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)

The human ISG20/HEM45 gene was identified independently on the basis of its increased level of expression in response to either interferon or estrogen hormone. Notably, the encoded protein is homologous with members of the 3' to 5' exonuclease superfamily that includes RNases T and D, and the proofreading domain of Escherichia coli DNA polymerase I. We provide here direct biochemical evidence that Isg20 acts as a 3' to 5' exonuclease in vitro. This protein displays a pH optimum of approximately 7.0, prefers Mn2+ as a metal cofactor, and degrades RNA at a rate that is approximately 35-fold higher than its rate for single-stranded DNA. Along with RNase L, Isg20 is the second known RNase regulated by interferon. Previous data showed that Isg20 is located in promyelocytic leukemia (PML) nuclear bodies, known sites of hormone-dependent RNA polymerase II transcription and oncogenic DNA viral transcription and replication. The combined data suggest a potential role for Isg20 in degrading viral RNAs as part of the interferon-regulated antiviral response and/or cellular mRNAs as a regulatory component of interferon and estrogen signaling.
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PMID:The human interferon- and estrogen-regulated ISG20/HEM45 gene product degrades single-stranded RNA and DNA in vitro. 1140 64

The cellular immune responses against major piroplasm surface protein (MPSP) of Theileria sergenti were characterized. Three cattle were immunized with recombinant MPSP (C type) encapsulated by mannan-coated liposome. The proliferative responses of peripheral blood mononuclear cells (PBMC) against MPSP were detected in all immunized animals. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that T cell lines derived from each animal expressed relatively high levels of interferon (IFN)-gamma mRNA, low levels of interleukin (IL)-2, IL-10, and tumor necrosis factor (TNF)-alpha mRNAs, but no detectable level of IL-4 mRNA. From the results of T cell epitope-mapping, T-cell lines from two animals responded to DTSKFTPTVAHRLKHAEDLF (residues 61 to 80), while other animal responded to GTGKVYDFVGNFKVTKVKFE (residues 141 to 160). The MPSP-type specific response of a T-cell line was observed in the latter region of MPSP. These data suggest that immunization with cocktail vaccine consisting of different types of MPSP may be necessary in the field trial.
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PMID:Epitope-Mapping of antigen-specific T lymphocyte in cattle immunized with recombinant major piroplasm surface protein of Theileria sergenti. 1155 46

Methods that allow the specific silencing of a desired gene are invaluable tools for research. One of these is based on RNA interference (RNAi), a process by which double-stranded RNA (dsRNA) specifically suppresses the expression of a target mRNA. Recently, it has been reported that RNAi also works in mammalian cells if small interfering RNAs (siRNAs) are used to avoid activation of the interferon system by long dsRNA. Thus, RNAi could become a major tool for reverse genetics in mammalian systems. However, the high cost and the limited availability of the short synthetic RNAs and the lack of certainty that a designed siRNA will work present major drawbacks of the siRNA technology. Here we present an alternative method to obtain cheap and large amounts of siRNAs using T7 RNA polymerase. With multiple transfection procedures, including calcium phosphate co-precipitation, we demonstrate silencing of both exogenous and endogenous genes.
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PMID:RNA interference in mammalian cells using siRNAs synthesized with T7 RNA polymerase. 1200 Aug 51

The purpose of this study was to address the prognostic significance of circulating melanoma cells by reverse transcriptase-polymerase chain reaction in the peripheral blood of stage IIB and III melanoma patients on high-dose adjuvant interferon at multiple sequential time points from initiation of treatment. Tyrosinase mRNA in peripheral blood from these patients was assayed by reverse transcriptase polymerase chain reaction prior to initiation of adjuvant interferon, at completion of 1 month of intravenous interferon and at 3 monthly intervals until progression. Four hundred and eighteen blood samples from 60 melanoma patients were analysed. The median follow-up time calculated from the time of inclusion in the study was 23 months (range 2-38 months). Tyrosinase mRNA in blood was detected in 42 (70%) of 60 patients: 16 (76%) of 21 stage IIB patients and 26 (66% ) of 39 stage III patients. The presence of tyrosinase mRNA in blood was correlated with a shorter disease-free survival (P : 0.03) and in multivariante analysis was an independent prognostic factor for relapse. Patients who seroconverted to a negative reverse-transcriptase-polymerase chain reaction after induction treatment had a significantly lower probability of recurrence. The presence of circulating melanoma cells is a marker of a high relapse risk and shorter disease-free survival whether detected postoperatively or during follow-up. Tyrosinase mRNA amplification by reverse-transcriptase-polymerase chain reaction may be a useful tool for monitoring the efficacy of adjuvant treatment in stage IIB and III melanoma patients.
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PMID:Prognostic significance of the sequential detection of circulating melanoma cells by RT-PCR in high-risk melanoma patients receiving adjuvant interferon. 1264 40

