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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2',5'-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2'-5'-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-alpha, IFN-beta, and IFN-gamma, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2',5'-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system reagents, both in cell culture and in whole animals, continues to provide important contributions to our understanding of the virus-host interaction and cellular antiviral response.
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PMID:Antiviral actions of interferons. 1158 85

Lipopolysaccharide (LPS) impairs classical swine fever virus (CSFV) replication in monocytic cells, which are primary targets for CSFV and mediators of virus-induced immunomodulation. Although soluble antiviral factors including interferons (IFN) were not detected, IFN-alpha and IFN-beta mRNA were induced. The serine threonine protein kinase inhibitor 2-aminopurine, impeded this antiviral activity. These results indicate that the LPS-induced antiviral state employs signaling pathways, in which the double-stranded RNA-dependent protein kinase (PKR) is actively involved.
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PMID:Lipopolysaccharide-induced impairment of classical swine fever virus infection in monocytic cells is sensitive to 2-aminopurine. 1168 17

Interferon alfa (IFN-alpha) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (<10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-alpha signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-beta, IFN-alpha receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-alpha, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx(+) and 2'-5' oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9- and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-alpha signaling in the liver of ALD patients.
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PMID:Expression of interferon alfa signaling components in human alcoholic liver disease. 1182 19

We have investigated the mechanisms by which prior exposure of mouse macrophages to lipopolysaccharides (LPS) induces a state of low responsiveness to subsequent exposure to IFN-gamma. We demonstrate that induction of this state requires both de novo gene expression and the suppression of phosphorylation events that lead to activation of transcription factor Stat1 alpha. These observations are mechanistically consistent with the known induction of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 proteins by LPS. In this regard, we demonstrate that overexpression of either SOCS protein suppresses induction of the mouse inducible nitric oxide synthase (iNOS) gene promoter: apparently by suppressing interactions between Stat1 alpha and IFN-gamma activated sites present in both the iNOS, and interferon regulatory factor-1, gene promoters. The induction of SOCS-1 and SOCS-3 by LPS or IFN-beta (an autocrine/paracrine mediator of LPS-induced SOCS-1 mRNA synthesis)occurs by way of multiple protein kinase pathways that include protein tyrosine kinases, protein kinase C, and mitogen-activated protein kinases. These results provide insight that may allow discrimination between LPS-induced inhibition of macrophage functions that are detrimental to the host (e.g. continued exposure to LPS) versus those that might potentially be beneficial (e.g. exposure to subsequent agonists that induce more specific macrophage functions).
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PMID:Low responsiveness to IFN-gamma, after pretreatment of mouse macrophages with lipopolysaccharides, develops via diverse regulatory pathways. 1187 Jun 15

Alpha/beta interferons (IFN-alpha/beta) are potent, endogenous antiviral cytokines that suppress the replication of RNA and DNA viruses, including herpes simplex virus type 1 (HSV-1). The present study compared the efficacies of IFN-alpha/beta transgenes, including IFN-alpha1, -alpha4, -alpha5, -alpha6, -alpha9, and -beta, against HSV-1 infection. L929 cells transfected with the IFN-alpha/beta transgenes produced similar levels of IFN, as measured by bioassay and enzyme-linked immunosorbent assay. In addition, transfected cells were less susceptible to HSV-1 infection than were cells transfected with a plasmid vector control. The murine IFN-beta plasmid construct exhibited the greatest reduction, while the murine IFN-alpha5 transgene showed a modest inhibitory effect in viral titers recovered from the supernatants of transfected, infected L929 cultures. Consistent with this observation, the IFN-beta transgene antagonized viral transcript levels, including infected cell protein 27, thymidine kinase, and glycoprotein B, to a greater extent than did the IFN-alpha transgenes at 6 to 10 h postinfection as determined by real-time PCR. Cells transfected with the IFN-alpha4, IFN-alpha9, or IFN-beta transgenes showed the greatest reduction in viral protein expression relative to the other transfected cells, which was associated with increased STAT1 expression. The absence of the IFN-responsive protein kinase R (PKR) gene completely abrogated the antiviral induction by all IFN-alpha/beta against HSV-1. In the absence of RNase L, viral yields were increased 10-fold, but the antiviral effect of IFN was either unaffected or enhanced. These results suggest that the predominant IFN-mediated, antiviral pathway during HSV-1 infection taken by IFN-alpha/beta in L929 cells utilizes PKR.
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PMID:Differential effect of murine alpha/beta interferon transgenes on antagonization of herpes simplex virus type 1 replication. 1205 Mar 68

Interferon (IFN) therapy is used worldwide as the best available treatment for hepatitis C virus (HCV) infection; however, little is known about how IFN or other drugs work against liver diseases. The effect of 6 drugs (glycyrrhizin, ursodeoxycholic acid, ribavirin, methylprednisolone, IFN-alpha, and IFN-beta) on HCV RNA translation from the HCV internal ribosome entry site (IRES) was investigated, using a bicistronic reporter containing the HCV IRES. IFNs suppressed both cap-dependent and HCV IRES-dependent translation, with HCV IRES-dependent translation being more significantly suppressed. In contrast to HCV IRES, IFN did not suppress either foot-and-mouth disease virus IRES-dependent or encephalomyocarditis virus IRES-dependent translation more than it suppressed cap-dependent translation. Moreover, dominant inhibition of HCV IRES-dependent over cap-dependent translation depended neither on the double-stranded RNA-activated protein kinase activation nor on La protein function. These results indicate a novel antiviral effect of IFNs against HCV.
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PMID:Interferons specifically suppress the translation from the internal ribosome entry site of hepatitis C virus through a double-stranded RNA-activated protein kinase-independent pathway. 1213 50

