Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The X protein (HBx) of the human Hepatitis B Virus (HBV) is a regulatory protein that exercises a transcriptional activator function on a variety of regulatory elements and is therefore considered to be involved in the development of human hepatocellular carcinoma (HCC). So far, most attempts at elucidating HBx function have been undertaken at the genetic level, reflecting the difficulties in detecting the very low amounts of the protein in infected livers. Consequently, the questions of intracellular localization and posttranslational modification have not yet been completely answered. We therefore constructed recombinant baculoviruses that allowed expression of HBx and the hexa histidine HBx fusion protein HBxHis in insect cells. Cell fractionation experiments revealed that only a minor part of HBx is detectable in a soluble form in the cytosolic fraction, whereas most of the protein forms intracellular aggregates. These results could be confirmed by confocal laser immunofluorescence. The fusion of a hexa-histidine tag to the amino terminus of HBx allowed a rapid one-step purification by metal chelate affinity chromatography. The detailed analysis of purified HBxHis using electrospray ionization mass spectrometry uncovered two major components: the unmodified, monomeric, fully oxidized form with five intramolecular disulfide bridges, and its N-acetylated modification. Additionally, two minor peaks with mass differences of delta m = +80 da suggested that a small fraction of HBx becomes posttranslationally phosphorylated in insect cells. No further modifications could be observed, indicating that only phosphorylation might play a role in a possible posttranslational regulation of this viral activator.
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PMID:Isolation and molecular characterization of hepatitis B virus X-protein from a baculovirus expression system. 932 33

Hepatitis C virus (HCV), a major etiologic agent of transfusion associated hepatitis, is a positive, single-stranded RNA virus and is also known to be implicated in liver cirrhosis and hepatocellular carcinoma. Nonstructural protein 5A (NS5A) of HCV contains acidic and proline-rich amino acids in its carboxy-terminal half. These structural features resemble eukaryotic transcription activators. In this report, we show that NS5A functions as a potent transcriptional activator when fused to the yeast (Saccharomyces cerevisiae) GAL4 DNA-binding domain (1-147). The potential transcriptional activator maps to the C-terminal half of NS5A in the yeast cell. Therefore, our data provides the first evidence that NS5A may modulate host cell function at the transcriptional level.
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PMID:Hepatitis C virus nonstructural protein 5A contains potential transcriptional activator domains. 938 55

Hepatitis B virus-X protein (HBV-X) is known to be an important factor in the formation of hepatocellular carcinoma by acting as a transcriptional activator on viral or cellular genes. To identify differentially expressed genes between the human hepatoblastoma cell line HepG2 and HBV-X gene transfected hepatoblastoma cell line HepG2-4X, we used a differential display polymerase chain reaction technique. The technique produced numerous up-regulated and down-regulated bands, each representing a partial cDNA fragment. We isolated 23 different kinds of cDNA fragments that showed marked differences in two cell lines. The fragments were used as templates for DNA sequencing analysis and as probes for Northern blot analysis. This analysis revealed that eight cDNA clones were differentially expressed in each cell line but fifteen cDNA clones were not. Among the 8 clones, 3 clones showed sequence similarities with human mitochondrial ATPase subunit 6 (mtATPase 6) and the human amidophosphoribosyl transferase (ATase) precursor, whereas 5 other clones were human novel protein encoding genes. Two genes having similarity with known genes were repressed by HBV-X. These results reflect that complex alterations of the expression of enzymes concerning the energy-generating system in mitochondria and metabolite synthesis are closely associated with the HBV-X function during the formation of hepatocellular carcinoma. These newly obtained genes will be useful for analyzing HBV-X functions. We are in the process of further characterizing these genes.
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PMID:Identification of differentially expressed genes in human hepatoblastoma cell line (HepG2) and HBV-X transfected hepatoblastoma cell line (HepG2-4x). 963 54

