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 influence of hepatocyte nuclear factor 3 (HNF3) on the level of transcriptional activity from the four hepatitis B virus promoters was investigated by transient-transfection analysis in the dedifferentiated hepatoma cell line, HepG2.1. It was found that the large surface antigen promoter and, to a much lesser extent, the nucleocapsid promoter were transactivated in the presence of HNF3. DNase I footprinting analysis demonstrated that purified recombinant HNF3 alpha protects one region of the large surface antigen promoter. Gel retardation analysis showed that a double-stranded oligonucleotide containing this HNF3-binding site formed a specific complex with DNA-binding proteins in the differentiated hepatoma cell lines, Huh7 and HepG2. The complex formed with Huh7 cell extract comigrated with exogenously expressed HNF3 beta in HeLa S3 extracts and was specifically inhibited from forming by the addition of HNF3 beta antiserum. The promoter element which appears to mediate the HNF3 transactivation was functionally mapped by mutational analysis to a region between nucleotides -65 and -54 relative to the transcriptional start site. This regulatory sequence is within the region protected from DNase I digestion by HNF3 alpha and contains 10 of 12 nucleotides homologous to the HNF3-binding-site consensus sequence. A synthetic promoter construct containing this HNF3-binding site was able to mediate transactivation by HNF3 beta. These and previous results suggest that the hepatitis B virus large surface antigen promoter is regulated by at least two liver-enriched transcription factors, HNF1 and HNF3, which together may contribute to the differentiated liver cell type specificity of this promoter.
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PMID:Regulation of transcription from the hepatitis B virus large surface antigen promoter by hepatocyte nuclear factor 3. 774 73

Hepatitis B viruses (hepadnaviruses) can cause chronic, productive infections of hepatocytes. Analyses of the enhancers and promoters of these viruses in cell lines have suggested a requirement of these elements for liver-enriched transcription factors. In this study, a minimum of seven factor-binding sites on the duck hepatitis B virus enhancer were detected by DNase I footprinting using duck liver nuclear extracts. Among the sites that were tentatively identified were one C/EBP-, one HNF1-, and two HNF3-binding sites. Mutations of the HNF1- and HNF3-like sites, which eliminated factor binding, as assessed by both DNase I footprinting and competitive gel shift assays, were evaluated for their effects on enhancer activity. Using a construct in which human growth hormone was expressed from the viral enhancer and core gene promoter, we found that all of the mutations, either alone or in combination, reduced expression two- to fourfold in LMH chicken hepatoma cells. The mutations in the HNF1 site and one of the HNF3 sites, when inserted into the intact viral genome, also suppressed virus RNA synthesis in primary hepatocyte cultures. Virus carrying the latter HNF3 mutation was also examined for its ability to infect and replicate in ducks. No significant inhibition of virus replication was observed in a short-term assay; however, virus with the HNF3 mutation was apparently unable to grow in the pancreas, a second site of duck hepatitis B virus replication in the duck.
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PMID:Identification of factor-binding sites in the duck hepatitis B virus enhancer and in vivo effects of enhancer mutations. 813 13

A double mutation which converts nucleotide 1765 from A to T and nucleotide 1767 from G to A is frequently found in the hepatitis B virus (HBV) genome isolated from HBV patients with chronic hepatitis symptoms. This double mutation is located in the core promoter that controls the transcription of the precore RNA and the core RNA. In addition, this double mutation also resides in the X protein coding sequence, converting codon 130 from Lys to Met and codon 131 from Val to Ile. Previous studies indicate that this double mutation removes a nuclear receptor binding site in the core promoter, suppresses specifically precore RNA transcription, and enhances viral replication. In this study, we further investigated how this double mutation suppresses precore RNA transcription. We found that this double mutation not only removed the nuclear receptor binding site but also created an HNF1 transcription factor binding site. Further transfection studies using Huh7 hepatoma cells indicate that the removal of the nuclear receptor binding site has no effect on the transcription of HBV RNAs, the two-codon change in the X protein sequence suppresses the transcription of both precore and core RNAs, and the creation of the HNF1 binding site restores the core RNA level. Hence, the specific suppression of precore RNA transcription by this frequent double-nucleotide mutation is the combined result of multiple factors.
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PMID:Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. 988 27

