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)

Feline leukemia virus, subgroup C/Sarma (FeLV-C/Sarma) induces pure red blood cell aplasia in cats. Although erythroid (BFU-E and CFU-E) and granulocyte/macrophage (CFU-GM) progenitors are infected with this virus, only erythropoiesis is impaired. Two to 3 weeks before the onset of anemia, CFU-E become undetectable in marrow cultures while earlier erythroid progenitors (BFU-E) persist, suggesting that FeLV-C/Sarma (presumably via its envelope glycoprotein gp70) inhibits the differentiation of BFU-E to CFU-E in vivo. To correlate in vitro observations with the progression of disease, prospective studies were performed in six cats. These studies showed that at the time that the frequencies of CFU-E decreased in marrow cultures, BFU-E no longer responded to hematopoietic growth factor(s), although the responses of CFU-GM were unchanged. In further studies, anemic cats received suramin, a reverse-transcriptase inhibitor with other diverse effects. Within 4 to 14 days, erythropoiesis improved and up to 1,616 CFU-E were detected per 10(5) marrow mononuclear cells. However, progenitor cells remained infected, suggesting that suramin modulated erythroid differentiation without inhibiting progenitor infection. These observations led to the hypothesis that the gp70 of FeLV-C/Sarma impairs BFU-E differentiation by interference with ligand/receptor interactions or signal transduction pathways unique to erythroid cells. Understanding this mechanism should provide insights into the interactions controlling early erythropoiesis.
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PMID:Retrovirus-induced feline pure red blood cell aplasia: pathogenesis and response to suramin. 184 31

A full-length molecular clone of equine infectious anemia virus (EIAV) was isolated from a persistently infected canine fetal thymus cell line (Cf2Th). Upon transfection of equine dermis cells, the clone, designated CL22, yielded infectious EIAV particles (CL22-V) that replicated in vitro in both Cf2Th cells and an equine dermis cell strain. Horses infected with CL22-V developed an antibody response to viral proteins and possessed viral DNA in peripheral blood mononuclear cells, as determined by polymerase chain reaction assays. In addition, horses infected with CL22-V became persistently infected and were capable of transmitting the infection by transfer of whole blood to uninfected horses. However, CL22-V, like the parental canine cell-adapted virus, did not cause clinical signs in infected horses. Reverse transcriptase assays of CL22-V- and virulent EIAV-infected equine mononuclear cell cultures indicated that the lack of virulence of CL22-V was not due to an inability to infect and replicate in equine mononuclear cells in vitro.
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PMID:Equine infectious anemia virus derived from a molecular clone persistently infects horses. 217 67

Ribavirin was administered orally in escalating doses for 2 or 4 weeks to 15 symptom-free, human immunodeficiency virus seropositive homosexual men with generalized lymphadenopathy. Reverse transcriptase activity was inhibited during therapy when steady-state plasma concentrations were greater than 6 mumol/L. These concentrations were achieved with 1200 or 2400 mg/day for 2 weeks or a loading dose of 2400 mg/day for 3 days followed by 600 mg/day for 4 weeks. Drug accumulation occurred at all doses. The elimination half-life appeared to be approximately 2 weeks. Reversible adverse reactions, principally resulting in central nervous system symptoms and anemia, correlated with dose and duration of therapy. Immunologic enhancement of T-lymphocyte-mediated mitogen-induced responses was observed in the majority of patients who had reduction in reverse transcriptase activity. However, specific T4+ lymphocyte-mediated antigen-induced responses increased to within the normal range in only three patients. Significant enhancement appeared to correlate with the severity of baseline antigen-induced functional impairment. These data indicate that oral ribavirin can be given for at least 1 month with acceptable toxicity at doses that appear to inhibit human immunodeficiency virus replication.
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PMID:Ribavirin pharmacodynamics in high-risk patients for acquired immunodeficiency syndrome. 244 79

The retroviruses human T-cell lymphotrophic virus-I (HTLV-I) and HTLV-III/LAV (lymphadenopathy-associated virus) are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV). Because HTLV-III infects only humans and chimpanzees, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT) is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.
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PMID:Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine. 346 67

We have used the vaccinia virus-T7 RNA polymerase-based expression system for studies on the activity of proteases from various retroviruses on homologous and heterologous Gag polyproteins in eukaryotic cells. Proteases from human immunodeficiency virus (HIV) types 1 and 2, equine infectious anaemia virus, human T cell leukaemia virus type 1 and human spumavirus were produced and were shown to cleave their cognate Gag substrates produced in trans. Analysis of cross reactivity revealed that lentivirus proteases cleaved only lentivirus Gag proteins and oncovirus proteases acted primarily on oncovirus Gag proteins. The HIV-2 protease cleaved the HIV-1 Gag precursor almost as efficiently as HIV-1 protease. Expression of the 5' end of the human spumavirus pol gene revealed that it encodes a functional protease that acts specifically on the human spumavirus Gag polyprotein. This assay will allow further investigation on the activity and specificity of retrovirus proteases in eukaryotic cells.
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PMID:Analysis of cross reactivity of retrovirus proteases using a vaccinia virus-T7 RNA polymerase-based expression system. 756 54

Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase, EC 3.6.1.23) catalyzes the hydrolysis of dUTP to dUMP and pyrophosphate, and plays important roles in nucleotide metabolism and DNA replication. The dUTPase gene of the retrovirus equine infectious anemia virus (EIAV) was cloned and overexpressed in Escherichia coli using the T7 RNA polymerase expression system. The recombinant vector (pET-3a/EDU), constructed by mutagenic PCR, was transformed into E. coli BL21 (DE3) pLysS cells, resulting in expression of EIAV dUTPase at about 40% of the extracted protein. This level of overproduction is very high compared to previous reports on heterologous expression of dUTPases in E. coli. A one-step purification procedure using phosphocellulose chromatography results in a homogeneous preparation of the enzyme in a yield of 45 mg liter-1 of bacterial culture. The purified EIAV dUTPase, run on a sodium dodecyl sulfate-polyacrylamide gel electrophoresis, shows an apparent molecular mass of 15.1 kDa in accordance with the gene structure. The isoelectric point (pI) was determined to 5.6. Gel filtration under nondenaturating conditions gives a retention volume corresponding to a molecular mass of 40.6 kDa, suggesting a trimeric organization of the enzyme. The amino acid composition and amino-terminal sequence of the recombinant dUTPase are in agreement with predictions from the DNA sequence.
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PMID:dUTPase from the retrovirus equine infectious anemia virus: high-level expression in Escherichia coli and purification. 766 76

Efficient replication of human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) requires the virus transactivator proteins known as Tat. In order to understand the molecular mechanisms involved in Tat transactivation, it is essential to identify the cellular target(s) of the Tat activation domain. Using an in vitro kinase assay, we previously identified a cellular protein kinase activity, Tat-associated kinase (TAK), that specifically binds to the activation domains of Tat proteins. Here it is demonstrated that TAK fulfills the genetic criteria established for a Tat cofactor. TAK binds in vitro to the activation domains of the Tat proteins of HIV-1 and HIV-2 and the distantly related lentivirus equine infectious anemia virus but not to mutant Tat proteins that contain nonfunctional activation domains. In addition, it is shown that TAK is sensitive to dichloro-1-beta-D-ribofuranosylbenzimidazole, a nucleoside analog that inhibits a limited number of kinases and is known to inhibit Tat transactivation in vivo and in vitro. We have further identified an in vitro substrate of TAK, the carboxyl-terminal domain of the large subunit of RNA polymerase II. Phosphorylation of the carboxyl-terminal domain has been proposed to trigger the transition from initiation to active elongation and also to influence later stages during elongation. Taken together, these results imply that TAK is a very promising candidate for a cellular factor that mediates Tat transactivation.
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PMID:Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor. 785 96

Reverse transcriptase-polymerase chain reaction showed that interleukin 3, IL-4, IL-5, IL-6, interferon-gamma and stem cell factor mRNA expression were higher in 15-deoxyspergualin-treated spleen cells than in control spleen cells. Increased IL-2 and IFN-gamma mRNA expression were observed in 15-deoxyspergualin-treated bone marrow cells. On the other hand, increased platelet counts in BALB/c-->C3H/He bone marrow chimeras were observed from days 20 to 33 in our previous work, when they were treated with 15-deoxyspergualin from days 14 to 25. In contrast, marked leukocytopenia and anemia were simultaneously observed, although a marked leukocytosis and a rapid recovery of anemia were observed on day 33 and thereafter. To analyze effects of 15-deoxyspergualin on hematopoiesis and the immune system, we examined mRNA expression in bone marrow and spleen cells from BALB/c-->C3H/He bone marrow chimeras treated with 15-deoxyspergualin from days 14 to 25. Reverse transcriptase-polymerase chain reaction showed that IL-3, IL-4, IL-6, stem cell factor, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor mRNA expression were higher in 15-deoxyspergualin-treated chimeras than in control chimeras, indicating that these cytokines are responsible for an enhancement of hematopoiesis. It was conceivable that IL-6 supported thrombopoiesis in concert with other cytokines. On the contrary, increased IFN-gamma, IL-2, IL-3, IL-4, and IL-10 mRNA expression may play an immunosuppressive role in vivo.
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PMID:Effects of 15-deoxyspergualin in vitro and in vivo on cytokine gene expression. 797 17

The genome of infectious salmon anemia virus (ISAV), which infects farmed Atlantic salmon (Salmo salar L.), is characterized here. The virus has an RNA genome, as shown by using specific DNA virus metabolic inhibitors and radioactive in vivo labeling of ISAV nucleic acid. Electrophoresis of [14C]uridine-labeled ISAV RNA revealed that the ISAV genome is segmented. The genome consists of eight segments that range from 1.0 to 2.3 kb, with a total molecular size of approximately 14.5 kb. One ISAV-specific molecular clone, corresponding to the smallest genome segment, was obtained by cDNA cloning of mRNA from an ISAV-infected cell culture. This clone gave a positive hybridization signal on Northern blots of pelleted ISAV. Pretreatment of the ISAV pellet with RNase A resulted in the disappearance of the positive hybridization signal, demonstrating that the genome is single stranded. Reverse transcriptase PCR with primers corresponding to sequences from the molecular clone and target RNA from ISAV-infected and noninfected fish tissues gave specific positive reactions. Alignments of the nucleotide sequence of the molecular clone did not reveal significant homology with any other available sequence in databases. However, the data presented here, together with morphological and replicational properties previously described, indicate that ISAV has a strong resemblance to members of the Orthomyxoviridae family. This is the first thoroughly characterized orthomyxo-like virus isolated from a teleost.
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PMID:Genomic characterization of the virus causing infectious salmon anemia in Atlantic salmon (Salmo salar L.): an orthomyxo-like virus in a teleost. 931 51

Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between proteins that comprise the transcription factor complex TFIIH raises the possibility that nucleotide excision repair, RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes, xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in Bloom syndrome (BLM) and Werner syndrome (WRN) show that both are DNA and RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and infertility. Although the first Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.
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PMID:Disorders of DNA replication and repair. 942 94


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