It is known that nuclear DNA helicase II (NDH II) links CREB-binding protein directly to RNA polymerase II holoenzyme, and that this interaction is essential for gene activation by CREB. Here, we report for the first time that some NDH II/RNA helicase A is a component of promyelocytic leukemia nuclear bodies (PML NBs). An autoimmune serum specific for PML NBs was identified and used in immunoprecipitation experiments. NDH II was present in the immunoprecipitates as shown by mass spectrometry and by immunoblotting. Immunofluorescence and ultrastructural studies showed that NDH II colocalizes with a small subset of PML NBs in control cells, however, colocalizes with practically all bodies in interferon-alpha-stimulated cells. After interferon stimulation, more PML NBs were found to contain newly synthesized RNA, as indicated by bromouridine incorporation. PML NBs also contain RNA polymerase II. The association of NDH II with PML NBs was transcriptionally dependent, and NDH II was present in all bodies with nascent RNA. Blocking of mRNA synthesis caused NDH II relocalization from nucleoplasm to nucleoli. Based on the data, we suggest that NDH II recruitment to PML NBs is connected with transcriptional regulation of interferon-alpha-inducible genes attached to PML NBs.
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PMID:Nuclear DNA helicase II is recruited to IFN-alpha-activated transcription sites at PML nuclear bodies. 1216 69

Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by excessive collagen synthesis by fibroblasts and by vascular hyperreactivity and obliteration phenomena. Excessive collagen production is the consequence of abnormal interactions between endothelial cells, fibroblasts and mononuclear cells. Immunological abnormalities are present very early in the development of SSc. Mononuclear cells, particularily macrophages and T lymphocytes play a prominent role in fibroblast activation and collagen synthesis through the cytokines they produce. Thus, lymphocytic infiltrates in the skin and in the lung are preferentially composed of CD8+ T lymphocytes, that produce important amounts of interleukin 4 (IL-4). The effects of IL-4 are added to these of transforming growth factor B (TGF-B) and connective tissue growth factor (CTGF) that stimulate collagen synthesis by fibroblasts. T lymphocytes produce important amounts of gamma interferon (INF-gamma) that is the best inhibitor of collagen synthesis by fibroblasts. However, the inhibitory effect of INF-gamma on collagen synthesis is diminished in SSc patients. Numerous autoantibodies can be evidenced in the serum of SSc patients. Three of them are specific for SSc and mutually exclusive: anti-centromere antibodies (Ab) in limited SSc, anti-Scl70 Ab in diffuse SSc and anti-RNA polymerase III Ab in diffuse SSc with renal involvement. These autoantibodies are good prognosis markers but their pathogenic role remains uncertain.
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PMID:[Pathogenesis of systemic scleroderma: immunological aspects]. 1221 99

In light of the important role of cytokines in the pathogenesis of bacterial infections, we analyzed the cytokine production induced by different Staphylococcus aureus (S. aureus), S. epidermidis and S. saprophyticus strains in human mononuclear cells (MNCs). MNCs secreted high amounts of interleukin-1beta (IL-1beta) and IL-6 proteins in responses to stimulation with all three species of Staphylococci. Interestingly, a large majority of the S. aureus strains induced significantly higher IL-12 and interferon (IFN) titers than did the S. epidermidis and S. saprophyticus strains. The RNase protection assay revealed high increases in IL-1alpha, IL-1 beta, IL-1 receptor antagonist, IL-6 and IL-12 p40 transcript levels in MNCs stimulated with Staphylococci. All of the tested Staphylococcal strains proved highly efficient in mediating the induction of these genes. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated considerable increases in IFNA transcript levels in MNCs stimulated with S. aureus strains, while only a very weak expression was stimulated by S. epidermidis and S. saprophyticus. These results confirm that heat-killed Staphylococci exert strong immunomodulatory effects, and suggest that the contribution of T-helper 1 (Th(1)) cells to the immune response may be much extensive in infections caused by S. aureus strains, due to their high IL-12p70 and IFN-alpha-inducing activities.
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PMID:Induction of cytokine production by different Staphylococcal strains. 1229 15

