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)

Core particles of hepatitis B virus are assembled from dimers of a single 185-residue (subtype adw) viral capsid or core protein (p21.5) which possesses two distinct domains: residues 1 to 144 form a minimal capsid assembly domain, and the arginine-rich, carboxyl-terminal residues 150 to 185 form a protamine-like domain that mediates nucleic acid binding. Little is known about the topography of the p21.5 polypeptide within either the p21.5 capsids or dimers. Here, using site-specific proteases and monoclonal antibodies, we have defined the accessibility of p21.5 residues in dimers and capsids assembled from wild-type and mutant hepatitis B virus core proteins in Xenopus oocytes and in vitro. The data reveal the protamine region to be accessible to external reagents in p21.5 dimers but largely cryptic in wild-type capsids. Strikingly, in capsids the only protease target region was a 9-residue peptide covering p21.5 residues Glu-145 to Asp-153, which falls largely between the two core protein domains. By analogy with protease-sensitive interdomain regions in other proteins, we propose that this peptide constitutes a hinge between the assembly and nucleic acid binding domains of p21.5. We further found that deletion or replacement of the terminal Cys-185 residue greatly increased surface exposure of the protamine tails in capsids, suggesting that a known disulfide linkage involving this residue tethers the protamine region inside the core particles. We propose that disruption of this disulfide linkage allows the protamine region to appear transiently on the surface of the core particle.
 ...
PMID:A protease-sensitive hinge linking the two domains of the hepatitis B virus core protein is exposed on the viral capsid surface. 752 91

The p21.5 capsid or core protein of hepatitis B virus carries two distinct classes of epitopes. Core (HBc) epitopes are found exclusively on the surface of the 28-nm viral icosahedral capsids or core particles, while HBe epitopes are normally expressed only by subparticulate forms of the core protein. Recent studies have suggested that a "particulate" form of HBe is expressed on the surface of capsid particles assembled from p17, a truncated core protein that lacks the carboxy-terminal protamine-like region of p21.5 and hence the ability to bind and encapsidate RNA. In this report we have used epitope-specific ELISAs in conjunction with capsids assembled from a series of carboxy-terminally truncated core proteins to address the mechanistic basis for particulate HBe. Specifically, we sought to test the idea that particulate HBe expression might be linked to the loss of RNA binding. However, our results strongly suggest that expression of HBe by mutant core particles is a result of their intrinsic instability which increases sharply when RNA binding is lost. We show that core particles assembled from mutant core proteins lacking Cys residues also express HBe, again because of capsid instability. We report mild conditions that can induce the dissociation of the mutant capsids and discuss our findings in terms of the factors that control capsid stability.
 ...
PMID:Stability governs the apparent expression of "particulate" hepatitis B e antigen by mutant hepatitis B virus core particles. 768 82

The properties of three different recombinant hepatitis B virus core proteins expressed in Escherichia coli were compared: an N-terminal fusion protein, a C-terminally truncated protein and a sequence-authentic protein. All three proteins assembled into capsid-like particles with typical HBc-antigenicity, sedimentation behavior and distinctive electron microscopical images. Apart from this, however, variant HBc proteins displayed properties different from sequence-authentic HBc protein p21.4. Unlike p21.4, the particles of the N-terminal fusion protein p22.2 were sensitive to proteolytic attack by trypsin at variable sites within its arginine-rich C-terminus but not in its extended N-terminus. We therefore conclude that the C-terminal region is located on the surface of the p22.2 particle. These particles also showed increased HBe-antigenicity, as did the C-terminally truncated core particles p17.6, and to an even greater extent p18* particles which were derived from p22.2 by tryptic digestion. This might be interpreted as evidence for an--albeit minor--structural change. All variant core particles were less stable and contained less RNA. Electron microscopic indication for DNA binding of C-terminal deleted p17.6 particles was obtained using an aqueous spreading technique.
 ...
PMID:Comparison of three different recombinant hepatitis B virus core particles expressed in Escherichia coli. 819 38

Assembly of hepatitis B virus capsid-like (core) particles occurs efficiently in a variety of heterologous systems via aggregation of approximately 180 molecules of a single 21.5-kDa core protein (p21.5), resulting in an icosahedral capsid structure with T = 3 symmetry. Recent studies on the assembly of hepatitis B virus core particles in Xenopus oocytes suggested that dimers of p21.5 represent the major building block from which capsids are generated. Here we determined the concentration dependence of this assembly process. By injecting serially diluted synthetic p21.5 mRNA into Xenopus oocytes, we expressed different levels of intracellular p21.5 and monitored the production of p21.5 dimers and capsids by radiolabeling and immunoprecipitation, by radioimmunoassay, or by quantitative enzyme-linked immunosorbent assay analysis. The data revealed that (i) p21.5 dimers and capsids are antigenically distinct, (ii) capsid assembly is a highly cooperative and concentration-dependent process, and (iii) p21.5 must accumulate to a signature concentration of approximately 0.7 to 0.8 microM before capsid assembly initiates. This assembly process is strikingly similar to the assembly of RNA bacteriophage R17 as defined by in vitro studies.
 ...
PMID:A micromolar pool of antigenically distinct precursors is required to initiate cooperative assembly of hepatitis B virus capsids in Xenopus oocytes. 841 71

