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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several epidemiological studies have demonstrated a link between chronic B virus infection and primary hepatocellular carcinoma (PHC). HBV DNA sequence integrations into the host cell genome have often been observed in hepatocarcinoma tissues. However, since only in a few cases of PHC the target of HBV-DNA insertion has been identified, alternative mechanisms for HBV-induced hepatocyte transformation have been investigated. Like many other DNA viruses, the hepatitis B virus bears a transactivational potential. Both full length and truncated versions of HBV X protein are able to influence the expression of cellular nuclear protooncogenes c-fos and c-myc. A second transcriptional activator is encoded by the PreS/S region of HBV, but its activity on viral and cellular genes become evident only after dislocations from its downstream sequences. Thus, HBV is able to influence infected cell growth and differentiation using both native proteins, newly generated truncated proteins and virus-cell fusion polypeptides.
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PMID:Hepatitis B virus and hepatocellular carcinoma: a possible role for the viral transactivators. 166 93

A putative transcription factor, C/EBP, isolated from rat liver nuclei, has been shown to bind to at least two different sequence motifs: the CCAAT promoter domain and a core sequence [GTGG(T/A)(T/A)(T/A)G] common to many viral enhancers, including simian virus 40 and human hepatitis B virus. It has been proposed that C/EBP might function as a positive transcription factor by facilitating the communication between promoter and enhancer elements through its dual binding activities to DNA. Surprisingly, results from three different approaches suggest that C/EBP functions as a transcriptional repressor to hepatitis B virus and simian virus 40. Further investigation indicated that C/EBP can function as both a transcriptional activator and a repressor, depending on the reporter gene system.
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PMID:Transcriptional activation and repression by cellular DNA-binding protein C/EBP. 215 40

Integrated hepatitis B virus DNA derived from hepatocellular carcinomas can express, in one third of the cases investigated so far, a transcriptional activator encoded from 3' terminal truncated surface (preS/S) genes resulting in a C-terminally truncated middle surface protein (MHBst). Since MHBst, in contrast to the secreted MHBs, is retained in the secretory pathway at the ER, the question as to whether the retention generates the transcriptional activator function was investigated. Through fusion of MHBs to the ER-retention signal KDEL, it was shown that the intracellular retention does not generate the transcriptional activator function. Tryptic digestions of microsomal vesicles revealed that the amino terminal domain of MHBst directs into the cytoplasmic compartment, whereas in MHBs this domain directs into the lumen of the ER. This structural difference appears to be why transcriptional activator function arises. Through deletion analysis it was shown that non-membrane-associated MHBst proteins are also functional activators. Nonmembrane associated MHBst proteins represent a second class of MHBst proteins. These MHBst-proteins are homogenously distributed all over the cell and show no difference in functionality as compared to the membrane-associated MHBst proteins. MHBst53 (truncated at aa53) was shown to be a minimal activator of this class. Both classes of MHBst proteins were found to form dimers; an which is involved in mediating the dimerization. The integrity of this domain was also revealed to be a prerequisite for the functionality of the activator, suggesting a linkage between dimerization and functionality.
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PMID:Characterization of essential domains for the functionality of the MHBst transcriptional activator and identification of a minimal MHBst activator. 747 25

The human hepatitis B virus (HBV) HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis in transgenic mice. HBx activates the RAS-RAF-mitogen-activated protein (MAP) kinase signaling cascade, through which it activates transcription factors AP-1 and NF-kappa B, and stimulates cell DNA synthesis. We show that HBx stimulates cell cycle progression, shortening the emergence of cells from quiescence (G0) and entry into S phase by at least 12 h, and accelerating transit through checkpoint controls at G0/G1 and G2/M. Compared with serum stimulation, HBx was found to strongly increase the rate and level of activation of the cyclin-dependent kinases CDK2 and CDC2, and their respective active association with cyclins E and A or cyclin B. HBx is also shown to override or greatly reduce serum dependence for cell cycle activation. Both HBx and serum were found to require activation of RAS to stimulate cell cycling, but only HBx could shorten checkpoint intervals. HBx therefore stimulates cell proliferation by activating RAS and a second unknown effector, which may be related to its reported ability to induce prolonged activation of JUN or to interact with cellular p53 protein. These data suggest a molecular mechanism by which HBx likely contributes to viral carcinogenesis. By deregulating checkpoint controls, HBx could participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations.
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PMID:Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. 747 68

The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
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PMID:The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. 758 4

Hepatocyte nuclear factor 4 (HNF-4), found in liver, kidney, and intestine, is a potent transcriptional activator that controls the expression of a wide variety of genes, including those involved in fatty acid and cholesterol metabolism, glucose metabolism, urea biosynthesis, blood coagulation, hepatitis B infections, and liver differentiation. HNF-4 is also a member of the steroid hormone receptor superfamily and has been highly conserved throughout evolution, suggesting that it might respond to an as yet unidentified ligand. In this presentation, some of the current findings regarding the role of HNF-4 in liver-specific gene expression are reviewed.
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PMID:Orphan receptor HNF-4 and liver-specific gene expression. 803 8