Currently available therapies for the treatment of chronic hepatitis C are effective in half of patients, but are expensive, often poorly tolerated, and unsuitable for certain patient populations. The ideal therapy would be highly effective, orally bioavailable, have minimal side effects, be cost effective, and suitable for the majority of patients with hepatitis C. Recent advances in understanding the replication cycle of hepatitis C virus (HCV) and structural, crystallographic definitions of components of the viral polyprotein have improved the prospects for development of novel therapies. The lack of a small animal model of HCV infection continues to hamper progress in the preclinical evaluation of new antivirals and vaccines. Strategies to enhance response to current therapies include the development of novel interferons and delivery systems, nucleoside analogues that have reduced hemolysis compared with ribavirin, inosine 5' monophosphate dehydrogenase inhibitors, and other immunomodulators that are being evaluated as adjunctive therapy to interferon-based regimens. Compounds in preclinical or early phase human trials include small molecules that inhibit virus specific enzymes (such as the serine proteases, RNA polymerase and helicase), or those that prevent translation initiation (such as antisense molecules and ribozymes). Antifibrotic agents are also being developed in an attempt to prevent disease progression in patients in whom HCV RNA cannot be eradicated. While the advent of these newer compounds represent an exciting phase in the treatment of HCV, their safety and efficacy need to be established. Most of these newer therapies are unlikely to be available for routine clinical use in the next 3 to 5 years.
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PMID:Future therapy of hepatitis C. 1240

Renewed interest in the mechanism of action of ribavirin results from its synergistic enhancement of interferon therapy and the need to develop more efficacious agents to treat hepatitis C virus infection. Since the discovery of ribavirin over 30 years ago by scientists at ICN Pharmaceuticals, many mechanisms of action for ribavirin have been proposed. These include inhibition of host inosine monophosphate dehydrogenase by ribavirin monophosphate, inhibition of viral capping enzymes, inhibition of viral RNA synthesis by ribavirin triphosphate, lethal mutagenesis of viral RNA genomes resulting from promiscuous incorporation of ribavirin triphosphate by the viral RNA polymerase, and modulation of the host immune responses. In this article, we will briefly review the evidence for these mechanisms, emphasizing recent findings. In addition, we will discuss strategies for development of nucleoside analogs that may replace ribavirin in the future.
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PMID:Pleiotropic mechanisms of ribavirin antiviral activities. 1245 63

The adenovirus VA1 RNA (VA1), a 160-nucleotide (nt)-long RNA transcribed by RNA polymerase III, is efficiently exported from the nucleus to the cytoplasm of infected cells, where it antagonizes the interferon-induced antiviral defense system. We recently reported that nuclear export of VA1 is mediated by a cis-acting RNA export motif, called minihelix, that comprises a double-stranded stem (>14 nt) with a base-paired 5' end and a 3-8-nt protruding 3' end. RNA export mediated by the minihelix motif is Ran-dependent, which indicates the involvement of a karyopherin-related factor (exportin) that remained to be determined. Here we show using microinjection in Xenopus laevis oocytes that VA1 is transported to the cytoplasm by exportin-5, a nuclear transport factor for double-stranded RNA binding proteins. Gel retardation assays revealed that exportin-5 directly interacts with VA1 RNA in a RanGTP-dependent manner. More generally, in vivo and in vitro competition experiments using various VA1-derived, but also artificial and cellular, RNAs lead to the conclusion that exportin-5 preferentially recognizes and transports minihelix motif-containing RNAs.
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PMID:Exportin-5 mediates nuclear export of minihelix-containing RNAs. 1250 41


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