Hepadnaviruses encode two core-related open reading frames. One directs the synthesis of the p21 core protein, which subsequently becomes a structural component of the viral nucleocapsid. The other produces a p25 precore protein that is targeted by a signal peptide to a cell secretory pathway where N-terminal processing will create a p22 species. This molecule will be further modified at the C-terminal region to generate p17, and the truncated protein is secreted from the cell as hepatitis B e antigen (HBeAg). The function of the precore gene in the biology of hepadnaviruses is unknown. We found that ablation of the precore gene resulted in the generation of a hepatitis B virus (HBV) species with a high-replication-level phenotype. More important, expression in trans of physiologic levels of p25 restored viral replication to wild-type levels. Moreover, transient or stable overexpression of the precore gene resulted in striking inhibition of HBV replication. The molecular species responsible for this viral inhibitory effect was identified as the p22 nonsecreted HBeAg precursor protein. By sucrose gradient sedimentation analysis, we determined that expression of p22 leads to the formation of nucleocapsids similar to those made with wild-type p21 core protein. Immunoprecipitation experiments revealed that the p21 and p22 physically interact and form hybrid nucleocapsid structures devoid of pregenomic viral RNA. These experiments suggest that expression of the precore gene may be important in the regulation of HBV replication and describe a possible molecular mechanism(s) for this effect.
 ...
PMID:Posttranscriptional regulation of hepatitis B virus replication by the precore protein. 898 56

The purpose of this paper was to study the mechanism of synergistic effect in hepatocarcinogenesis induced by hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) intake. Immunohistochemical staining was used in formalin-fixed, paraffin-embedded sections of cancer and liver tissues. The incidence of hepatocellular carcinomas (HCCs) was 52.9% in experimental tree shrews that received both HBV and AFB1. It was significantly higher than that of animals exposed to HBV (11.1%, Group B), or (AFB1) (15.8%, group C) alone. HCC was not found in the control animals (group D). The expressions of insulin-like growth factor II (IGF-II) were 82.4%, 22.2%, 26.3% and 0 in groups A, B, C and D, respectively. The significant differences of IGF-II were observed between groups A and B, C and D (P < 0.05). The expressions of p21 were 29.4%, 11.1%, 15.8% and 0 in group A, B, C and D, respectively. The positive rate of hepatitis B x antigen (HbxAg) was significantly higher in the group A than that in the group B (52.9% vs. 11.1%, P < 0.05). The parallel relations between the incidence of HCC and the overexpressions of these genes protein have been found in each group. On the other hand, the expressions of these genes in tumour-bearing tree shrews were significantly higher than that in nontumour-bearing animals. These findings suggest a synergistic effects of HBV and AFB1 in activation of these genes in tree shrews. Overexpressions of these genes may take an important role in the course of hepatocarcinogenesis in tree shrews.
 ...
PMID:The expression of insulin-like growth factor II, hepatitis B virus X antigen and p21 in experimental hepatocarcinogenesis in tree shrews. 1037 27

The hepatitis B viral X protein (HBx) is known as a transcription factor and potential oncogene. To gain a better view of the effect of HBx on the transcriptional regulation in the human liver cell, we constructed a HepG2 cell line stably expressing HBx (HepG2-HBx), and performed cDNA microarray analysis on 588 cellular cDNAs comparing with untransformed control cells. Two genes (IGFR-2, RhoA) of oncogenes, one gene (p55CDC) of cell cycle regulators, three genes (thrombin receptor, MLK-3, MacMARCKS) of intracellular transducers, one gene (HSP27) of stress response proteins, two genes (FAST kinase, Bak) of apoptosis response proteins, one gene (p21(WAF)) of transcription factors were highly up-regulated; one gene (transcription elongation factor SII) of transcription factors and two genes (monocyte chemotactic protein 1, T-lymphocyte-secreted protein I-309) of growth factors were highly down-regulated. These results showed selective transcriptional regulation by HBx in the human liver cell.
 ...
PMID:Selective transcriptional regulations in the human liver cell by hepatitis B viral X protein. 1083 46