The AIR-1-encoded CIITA transcriptional activator is crucial for both constitutive and IFN-gamma-induced MHC class II gene transcription. We show here that the MHC class II negative phenotype of the human hepatocarcinoma cell lines Alexander and HepG2 remains unmodified after treatment with IFN-gamma, although MHC class I expression is up-modulated. This correlates with absence of CIITA mature transcripts. Transfection of an expressible CIITA cDNA in Alexander cells resulted in a very high cell surface expression of all three human class II subsets, HLA-DR, -DP and -DQ, indicating that normally observed induction of CIITA expression by IFN-gamma is probably blocked, in the hepatocarcinoma cell lines, at the level of CIITA transcription and not at the level of IFN-gamma receptor binding and signal transduction mechanisms. To assess whether MHC class II expression on CIITA-transfected Alexander cells could have functional relevance, we tested their capacity to present antigenic peptides to an HLA-DR-restricted T cell line specific for a peptide of Mycobacterium tuberculosis Ag85 protein. It was found that the transfected cells could not only present the exogenously supplemented peptide but also process Ag85 protein to generate the specific epitope recognized by the HLA-DR-restricted T cell line. Similar results were obtained with CIITA-transfected CFPAC-1 pancreatic adenocarcinoma cells, which differed from Alexander cells in that they were inducible by IFN-gamma. These results suggest new strategies to act on CIITA for increasing the potential of a tumor cell to present putative tumor Ags to the immune system.
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PMID:HLA class II expression in uninducible hepatocarcinoma cells after transfection of AIR-1 gene product CIITA: acquisition of antigen processing and presentation capacity. 967 Sep 58

The X protein (HBx) of human hepatitis B virus (HBV) is a transcriptional activator protein. The HBx protein plays an important role in viral replication in HBV infected cells and the liver diseases including hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Therefore, the repression of HBx gene expression by hammerhead ribozymes may be a good way to inhibit HBV replication and cure HBV-related liver diseases. We designed two hammerhead ribozymes, RzA and RzB, to cleave target sites at nucleotides 114 and 309 in the HBx open reading frame (ORF), respectively. In vitro, RzA and RzB cleaved HBx RNAs at their target sites up to 52 and 75%, respectively; however, the disabled ribozymes (dRzs) which have mutations in the catalytic site did not cleave the target RNAs at all. When each of the ribozymes were cotransfected into HepG2 cells with HBx expression plasmid, RzA and RzB reduced the level of HBx mRNA to 40 and 57%, respectively. The transactivation activity of HBx protein was also reduced dramatically by the ribozymes. These results suggest that the hammerhead ribozymes, RzA and RzB, can be used for the gene therapy of liver diseases caused by HBV.
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PMID:Repression of hepatitis B virus X gene expression by hammerhead ribozymes. 1020 56

The hepatitis B virus (HBV)-encoded transcriptional activator HBV-X protein (HBx) was known to be involved in hepatocarcinogenesis. Hepatocarcinogenesis generally included an active angiogenesis that was mainly considered to be due to a local hypoxia in liver tissues. However, the exact mechanisms of HBx-induced hepatocarcinogenesis were poorly understood. In this study, we examined the role of HBx in the increased angiogenesis and the possible regulating mechanisms of HBx by hypoxia. We demonstrated that HBx stimulated the transcription of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in HBx-stable transfectants. HBx-induced angiogenesis was confirmed by in vivo tumor angiogenesis assay, resulting in that the HBx transfectants increased the formation of new blood vessels compared to the control transfectants. Then, we demonstrated that the expression of HBx was enhanced after incubating HBV-infected hepatoma cells under hypoxia. Moreover, the activity of HBV enhancer 1 (Enh1) was increased when hepatoma cells transfected with the reporter plasmid containing HBV Enh1 were exposed to hypoxic conditions. These results strongly suggest that HBx may play a critical role in the hypoxia-induced angiogenesis through transcriptional activation of VEGF during hepatocarcinogenesis.
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PMID:Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. 1067 26