Carboxy-terminally truncated hepatitis B virus (HBV) middle surface proteins (MHBst) show a transcriptional activator function. Two different subtypes of MHBst activators can be distinguished: an ER-localized type, represented here by MHBst76 (truncated at amino acid 76), and a cytosol-localized type, represented here by MHBst63. To characterize the MHBst activator on the protein level and to analyze posttranslational modifications, we established recombinant baculoviruses encoding for fusion proteins of MHBst76 or MHBst63 and of an amino terminal hexa-his tag. Both proteins could be obtained in high purity by affinity chromatography using Ni-nitrilo-tri-acetate agarose. In addition, 6H-MHBst76 was also isolated from transiently transfected HepG2 cells. Both the Spodoptera frugiperda (Sf9) cell-derived and the HepG2 cell-derived MHBst proteins were found to be unglycosylated. A detailed analysis of Sf9 cell-derived 6H-MHFBst76 by electrospray-ionization mass spectrometry showed that a fraction of this protein is N-terminally acetylated and phosphorylated or sulfated. Electric-field-mediated transfer of the highly purified proteins into reporter cells demonstrated that the isolated proteins are functional transcriptional activators. These experiments further showed that Sf9 cell-derived and HepG2 cell-derived 6H-MHBst do not differ in their functionality. This system allowed production and purification of functional 6H-MHBst in amounts sufficient enough to allow a further detailed analysis of MHBst activators on the protein level.
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PMID:Isolation of highly purified, functional carboxy-terminally truncated hepatitis B virus middle surface protein activators from eucaryotic expression systems. 878 14

The hepatitis B virus (HBV) genome encodes a 154 amino acid protein termed X (HBx, hepatitis B x protein), which is a promiscuous transcriptional activator of polymerase II and III promoters. HBx upregulates a wide range of cellular and viral genes and is thought to facilitate viral pregenome and mRNA transcription; however, its precise role in the viral replication cycle remains to be elucidated. The functional mechanisms of HBx appear very complex. It was shown to activate transcription factors AP-1 and NF-kappa B vis cytoplasmic pathways including ras-MAP kinase. In contrast, nuclear HBx is thought to activate the transcriptional machinery directly. A second transcriptional activator protein (Mst, middle s transactivator) is encoded by 3'-truncated preS2/S sequences of integrated HBV DNA, but not by the intact viral gene. HBx and Mst may contribute to the pathogenicity of chronic hepatitis B and are suggested to promote hepatocyte transformation via upregulation of cellular proto-oncogenes. Further, HBx may enhance HBV related carcinogenesis by inactivation of the tumour suppressor gene product p53.
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PMID:Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. 887 69

It has been shown that a C-terminally truncated form of the middle-sized hepatitis B virus (HBV) surface protein (MHBst) functions as a transcriptional activator. This function is dependent on the cytosolic orientation of the N-terminal PreS2 domain of MHBst, but in the case of wild-type MHBs, the PreS2 domain is contranslationally translocated into the ER lumen. Recent reports demonstrated that the PreS2 domain of the large HBV surface protein (LHBs) initially remains on the cytosolic side of the ER membrane after translation. Therefore, the question arose as to whether the LHBs protein exhibits the same transcriptional activator function as MHBst. We show that LHBs, like MHBst, is indeed able to activate a variety of promoter elements. There is evidence for a PKC-dependent activation of AP-1 and NF-kappa B by LHBs. Downstream of the PKC the functionality of c-Raf-1 kinase is a prerequisite for LHBs-dependent activation of AP-1 and NF-kappa B since inhibition of c-Raf-1 kinase abolishes LHBs-dependent transcriptional activation of AP-1 and NF-kappa B.
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PMID:The hepatitis B virus large surface protein (LHBs) is a transcriptional activator. 891 53

Two similar, yet functionally distinct genomic RNAs are transcribed from the DNA genome of the human hepatitis B virus. The pre-C RNAs encode the precore protein which is proteolytically processed to yield e antigen. The pregenomic RNAs encode both the nucleocapsid protein and reverse transcriptase and serve as the templates for viral DNA replication. To determine whether synthesis of these two RNAs is directed from a single or a closely spaced pair of promoters, we introduced point and insertion mutations into the basal elements of the promoter that directs their synthesis. Transcription from these mutants was examined both in cell-free transcription systems derived from hepatoma (HepG2) and nonliver (HeLa) cell lines and by transient transfection of hepatoma cell lines (Huh7 and HepG2). The data from these experiments indicated that synthesis of the pre-C and pregenomic RNAs is directed by two distinct promoters and that the basal elements of these two promoters partially overlap, yet are genetically separable, with each consisting of its own transcriptional initiator and a TATA box-like sequence situated approximately 25 to 30 bp upstream of its sites of initiation. A 15-bp insertion was found to be sufficient to physically separate these two promoters. Furthermore, these two promoters can be differentially regulated, with the transcriptional activator Sp1 specifically activating transcription from the pregenomic promoter and the hepatocyte nuclear factor 4 specifically repressing transcription from the pre-C promoter. Thus, we conclude that the promoters used in synthesis of the pre-C and pregenomic mRNAs are genetically distinct and separately regulated.
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PMID:Promoters for synthesis of the pre-C and pregenomic mRNAs of human hepatitis B virus are genetically distinct and differentially regulated. 897 Sep 99


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