The role of hepatocyte nuclear factor 1alpha (HNF1 alpha) in the regulation of hepatitis B virus (HBV) transcription and replication in vivo was investigated using a HNF1 alpha-null HBV transgenic mouse model. HBV transcription was not measurably affected by the absence of the HNF1 alpha transcription factor. However, intracellular viral replication intermediates were increased two- to fourfold in mice lacking functional HNF1 alpha protein. The increase in encapsidated cytoplasmic replication intermediates in HNF1 alpha-null HBV transgenic mice was associated with the appearance of nonencapsidated nuclear covalently closed circular (CCC) viral genomic DNA. Viral CCC DNA was not readily detected in HNF1 alpha-expressing HBV transgenic mice. This indicates the synthesis of nuclear HBV CCC DNA, the proposed viral transcriptional template found in natural infection, is regulated either by subtle alterations in the levels of viral transcripts or by changes in the physiological state of the hepatocyte in this in vivo model of HBV replication.
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PMID:Nuclear covalently closed circular viral genomic DNA in the liver of hepatocyte nuclear factor 1 alpha-null hepatitis B virus transgenic mice. 1122 15

A natural hepatitis B virus (HBV) variant associated with seroconversion from HBeAg to anti-HBe antibody contains two nucleotide substitutions (A1764T and G1766A) in the proximal nuclear hormone receptor binding site in the nucleocapsid promoter. These nucleotide substitutions prevent the binding of the retinoid X receptor alpha (RXR alpha)-peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer without greatly altering the efficiency of binding of hepatocyte nuclear factor 4 (HNF4) to this recognition sequence. In addition, these nucleotide substitutions create a new binding site for HNF1. Analysis of HBV transcription and replication in nonhepatoma cells indicates that RXR alpha-PPAR alpha heterodimers support higher levels of pregenomic RNA transcription from the wild-type than from the variant nucleocapsid promoter, producing higher levels of wild-type than of variant replication intermediates. In contrast, HNF4 supports higher levels of pregenomic RNA transcription from the variant than from the wild-type nucleocapsid promoter, producing higher levels of variant than of wild-type replication intermediates. HNF1 can support variant virus replication at a low level but is unable to support replication of the wild-type HBV genome. These observations indicate that the replication of wild-type and variant viruses can be differentially regulated by the liver-specific transcription factors that bind to the proximal nuclear hormone receptor binding site of the nucleocapsid promoter. Differential regulation of viral replication may be important in the selection of specific viral variants as a result of an antiviral immune response.
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PMID:Replication of the wild type and a natural hepatitis B virus nucleocapsid promoter variant is differentially regulated by nuclear hormone receptors in cell culture. 1153 57

The human homologue of the Drosophila melanogaster orphan nuclear receptor fushi tarazu factor 1 (Ftz-F1), NR5A2 (hB1F), was initially identified as a regulatory factor that binds and activates enhancer II of hepatitis B virus. NR5A2 (hB1F) is expressed specifically in pancreas and liver, playing important roles in the regulation of several liver-specific genes. A detailed analysis on the genomic structure and promoter activity will greatly promote future studies on the function of the NR5A2 (hB1F) gene. In this report, a bacterial artificial chromosome clone and several phage clones covering the NR5A2 (hB1F) gene were isolated and the complete genomic sequence was obtained. Alignment of different cDNAs of the NR5A2 (hB1F) gene with the genomic sequence facilitated the delineation of its structural organization, which spans over 150 kb and consists of eight exons interrupted by seven introns. RT-PCR and 3'-RACE revealed that utilization of two polyadenylation signals results in the 3.8 and 5.2 kb transcripts that were observed previously. The transcription start site of the NR5A2 (hB1F) gene was mapped downstream of a canonical TATA box. An upstream fragment containing binding sites for several liver-specific and ubiquitous transcription factors exhibits hepatocyte-specific promoter activity. Transient transfections indicated that hepatocyte nuclear factors HNF1 and HNF3beta could activate NR5A2 (hB1F) promoter.
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PMID:Characterization of the genomic structure and tissue-specific promoter of the human nuclear receptor NR5A2 (hB1F) gene. 1159 70