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the regulation of gene expression during growth, differentiation, apoptosis, and inflammation. Autoregulation is relatively common in the modulation of C/EBP gene expression and, for the human and murine C/EBPalpha, it is known that species-specific autoregulatory mechanisms operate. It is therefore essential to investigate the autoregulation of additional C/EBP genes from a wider range of different species to gauge the degree of commonality, or otherwise, which exists. As an important step towards this goal, we report here the cloning and the characterisation of the ovine C/EBPdelta gene (ovC/EBPdelta) and analysis of its promoter region. Transient transfection assays reveal that ovC/EBPdelta acts as a transcriptional activator. Although several motifs that are characteristic of C/EBPdelta genes are conserved in the ovine sequence, including the basic region, leucine zipper, and activation domains, two regions have been identified that are specifically absent in the ovine and bovine homologues. The ovC/EBPdelta promoter is active in both the hepatoma Hep3B and the mammary epithelial HC11 cell lines, induced by the cytokine interleukin-6 and autoregulated by mechanisms that are potentially different from those described for the rat promoter. These results suggest that, in common with C/EBPalpha, the C/EBPdelta genes may also be subject to autoregulation by distinct species-specific mechanisms.
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PMID:The ovine CCAAT-enhancer binding protein delta gene: cloning, characterization, and species-specific autoregulation. 1079

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.
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PMID:Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. 1082 73

Ceramide is known to induce pRb (retinoblastoma gene product) dephosphorylation through the activation of ceramide-activated protein phosphatase (CAPP) during G1 arrest, but other molecular mechanisms linked to regulation of pRb dephosphorylation during ceramide-induced G1 arrest are poorly understood. In this paper, we investigated whether p21, a cdk (cyclin-dependent kinase) inhibitor, is involved in the induction of pRb dephosphorylation during ceramide-induced G1 arrest. In SK-Hep-1 cells, the addition of ceramide resulted in pRb dephosphorylation and G1 arrest. The activity of cdk2 was inhibited in response to ceramide during this process. p21 protein and mRNA were remarkably induced, while the protein level of p53, known as a transcriptional activator of p21, was not elevated at the same condition. p21 induction was also observed in the Hep3B cells lacking a functional p53 after exposure to ceramide. Although p21 is induced in ceramide-treated Hep3B cells, Hep3B cells do not induce G1 arrest, because Hep3B cells are deficient in a functional pRb protein. To confirm that pRb is a critical target for the induction of G1 arrest by inhibiting cdk2 activity through p53-independent p21, pRb-expressing vector was transfected into Hep3B cells. After treatment with ceramide, pRb-expressing cells (pRb+/+), but not pRb-/- cells, were arrested in G1 phase. In pRb+/+ cells, ceramide-mediated G1 arrest was accompanied by the accumulation of hypophosphorylated pRb and p21 associated with cdk2. Together, these results suggest that p21, induced through p53-independent pathway, participates in the induction of pRb dephosphorylation by inhibiting cdk2 activity during ceramide-mediated G1 arrest in hepatocarcinoma cells.
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PMID:Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. 1087 74

Hepatitis B virus (HBV) gene expression is mainly regulated at the transcription initiation level. The viral X protein (pX) is a transcription coactivator/mediator targeting TFIIB for the recruitment of RNA polymerase II. Here we report a novel pX nuclear target designated HBXAP (hepatitis B virus X-associated protein). HBXAP is a novel cellular nuclear protein containing a PHD (plant homology domain) finger, a domain shared by many proteins that play roles in chromatin remodeling, transcription coactivation, and oncogenesis. pX physically interacts with HBXAP in vitro and in vivo via the HBXAP region containing the PHD finger. At the functional level HBXAP increases HBV transcription in a pX-dependent manner suggesting a role for this interaction in the virus life cycle. Interestingly, HBXAP collaborates with pX in coactivating the transcriptional activator NF-kappaB. Coactivation of NF-kappaB was also observed in tumor necrosis factor alpha-treated cells suggesting that pX-HBXAP functional collaboration localized downstream to the NF-kappaB nuclear import. Collectively our data suggest that pX recruits and potentiates a novel putative transcription coactivator to regulate NF-kappaB. The implication of pX-HBXAP interaction in the development of hepatocellular carcinoma is discussed.
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PMID:Hepatitis B virus pX interacts with HBXAP, a PHD finger protein to coactivate transcription. 1178 98


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