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)

Hepatitis B virus is a major risk factor in human hepatocellular carcinomas. We have used protein affinity chromatography to show that the 17-kDa hepatitis B virus gene product, HBx, binds directly to the human tumor suppressor gene product, p53. Interaction of HBx with p53 did not prevent p53 from specifically binding DNA. Instead, HBx enhanced p53's oligomerization state on a DNA oligonucleotide containing a p53 response element. Optimal binding of HBx to p53 required intact p53, but weaker binding to both the N-terminal activation domain of p53 and a protein fragment containing the C-terminal DNA-binding and oligomerization domains of p53 was observed. In transient transfection experiments with human Calu-6 cells, HBx inhibited transactivation by p53 of a reporter gene containing a p53 response element. Also, HBx inhibited p53-stimulated transcription in vitro even when added to the reaction mixture after the formation of the preinitiation complex. Interaction of HBx with p53 did not prevent the activation domain of p53 from binding two general initiation factors, the TATA-box binding protein subunit of TFIID and the p62 subunit of TFIIH. To explain these results, we propose that localization of HBx to a promoter by interaction with DNA-bound p53 enables a repression domain in HBx to directly contact the basal transcription machinery and thereby repress transcription.
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PMID:Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. 785 26

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 X protein of hepatitis B virus (HBV) coactivates activators bearing potent (mostly acidic) activation domains. Here, we investigated the molecular mechanisms of this coactivation. We show that pX interacts with general transcription factors TFIIB and TFIIH, as well as with the potent activation domain of VP16. TFIIB interacts with both pX and VP16 simultaneously. In addition, the RNA polymerase II enzyme itself binds to pX. By reducing the activity of cellular coactivators, through squelching, we intensify the dependence of the activator on pX-mediated coactivation. Squelching is essentially diminished in the presence of pX, both in vivo and in vitro. The target of pX in this activity is the template-bound activator, and not the squelcher. Furthermore, by following transcription in a TAF-deprived reaction, we demonstrate absolute dependence of the activator on the activity of pX. We propose that pX coactivates transcription by substituting cellular coactivators in activator-preinitiation complex interactions.
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PMID:pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner. 867 Aug 43

Human hepatitis B virus genome encodes a protein, termed HBx, that is widely recognized as a transcriptional transactivator. While HBx does not directly bind cis-acting transcriptional control elements, it has been shown to associate with cellular proteins that bind DNA. Because HBx transactivated a large number of viral/cellular transcriptional control elements, we looked for its targets within the components of the basal transcriptional machinery. This search led to the identification of its interactions with TFIIH. Here, we show that HBx interacts with yeast and mammalian TFIIH complexes both in vitro and in vivo. These interactions between HBx and the components of TFIIH are supported by several lines of evidence including results from immunoprocedures and direct methods of measuring interactions. We have identified ERCC3 and ERCC2 DNA helicase subunits of holoenzyme TFIIH as targets of HBx interactions. Furthermore, the DNA helicase activity of purified TFIIH from rat liver and, individually, the ERCC2 component of TFIIH is stimulated in the presence of HBx. These observations suggest a role for HBx in transcription and DNA repair.
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PMID:Hepatitis B virus transactivator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH. 885 20

pX, the hepatitis B virus (HBV)-encoded regulator, coactivates transcription through an unknown mechanism. pX interacts with several components of the transcription machinery, including certain activators, TFIIB, TFIIH, and the RNA polymerase II (POLII) enzyme. We show that pX localizes in the nucleus and coimmunoprecipitates with TFIIB from nuclear extracts. We used TFIIB mutants inactive in binding either POLII or TATA binding protein to study the role of TFIIB-pX interaction in transcription coactivation. pX was able to bind the former type of TFIIB mutant and not the latter. Neither of these sets of TFIIB mutants supports transcription. Remarkably, the latter TFIIB mutants fully block pX activity, suggesting the role of TFIIB in pX-mediated coactivation. By contrast, in the presence of pX, TFIIB mutants with disrupted POLII binding acquire the wild-type phenotype, both in vivo and in vitro. These results suggest that pX may establish the otherwise inefficient TFIIB mutant-POLII interaction, by acting as a molecular bridge. Collectively, our results demonstrate that TFIIB is the in vivo target of pX.
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PMID:Hepatitis B virus pX targets TFIIB in transcription coactivation. 948 73

