Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus (EBV) is frequently found in Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Epstein-Barr virus has transforming properties in vitro and might be involved in the pathogenesis of certain types of Hodgkin's disease. One of the possible mechanisms is the upregulation of the human proto-oncogene bcl-2 by the latent membrane protein 1 of EBV in vitro. Another possibility might be the expression of the viral 'bcl-2 homologue' BHRF-1. In the present study of 64 cases of Hodgkin's disease we investigated the expression of bcl-2 at the protein level in relation to the presence of EBV. Moreover, in 10 EBV positive cases we investigated, the expression of the bcl-2 homologue, BHRF-1, by reverse-transcriptase PCR. bcl-2 was detected in 14 of 22 (64%) EBV positive and in 37 of 42 (88%) EBV negative cases. In 17 of 22 (77%) EBV positive cases Reed-Sternberg cells were negative (n = 8) or expressed the bcl-2 protein in a very low percentage ( < 5%) of cells (n = 9), whereas in 20 of 42 (43%) of the EBV negative cases the majority ( > 50%) of the neoplastic cells were bcl-2 positive. Using the reverse-transcriptase PCR with primers amplifying transcripts of BHRF-1 we were able to detect BHRF-1 transcripts in only one of the 10 tested cases of EBV positive Hodgkin's disease. Our data indicate that in EBV positive Hodgkin's disease growth advantage of Reed-Sternberg cells is not obtained by upregulation of bcl-2 or by the EBV homologue BHRF-1.
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PMID:Expression of bcl-2 protein and transcription of the Epstein-Barr virus bcl-2 homologue BHRF-1 in Hodgkin's disease: implications for different pathogenic mechanisms. 884 76

EBNA 1 is the only antigen expressed in both Epstein-Barr virus (EBV)-infected nasopharyngeal carcinoma (NPC) and Burkitt's lymphoma cells. Previous studies showed that the mRNA of EBNA 1 in these two tumor tissues was initiated from a promoter located in the Bam HI F fragment (Fp) on the viral genome. Two regulatory elements located in the downstream Bam HI Q region include an EBNA 1 binding site and a positive regulatory region between the Fp and the EBNA1 binding site. This data strongly suggested that a cellular factor(s) may modulate the usage of the Fp. To locate the shortest responsible viral sequence, we constructed a series of luciferase gene and chloramphenicol acetyltransferase (CAT) gene plasmids that contained various portions of the Bam HI F/Q region. Plasmid DNA was then introduced into cells to examine the promoter activity of each construct. By this method, we identified a 186-bp fragment within the Bam HI Q region that possessed the highest activity. This promoter was designated as Qp and found to be orientation-dependent and down-regulated by EBNA 1 in both the type I BL cells and human epithelial cells. Furthermore, RNase protection assay showed that a transcription initiation site was located at nucleotide 62,416 of the EBV genome. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis further confirmed that the transcript was initiated from the Qp, and not the Fp. Therefore, our data suggested that a novel promoter, Qp, located within the Bam HI Q existed for the EBNA 1 expression in the latently infected type 1 BL cells. The biological significance of the selection of the Qp needs further investigation.
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PMID:Identification of a novel promoter located within the Bam HI Q region of the Epstein-Barr virus genome for the EBNA 1 gene. 766 54

One of the important regulatory concepts to emerge from studies of eukaryotic gene expression is that RNA polymerase II promoters and their upstream activators are composed of functional modules whose synergistic action regulates the transcriptional activity of a nearby gene. Biochemical analysis of synergy by ZEBRA, a non-acidic activator of the Epstein-Barr virus (EBV) lytic cycle, showed that the synergistic transcriptional effect of promoter sites and activation modules correlates with assembly of the TFIID:TFIIA (DA) complex in DNase I footprinting and gel shift assays. The activator-dependent DA complex differs from a basal DA complex by its ability to bind TFIIB stably in an interaction regulated by TATA-binding protein-associated factors (TAFs). TFIIB enhances the degree of synergism by increasing complex stability. Similar findings were made with the acidic activator GAL4-VP16. Our data suggest a unifying mechanism for gene activation and synergy by acidic and non-acidic activators, and indicate that synergy is manifested at the earliest stage of preinitiation complex assembly.
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PMID:A general mechanism for transcriptional synergy by eukaryotic activators. 767 13