We identified, cloned, and functionally characterized a new avian hepadnavirus infecting storks (STHBV). STHBV has the largest DNA genome of all avian hepadnaviruses and, based on sequence and phylogenetic analysis, is most closely related to, but distinct from, heron hepatitis B virus (HHBV). Unique for STHBV among the other avian hepadnaviruses is a potential HNF1 binding site in the preS promoter. In common only with HHBV, STHBV has a myristylation signal on the S and not the preS protein, two C terminally located glycosylation sites on the precore/core proteins and lacks the phosphorylation site essential for the transcriptional transactivation activity of duck-HBV preS protein. The cloned STHBV genomes were competent in gene expression, replication, and viral particle secretion. STHBV infected primary duck hepatocytes very inefficiently suggesting a restricted host range, similar to other hepadnaviruses. This discovery of stork infections unravels novel evolutionary aspects of hepadnaviruses and provides new opportunities for hepadnavirus research.
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PMID:Identification and analysis of a new hepadnavirus in white storks. 1160 23

The protein-DNA interactions in the enhancer II (ENII) and core promoter regions of hepatitis B virus (HBV) were investigated by the ligation-mediated polymerase chain reaction (LMPCR) in vivo footprinting in HepG2.2.15 cell line. Major footprints are evident at the enhancer II and core promoter regions. In particular, proteins appear to interact with the sites for Sp1, C/EBP, HNF4, HNF3, HNF1 and hB1F, as well as the TATA-like element. It confirmed that these protein-DNA interactions defined in vitro play important roles in the regulation of 3.5 kb RNAs transcription of HBV in vivo. Notably, three novel sites nt 1774-1789, nt 1801-1818 and nt 1835-1843 were found to be protected or hypersensitive, indicating that they were also involved in protein-DNA interactions in vivo. Functional analysis using CAT reporter gene demonstrated that the site from nt 1801 to 1818 was important for the function of HBV core promoter.
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PMID:Investigation of Protein-DNA Interactions in Enhancer II and Core Promoter of HBV by in vivo Footprinting. 1211 57

Enhancer II (ENII) is one of the critical cis-elements in the Hepatitis B Virus (HBV) genome for the hepatic viral gene transcription and DNA replication. The liver-specific activity of ENII is regulated by multiple liver-enriched transcription factors, including LRH-1/hB1F, HNF1, HNF3b, HNF4 and C/EBP. Knowledge on the interplay of these important factors is still limited. In this study, we demonstrate a functional synergism between the orphan nuclear receptor LRH-1/hB1F and the homeoprotein HNF1 in up-regulating the liver-specific activity of ENII. This synergism is sufficient for initiating the viral gene transcription and DNA replication in non-hepatic cells. We have defined the activation domains in hB1F and HNF1 that contribute to the synergism. We further show that hB1F and HNF1 can interact directly in vitro and have mapped the domains required for this interaction.
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PMID:LRH-1/hB1F and HNF1 synergistically up-regulate hepatitis B virus gene transcription and DNA replication. 1472 1

Hepatitis B virus (HBV) core promoter contains a binding site for nuclear receptors. A natural double mutation in this binding site, which changes nucleotide (nt) 1765 from A to T and nt 1767 from G to A, selectively abolishes the binding of several nuclear receptors without affecting that of HNF4. This double mutation also creates a binding site for the transcription factor HNF1 and changes two amino acids in the overlapping X protein sequence. In this study, we have examined the roles of HNF1, HNF4, and the X protein in the regulation of the core promoter activities in Huh7 hepatoma cells. Our results indicate that HNF4 could stimulate the expression of the precore RNA and the core RNA from the core promoter of both the wild-type (WT) HBV and the double mutant, although its effect on the former was more prominent. In contrast, HNF1, which did not affect the WT core promoter, suppressed the precore RNA expression of the double mutant. Further analysis using HBV genomic constructs, with and without the ability to express the X protein, indicates that the X protein did not affect the HNF4 activity on the core promoter and affected the HNF1 activity on the core promoter of only the double mutant. Thus, our results indicate that the phenotypic differences of HBV WT and double-mutant core promoters are at least partially due to the differential activities of HNF1, HNF4, and the X protein on these two promoters.
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PMID:Regulation of hepatitis B virus core promoter by transcription factors HNF1 and HNF4 and the viral X protein. 1519 67


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