Human hepatitis B virus (HBV) is a major risk factor of human hepatocellular carcinoma. Both in vivo and in vitro studies have shown that HBV X protein (HBx) can bind to the p53 tumor-suppressor protein and interfere with the role that p53 plays in the cellular response to DNA damage. Our previous work has shown that HBx protein inhibits p53 sequence-specific transcriptional activation, p53-mediated apoptosis and p53 binding to the TFIIH transcription-nucleotide excision repair (NER) factors, including XPB and XPD. To investigate whether HBx interferes with the NER pathway, we utilized cell-proliferation and colony-formation assays to determine if cells expressing HBx are more sensitive to UVC-induced DNA damage. NER was also measured by a plasmid host cell re-activation assay using a vector containing a luciferase reporter gene. UV-irradiated plasmids were transfected into a human RKO colon carcinoma cell line that contains wild-type (wt) p53 as well as its derivatives, either mutant p53-143ala (RKO-143ala) or human papillomavirus E6 (RKO-E6, a wt p53 protein that is rapidly degraded and non-functional). We found that cells expressing HBx are more sensitive to UVC-induced killing. Moreover, expression of HBx resulted in a reduction of NER efficiency in RKO cells to 52 +/- 2% (compared with control), RKO-143a1a cells to 46 +/- 3% and RKO-E6 cells to 60 +/- 3%. Similar results were also obtained with a HepG2 hepatoblastoma cell line carrying wt p53. In addition, we found that HBx bound directly to either XPB or XPD DNA helicase in vitro. Thus, our data indicate that HBx may interfere with the NER pathway through both p53-dependent and p53-independent mechanisms. Because HBx binds to TFIIH-associated proteins, we propose that HBx may interfere with the NER pathway also through binding to and altering the activities of helicases necessary for NER and, thereby, increase the mutation rate induced by chemical carcinogens, such as aflatoxin B1, during human liver carcinogenesis.
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PMID:Hepatitis B virus X protein inhibits nucleotide excision repair. 1007 21

Human hepatitis B virus is a risk factor for the development of hepatocellular carcinoma. The hepatitis B virus x protein (HBx) has been shown to inactivate the p53 tumor suppressor protein and impair DNA repair, cell cycle, and apoptosis mechanisms. Herein we report that HBx represses two components of the transcription-repair factor TFIIH, XPB (p89), and XPD (p80), both in p53-proficient and p53-deficient liver cells. This inhibition is observed while HBx maintains its transactivation function. Expression of HBx in liver cells results in down-regulation of endogenous XPB and XPD mRNAs and proteins; this inhibition is not observed with other TFIIH subunits, XPA or PCNA. In liver tissue from HBx transgenics, XPB and XPD proteins are down-regulated in comparison to matched normal liver tissue. HBx has been shown to interact with Sp1 transcription factor and affects its DNA binding activity. Sp1 is essential for the basal promoter activity of XPB in liver cells and Drosophila SL2 cells. In the Sp1-deficient SL2 cells, HBx-induced XPB and XPD inhibition is Sp1-dependent. In summary, our results provide evidence that HBx represses the expression of key TFIIH proteins at least in part through Sp1 elements; this repression may impair TFIIH function in DNA repair mechanisms.
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PMID:Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue. 1127 65

The X protein (HBx) of hepatitis B virus (HBV) is thought to compromise TFIIH function during hepatocyte nucleotide excision repair (NER) to cause the accumulation of hepatocarcinogenic mutations. The TFIIH holoenzyme, including XPB and XPD helicases, is absolutely required for transcription coupled (TCR) as well as global genome (GGR) NER pathways. Using an assay in which GGR carried out by extracts of foetal hepatocytes is reconstituted, we found that incisions [Formula: see text] and [Formula: see text] to a defined cisplatin DNA lesion occurred normally in the presence of functional recombinant HBx. Moreover, HBx did not significantly impair synthesis of the repair patch that completes the NER pathway. These data indicate that HBx does not directly interrupt the function of TFIIH during GGR and suggest that any HBx-mediated inhibitory effect on TFIIH is a transcription-coupled event.
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PMID:Hepatitis B virus X protein does not influence essential steps of nucleotide excision repair effected by human liver extracts. 1468 Aug 37