Interleukin-10 (IL-10) is a cytokine known to regulate growth and differentiation in activated human B cells. We studied IL-10 production in a B-cell line derived from Epstein-Barr virus associated post-transplant lymphoproliferative disease (PTLD). Reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated IL-10 mRNA within the cells. Transcripts of the virally encoded homologue BCRF-1 were not detected. ELISA assays demonstrated translation of IL-10 message into the corresponding cytokine, and its subsequent secretion into the culture medium. The rate of 3H-thymidine incorporation by the PTLD cells was not affected by immunologic neutralization of the secreted cytokine, or, by addition of exogenous recombinant IL-10 to the culture medium. Thus, IL-10 does not have an autocrine growth regulatory role in this PTLD line.
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PMID:Interleukin-10 production by a B-cell line derived from human post-transplant lymphoproliferative disease. 775 Sep 24

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal defect of hematopoietic stem cells in which affected cells are characterized by the lack of glycosylphosphatidylinositol (GPI)-anchored proteins. The lesion in PNH lies in the defective synthesis of N-acetyl-D-glucosaminyl-phosphatidylinositol (GlcNAc-Pl), the first intermediate in GPI biosynthesis. Reintroduction of the PIG-A gene into GPI(-) patient cells reportedly complements this defect. We have analyzed here PIG-A transcripts of six PNH patients. GPI+ and GPI- cell lines from each individual were used, ie, Epstein-Barr virus-transformed B-lymphoblastoid cell lines, T-cell lines, and natural killer cell clones. Reverse transcriptase polymerase chain reaction and sequencing showed three different PIG-A splicing variants in GPI+ cell lines, in which the largest transcript contained the wild-type PIG-A coding region sequence. GPI-deficient cell lines showed abnormal splicing variants. Sequencing of PIG-A complementary DNA and genomic DNA showed heterogeneous mutations ranging from different point mutations to small deletions. Two lymphocyte cell lines (T- and B-cell lines) of one patient presented with the same mutation. For another patient, two different mutations were detected in one natural killer cell line. Therefore, different cell lineages have somatic mutations in PIG-A that lead to PNH.
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PMID:Heterogeneous PIG-A mutations in different cell lineages in paroxysmal nocturnal hemoglobinuria. 788 83

TATA-binding protein (TBP)-associated factors (TAFs) in TFIID are required for activator proteins to stimulate transcription, but the mechanism by which TAFs function is poorly understood. To study how TAFs participate in transcriptional activation by the Epstein-Barr virus activator Zta, we used agarose gel electrophoresis and DNase I footprinting to compare transcription complex assembly in reactions with either TFIID or TBP in the presence and absence of wild-type Zta or a deletion of Zta lacking its activation domain. A stable complex of promoter DNA with Zta, TFIIA, and TFIID rapidly formed on a template with Zta-binding sites. Zta stimulation of stable complex formation required TAFs as well as the Zta activation domain and TFIIA. The Zta activation domain also induced a TAF-dependent DNA-protein interaction near and downstream of the transcription star site. Stable complexes formed within 1 min supported activated transcription when RNA polymerase II and the remaining general transcription factors were subsequently added. This rapid assembly of a stable Zta-TFIIA-TFIID-promoter complex is probably a significant component of the mechanism by which TAFs and the Zta activation domain cooperate to stimulate transcription.
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PMID:A mechanism for TAFs in transcriptional activation: activation domain enhancement of TFIID-TFIIA--promoter DNA complex formation. 792 93

Nuclear antigen 1 (EBNA-1) is one of the key functions of the oncogenic DNA virus, Epstein-Barr virus (EBV), and is the only viral protein consistently expressed in EBV-associated malignancies. EBNA-1 binds in a site-specific manner to the viral DNA and is essential for viral replication, as well as for maintaining the genome as an extrachromosomal episome within infected cells. EBNA-1 is not recognized by the cellular immune system. Here we demonstrate that, in addition to its known DNA binding properties, EBNA-1 can also act as a strong RNA binding protein, interacting with diverse substrates in vitro, including the EBV-encoded RNA polymerase III transcript EBER1 and the HIV-encoded transactivation response (TAR) element. We also show that EBNA-1 can bind exon sequences derived from its own RNA expressed from the Fp promoter, as found in Burkitt's lymphoma-related cells and in nasopharyngeal carcinomas. EBNA-1 has been identified as a component in an RNA complex; moreover, an anti-EBNA-1 antibody 1H4-1, that does not inhibit DNA binding, blocks binding to RNA. Arginine/glycine-containing (so-called 'RGG') motifs have been found in an increasing number of proteins that interact with RNA. The EBV antigen contains three potential 'RGG' motifs located around an internal glycine/alanine-rich repetitive sequence in the protein, and outside the region of EBNA-1 mapped previously as essential for viral DNA replication and other functionally defined properties. These motifs could be involved in the observed binding between EBNA-1 and RNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:EBNA-1, the major nuclear antigen of Epstein-Barr virus, resembles 'RGG' RNA binding proteins. 795 53