Progression through the cell cycle is controlled by the induction of cyclins and activation of cognate cyclin-dependent kinases. The human hepatitis B virus-X (HBV-X) protein functions in gene expression alterations, in the sensitization of cells to apoptotic killing and deregulates cell growth arrest in certain cancer cell types. We have pursued the mechanism of growth arrest in Hep3B cells, a p53-mutant human hepatocellular carcinoma (HCC) cell line. In stable or transient HBV-X transformed Hep3B cells, HBV-X increased protein and mRNA levels of the cyclin-dependent kinase inhibitor (CDKI) p21(waf1/cip1) increased binding of p21(waf1/cip1) with cyclin-dependent kinase 2 (CDK2), markedly inhibited cyclin E and CDK2 associated phosphorylation of histone H1 and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the HBV-X responsive element was mapped to a region between -1185 and -1482, relative to the transcription start site. Promoter mutation analysis indicated that the HBV-X responsive site coincides with the ets factor binding sites. These data indicate that in human hepatocellular carcinoma cells, HBV-X can circumvent the loss of p53 functions and induces critical downstream regulatory events leading to transcriptional activation of p21(waf1/cip1). As a consequence, there is an increased chance of acquisition of mutations which can enhance the genesis of hepatomas. Our results also emphasize the chemotherapeutic potential of p21(waf1/cip1) inhibitors, particularly in the HBV-X infected hepatoma which lacks functional p53.
 ...
PMID:Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells. 1091 95

Hepatitis B virus (HBV) is a major etiological factor associated with hepatocarcinogenesis, but its role in the transformation process remains unclear. We previously documented the accumulation of genetic alterations in a HBV-transfected cell line. In the present study, we addressed the effect of HBV and its replication on the genome and phenotype of the host cell. Parental HBV-free Hep G2 cells and two HBV-transfected variant lines Hep G2215 and Hep G2T14. 1, which do and do not replicate HBV, respectively, were used to monitor genetic alterations in conjunction with HBV profile in vitro and in vivo. Comparison of in vitro growth rates showed that Hep G2T14.1 cells grew more rapidly, while Hep G2215 cells, replicating HBV, grew slower than parental Hep G2 cells. Molecular analysis confirmed an HBV integration site (s) in both variants, and reverse trancriptase-polymerase chain reaction (RT-PCR) amplification documented expression of transcript for the HBX protein, which has recently been implicated in the compromised efficiency of cellular DNA repair. Tumorigenisity testing indicate a comparable rate of tumor formation in nude mice of both HBV-transfected variants, giving rise to tumors in 3 weeks; parental Hep G2 cells did not form tumors in nude mice. Tumor tissue from nude mice injected with Hep G2T14.1 cells showed no change in HBV status. However, a new HBV integration site was detected in tumor tissue from Hep G2215-injected mice. Two cell lines derived from the respective tumor tissue grew in vitro at rates compatible to those observe before passage in nude mice. The Hep G2215 tumor-derived line continued to replicate HBV, while HBV status remained unchanged in the Hep G2T14.1 tumor-derived line. Unique genetic alterations were detected in both transfected cell lines, and Hep G2215 cells particularly showed cellular mosaicism and clonal selection when analyzed after the passage in nude mice. Further genetic alterations were detected in tumor-derived cell lines. Interestingly, the de novo genetic alterations in the Hep G2215 cells, which maintain the ability to replicate HBV, included a new HBV integration site, several chromosome rearrangements and loss of heterozygosity (LOH) of one p53 allele. Western analyses of p21/Waf1 protein indicate an upregulation of the protein in cells that replicate HBV. Based on the combined data, we hypothesize that the genetic alterations in the cellular genome could also be generated as a function in the presence of HBV and HBV replication. Possible mechanisms that could be implicated in cumulative mutagenetic events are discussed.
 ...
PMID:Hepatitis B virus-transfected Hep G2 cells demonstrate genetic alterations and de novo viral integration in cells replicating HBV. 1102 76

Deranged expression of cell cycle modulators has been reported to contribute to the development and progression of hepatocellular carcinoma (HCC). However, their expression patterns remain poorly understood in hepatitis B virus (HBV)-related HCC, which constitutes about 65-70% of HCC in Korea. The aims of this study were to evaluate the expressions of G1-S modulators in HBV-related HCCs and dysplastic nodules (DNs), and to correlate with the histopathologic features of HCCs. Immunohistochemical expressions of cyclin D1, cyclin E, p53, p27, p21, p16, Rb, and PCNA proteins were investigated in 80 HCCs and 22 DNs. Cyclin D1 overexpression showed positive relationships with advanced tumor stage, poor differentiation, larger tumor size, microvascular invasion, intrahepatic meta-stasis, no tumor capsule formation, infiltrative growth, aberrant p53 expression, and high PCNA labeling index (LI) of HCC (p<0.05). Aberrant p53 expression showed positive relationship with poor differentiation of HCC (p<0.01). Expression of cyclin D1 or p53 was not observed in DNs. The p27 LI and p16 LI were lower in HCCs with intrahepatic metastasis (p<0.05). Cyclin D1 overexpression and aberrant p53 expression could be associated with the progression of HBV-related HCC, and might have a less crucial role in the DN-HCC sequence. In addition, elevated expression of p27 and p16 proteins might have inhibitory action to the intrahepatic metastasis of HBV-related HCC.
 ...
PMID:Expression of the G1-S modulators in hepatitis B virus-related hepatocellular carcinoma and dysplastic nodule: association of cyclin D1 and p53 proteins with the progression of hepatocellular carcinoma. 1151 87


<< Previous 1 2 3 4 5 6 7 8 Next >>