The murine 200 family proteins p202a, p202b, and p204, and also RNA-dependent protein kinase (PKR) are inducible by interferons (IFNs). p202a, p202b, and p204 modulate the activity of a large variety of transcription factors and also are involved in muscle differentiation. PKR is a multifunctional serine/threonine kinase, which is involved in antiviral defense and cell growth control and in the response to various stress signals. We reported earlier that the level of p204 increases during cultured C2C12 myoblast differentiation to myotubes in consequence of transactivation by the skeletal muscle-specific MyoD protein. The levels of p202a, p202b, and PKR also increase during the differentiation. We report here that these increased protein levels also are due to the transactivation of their genes by MyoD. This is made possible by the occurrence in each of these genes of at least six E boxes, which are recognition sites for MyoD. We also show that the distribution of the p204, p202a, p202b, and PKR proteins in five tissues of adult C129 mice is the same in wild-type mice and mice lacking the IFN-alpha, IFN-beta, and IFN-gamma receptors. This indicates that the synthesis and distribution of these proteins in uninfected adult mice are not affected by endogenous IFNs.
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PMID:The increase in levels of interferon-inducible proteins p202a and p202b and RNA-dependent protein kinase (PKR) during myoblast differentiation is due to transactivation by MyoD: their tissue distribution in uninfected mice does not depend on interferons. 1216 85

Type I IFNs (IFN-alpha/beta) modulate innate immune responses. Here we show activation of transcription factor IFN regulatory factor 3, the synthesis of large amounts of IFN-beta mRNA, and type I IFN signal transduction in macrophages infected with Listeria monocytogenes. Expression of the bacterial virulence protein listeriolysin O was necessary, but not sufficient, for efficient IFN-beta production. Signaling through a pathway involving the type I IFN receptor and Stat1 sensitized macrophages to L. monocytogenes-induced cell death in a manner not requiring inducible NO synthase (nitric oxide synthase 2) or protein kinase R, potential effectors of type I IFN action during microbial infections. The data stress the importance of type I IFN for the course of infections with intracellular bacteria and suggest that factors other than listeriolysin O contribute to macrophage death during Listeria infection.
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PMID:Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes. 1244 63

Theiler's virus infection in the central nervous system (CNS) induces a demyelinating disease very similar to human multiple sclerosis. We have assessed cytokine gene activation upon Theiler's murine encephalomyelitis virus (TMEV) infection and potential mechanisms in order to delineate the early events in viral infection that lead to immune-mediated demyelinating disease. Infection of SJL/J primary astrocyte cultures induces selective proinflammatory cytokine genes (interleukin-12p40 [IL-12p40], IL-1, IL-6, tumor necrosis factor alpha, and beta interferon [IFN-beta]) important in the innate immune response to infection. We find that TMEV-induced cytokine gene expression is mediated by the NF-kappaB pathway based on the early nuclear NF-kappaB translocation and suppression of cytokine activation in the presence of specific inhibitors of the NF-kappaB pathway. Further studies show this to be partly independent of dsRNA-dependent protein kinase (PKR) and IFN-alpha/beta pathways. Altogether, these results demonstrate that infection of astrocytes and other CNS-resident cells by TMEV provides the early NF-kappaB-mediated signals that directly activate various proinflammatory cytokine genes involved in the initiation and amplification of inflammatory responses in the CNS known to be critical for the development of immune-mediated demyelination.
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PMID:Infection with Theiler's murine encephalomyelitis virus directly induces proinflammatory cytokines in primary astrocytes via NF-kappaB activation: potential role for the initiation of demyelinating disease. 1274 89

IFNs are a family of cytokines with pleiotropic biological effects mediated by scores of responsive genes. IFNs were the first human proteins to be effective in cancer therapy and were among the first recombinant DNA products to be used clinically. Both quality and quantity of life has been improved in response to IFNs in various malignancies. Despite its beneficial effects, unraveling the mechanisms of the anti-tumor effects of IFN has proven to be a complex task. IFNs may mediate anti-tumor effects either indirectly by modulating immunomodulatory and anti-angiogenic responses or by directly affecting proliferation or cellular differentiation of tumor cells. Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). In addition to the ISGs implicated in anti-viral, anti-angiogenic, immunomodulatory and cell cycle inhibitory effects, oligonucleotide microarray studies have identified ISGs with apoptotic functions. These include TNF-alpha related apoptosis inducing ligand (TRAIL/Apo2L), Fas/FasL, XIAP associated factor-1 (XAF-1), caspase-4, caspase-8, dsRNA activated protein kinase (PKR), 2'5'A oligoadenylate synthetase (OAS), death activating protein kinases (DAP kinase), phospholipid scramblase, galectin 9, IFN regulatory factors (IRFs), promyelocytic leukemia gene (PML) and regulators of IFN induced death (RIDs). In vitro IFN-alpha, IFN-beta and IFN-gamma induced apoptosis in multiple cell lines of varied histologies. This review will emphasize possible mechanisms and the role of ISGs involved in mediating apoptotic function of IFNs.
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PMID:Apoptosis and interferons: role of interferon-stimulated genes as mediators of apoptosis. 1276 84


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