The Epstein-Barr virus (EBV) latent origin of DNA replication (oriP) is composed of two elements that contain binding sites for the sole viral gene product required for latent cycle replication, EBNA-1. One of these elements, region I, functions as an EBNA-1-dependent enhancer for RNA polymerase II-transcribed genes, may play a role in plasmid segregation, and is required for origin function in B cells latently infected with EBV. The second element, region II, contains or is very near the site of initiation of DNA replication. A genetic approach was taken to determine the contribution of the EBNA-1 binding sites in oriP to origin function. Although region I is required for the transient replication of plasmids bearing region II in EBV-infected B cells, a plasmid lacking region I but containing region II, was observed to replicate transiently in both D98/Raji and HeLa cells expressing EBNA-1. Thus, binding of EBNA-1 to region I is not absolutely required for the molecular events that lead to initiation of DNA replication at region II. Site-directed mutagenesis of the four EBNA-1-binding sites in region II, individually and in various combinations, demonstrated that only two EBNA-1-binding sites are required for region II function. The results obtained with these mutants, together with the analysis of the replicative ability of plasmids containing insertions between EBNA-1-binding sites, suggested that the spatial relationship of the two sites is critical. Mutants that contain only two EBNA-1-binding sites separated by 26 to 31 bp in region II were not maintained as plasmids over many cell generations and were greatly reduced in their ability to replicate transiently in D98/Raji cells. The EBNA-1-induced bending or untwisting of the DNA in EBNA-1-binding sites 1 and 4 in region II did not, however, demonstrate this spatial constraint. It may be concluded from these results that specific protein-protein interactions between EBNA-1 and/or between EBNA-1 and a cellular protein(s) are required for origin function.
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PMID:Sequence requirements of the Epstein-Barr virus latent origin of DNA replication. 810 51

Human interleukin-10 (h-IL-10) is a pleiotropic cytokine with stimulatory activity on B-lymphocytes. Recent evidence indicates that infection with Epstein-Barr virus (EBV) induces h-IL-10 production in B-cells and that this cytokine may contribute to EBV-induced B-cell transformation. It is not known whether h-IL-10 induction by EBV correlates with distinct phenotypic features of the infected cells or with the expression of particular viral genes. We have approached these questions by investigating the expression of h-IL-10 mRNA in a panel of B-cell lines including: in vitro EBV-transformed lymphoblastoid cell lines (LCLs), EBV-carrying Burkitt lymphoma (BL) lines, EBV-negative BL lines and their sublines infected with different EBV strains, or transfected with the transformation-associated viral gene. h-IL-10 mRNA was detected by reverse-transcriptase-assisted (RT)-PCR in a subset of EBV-negative BLs and in all EBV-positive BL lines and LCLs investigated except Daudi. This cell line carries an EBV nuclear antigen (EBNA)-2 gene-defective virus strain. h-IL-10 mRNA was induced by conversion of 3 EBV-negative and h-IL-10-negative BL lines (BL41, BL47 and BL49) with the transforming, B95.8-derived EBV strain. P3HR-I virus convertants that do not express the viral EBNA-2 and the EBV latent membrane protein (LMP)-1, and fail to progress towards a LCL-like cell phenotype, showed no evidence of h-IL-10 up-regulation. Expression of LMP1 was sufficient to induce h-IL-10 mRNA in transfected sublines of the EBV-negative DG75 and BL41 cell lines, whereas expression of EBNA1, 2, 5, or 6 had no effect. h-IL-10 was detected in the culture supernatants of the LMP1 transfectants by specific ELISA assays. The present findings confirm the role of LMP1 in the transactivation of a wide variety of cellular genes which may be involved in EBV-induced B-cell transformation.
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PMID:The Epstein-Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines. 815 62

The Epstein-Barr virus-encoded small RNA (EBER) genes are transcribed by RNA polymerase III, but their transcription unit appears to contain both class II and class III promoter elements. One of these promoter element, a TATA-like box which we call the EBER TATA box, or ETAB, is located in a position typical for a class II TATA box but contains G/C residues in the normal T/A motif and a conserved thymidine doublet. Experiments using chloramphenicol acetyltransferase constructs and mutations in the TATA box of the adenovirus major late promoter showed that the ETAB promoter element does not substitute for a class II TATA box. However, when the ETAB promoter element sequence was changed to a class II TATA box consensus sequence, the EBER 2 gene was transcribed in vitro by both RNA polymerases II and III. From these results, we conclude that the ETAB promoter element is important for the exclusive transcription of the EBER 2 gene by RNA polymerase III.
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PMID:Upstream basal promoter element important for exclusive RNA polymerase III transcription of the EBER 2 gene. 838 14


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