivator may alter the host gene expression and lead to the development of hepatocellular carcinoma. The x gene under its own regulatory element caused progressive histopathological changes specifically in the transgenic mouse liver, beginning with multifocal foci of altered hepatocytes, followed by the appearance of neoplasia. This finding shows, for the first time, the direct involvement of HBV in the development of liver cancer. Analyses of events that follow the expression of the x gene suggest that the x gene acts at the early stage of carcinogenesis in the liver.
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PMID:[Transgenic mouse model for hepatocellular carcinoma in human hepatitis B virus infection]. 838 45

Hepatitis B virus gene expression is to a large extent under the control of enhancer I (EnhI). The activity of EnhI is strictly dependent on the enhancer factor C (EF-C) site, an inverted repeat that is bound by a ubiquitous nuclear protein known as EF-C. Here we report the unexpected finding that EF-C is in fact identical to RFX1, a novel transcription factor previously cloned by virtue of its affinity for the HLA class II X-box promoter element. This finding has allowed us to provide direct evidence that RFX1 (EF-C) is crucial for EnhI function in HepG2 hepatoma cells; RFX1-specific antisense oligonucleotides appear to inhibit EnhI-driven expression of the hepatitis B virus major surface antigen gene, and in transfection assays, RFX1 behaves as a potent transactivator of EnhI. Interestingly, transactivation of EnhI by RFX1 (EF-C) is not observed in cell lines that are not of liver origin, suggesting that the ubiquitous RFX1 protein cooperates with liver-specific factors.
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PMID:RFX1 is identical to enhancer factor C and functions as a transactivator of the hepatitis B virus enhancer. 841 36

The p53 tumor suppressor gene product is a transcriptional transactivator and a potent apoptotic inducer. The fact that many of the DNA tumor virus oncoproteins bind to p53 and affect these p53 functions indicates that this interaction is an important step in oncogenic transformation. We and others have recently demonstrated that the hepatitis B virus oncoprotein, HBx, can form a complex with p53 and inhibit its DNA consensus sequence binding and transcriptional transactivator activity. Using a microinjection technique, we report here that HBx efficiently blocks p53-mediated apoptosis and describe the results of studies exploring two possible mechanisms of HBx action. First, inhibition of apoptosis may be a consequence of the failure of p53, in the presence of HBx, to upregulate genes, such as p21WAF1, Bax, or Fas, that are involved in the apoptotic pathway. Data consistent with this hypothesis include HBx reduction of p53-mediated p21WAF1 expression. Alternatively, HBx could affect p53 binding to the TFIIH transcription-nucleotide excision repair complex as HBx binds to the COOH terminus of p53 and inhibits its binding to XPB or XPD. Binding of p53 to these constituents of the core TFIIH is a process that may be involved in apoptosis. Because the HBx gene is frequently integrated into the genome of hepatocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing this integrated viral gene during the early stages of human liver carcinogenesis.
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PMID:Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. 852 83

The hepatoma-derived hepatitis B virus (HBV) DNA insert HU-a has recently been shown to contain two viral transactivator genes, X and preS2 /S. We report here that HU-a induces malignant transformation after stable transfection of the fetal mouse hepatocyte line FMH202, as indicated by soft agar growth and nude mouse tumorigenicity. Transfections with HU-a subclones, containing the X gene of the preS2 /S gene alone or sequences without transactivator gene, respectively, suggested that the X gene is essential for transformation. Sequential stages of transformation and tumor progression were analysed by injection of the stably transfected FMH202 lines into nude mice, explanation of the resulting tumors and re-establishment of cell lines from the tumors. Comparison of two HU-a-transformed cell lines by HBV mRNA hybridization, Southern analysis and chromosomal in situ hybridization revealed that integrated HBV DNAs were involved in major chromosomal rearrangements in both cases. Interestingly, recombination of the HBV Dna insert during the nude mouse passage had completely abolished HBV-specific transcription in one case, indicating that expression of integrated HBV genes, while presumably involved in early transformation, is dispensable at later stages of tumor progression. The sequential transformation observed in this experimental system suggests that expression of the X gene by integrated viral DNA and subsequent hepatocyte genome mutations might both contribute to HBV-associated liver carcinogenesis.
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PMID:Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro. 862 79


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