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)

Transcription of several interferon-inducible human genes is also induced by double-stranded RNA. The nature and the mechanism of action of signals generated by interferons and by double-stranded RNA which mediate the induction of these genes are under investigation. Here we report that 2-aminopurine, a known inhibitor of protein kinases, could selectively block this induction process. Induction of mRNAs 561 and 6-16 in HeLaM cells by double-stranded RNA was completely inhibited by 10 mM 2-aminopurine, whereas cellular protein and RNA syntheses as well as the induction of metallothionein mRNA by CdCl2 were unaffected by this inhibitor. In addition, 2-aminopurine blocked the induction of the same two mRNAs and of mRNAs 2-5(A) synthetase, 2A, and 1-8 by alpha interferon and of mRNAs 2A and 1-8 by gamma interferon in HeLaM cells. The observed inhibition was at the level of transcription, and for establishing efficient inhibition, the 2-aminopurine treatment had to begin at early stages of interferon treatment. In GM2767 cells, 2-aminopurine inhibited induction of mRNAs 561 and 6-16 by double-stranded RNA but not by alpha interferon. These results suggest that double-stranded RNA-induced signal 2 is distinct from the interferon-alpha-induced signal 2 (R. K. Tiwari, J. Kusari, and G. C. Sen, EMBO J. 6:3373-3378, 1987) and that 2-aminopurine can block the former but not the latter. Moreover, it appeared that 2-aminopurine could block the production of signal 1 by interferons. This was confirmed by experiments in which we separately tested the effects of 2-aminopurine on signal 1 and signal 2 production by interferons in HeLaM cells. Although no direct experimental evidence is available as yet, our results are consistent with the hypothesis that the functioning of a protein kinase activity may be necessary for transcriptional induction of genes by double-stranded RNA and for gene induction by interferons in those cells in which signal 1 production is needed.
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PMID:Gene induction by interferons and double-stranded RNA: selective inhibition by 2-aminopurine. 246 Jul 41

In this report we demonstrate that reovirus serotype 1-infected cells contain an inhibitor of the interferon-induced, double-stranded RNA (dsRNA)-dependent protein kinase. We provide evidence that suggests that the virus-encoded sigma 3 protein is likely responsible for this kinase inhibitory activity. We could not detect activation of the dsRNA-dependent protein kinase in extracts prepared from either interferon-treated or untreated reovirus serotype 1-infected mouse L cells under conditions that led to activation of the kinase in extracts prepared from either interferon-treated or untreated, uninfected cells. Extracts from reovirus-infected cells blocked activation of kinase in extracts from interferon-treated cells when the two were mixed prior to assay. The kinase inhibitory activity in extracts of reovirus-infected cells could be overcome by adding approximately 100-fold excess of dsRNA over the amount required to activate kinase in extracts of uninfected cells. Kinase inhibitory activity in extracts of interferon-treated, virus-infected cells could be overcome with somewhat less dsRNA (approximately 10-fold excess). Most of the inhibitory activity in the extracts could be removed by adsorption with immobilized anti-reovirus sigma 3 serum or immobilized dsRNA, suggesting that the dsRNA-binding sigma 3 protein is necessary for kinase inhibitory activity. Purified sigma 3 protein, when added to reaction mixtures containing partially purified kinase, inhibited enzyme activation. Control of activation of this kinase, which can modify eukaryotic protein synthesis initiation factor 2, may be relevant to the sensitivity of reovirus replication to treatment of cells with interferon and to the shutoff of host protein synthesis in reovirus-infected cells.
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PMID:Inhibitory activity for the interferon-induced protein kinase is associated with the reovirus serotype 1 sigma 3 protein. 246 Aug 57

When the assay for the interferon-induced protein kinase is performed in the presence of ammonium sulfate, the activity of other cellular kinases is selectively inhibited. Ammonium sulfate has little effect on the autophosphorylation of the interferon-induced kinase or the phosphorylation of a secondary acceptor, calf thymus histone. Conditions are described for the measurement of interferon-induced kinase activity by trichloroacetic acid precipitation.
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PMID:Addition of ammonium sulfate improves the specificity of the assay for the interferon-induced protein kinase. 246 Nov 22

Interferons, via specific membrane-bound receptors, induce various cellular functions of which antiviral protection is the most extensively studied. We have previously reported the existence of interferon antagonists (referred to as sarcolectins) in various tissue extracts from placental blood, cartilage, brain, muscle, or from sarcomas. These sarcolectins have been fully characterized and purified to homogeneity. In interferon-treated cells, they restore virus sensitivity 4-6 h after the establishment of antiviral protection. In the present study we investigate the effect of sarcolectins on the steady state levels of two double-stranded RNA dependent enzymes, 2-5A (p chi (A2'p)nA) synthetase and protein kinase. Several authors have previously emphasized the role of these enzymes in the mechanism of interferon's antiviral action. Interferon promotes a 4-8 fold increase in protein kinase and 2-5A synthetase in cells. Addition of sarcolectin 5 h after interferon results in a dramatic reduction in the steady state levels of both these enzymes, as shown by their decreased activity and yield observed in Western blot assays. The degradation of the antiviral response in sarcolectin-treated cells might therefore be at least partially attributed to a reduced synthesis of protein kinase and 2-5A synthetase. Since there are no direct interactions between sarcolectins and interferon or its receptors, it can be postulated that sarcolectins exert their effect through these interferon-dependent proteins. We postulate that the opposing biological effects of interferon and sarcolectins strike a balance which may, however, be modified in one direction or the other, depending on their respective concentrations.
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PMID:Interferon- and sarcolectin-dependent cellular regulatory interactions. 246 34

A partially purified plant inhibitor (Meliacin) isolated from Melia azedarach L induced in cells a refractory state to virus infection. Meliacin was active in a large variety of continuous and/or primary cell cultures. A state of maximum virus resistance was achieved after 2 h of incubation and was maintained for at least 15 h; later on it declined but it was fully regained after a second pulse of Meliacin. Interferon was not detected in the supernatant of cells treated with Meliacin and a measurable increase in ds-RNA dependent protein kinase activity was not observed in extracts of Meliacin-treated cells. The antiviral state was not transferred by either extracellular fluid or direct cell-to-cell contact. An active cell metabolism was required for Meliacin action, which was partially reversed in the presence of actinomycin D. It appears that Meliacin is not an interferon-like substance, which induces an antiviral state based on a still unexplained mechanism.
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PMID:Induction of a refractory state to viral infection in mammalian cells by a plant inhibitor isolated from leaves of Melia azedarach L. 246 4

The ability of pure viral and cellular single-strand (ss) RNAs to activate the interferon-induced, double-stranded (ds) RNA-dependent P1/eIF-2 protein kinase purified from human amnion U cells was examined. In addition to the well-established activation of P1 kinase autophosphorylation in vitro by reovirus genome dsRNA, the P1 kinase was also efficiently activated by certain reovirus ssRNAs. The reovirus s1 mRNA was a potent activator of the kinase. By contrast, the reovirus s4 mRNA was a poor activator of the kinase. Likewise, adenovirus VAI RNA, transfer RNA, 5 S ribosomal RNA, and rabbit globin mRNA were not activators or were very poor activators of the purified P1/eIF-2 protein kinase. Analysis of hybrid ssRNAs produced between the reovirus s1 and s4 mRNAs revealed that both the 5' and the 3' portions of the s1 mRNA possessed nucleotide sequences capable of mediating kinase activation. Subsequent deletion analysis of the 5' portion of the s1 mRNA identified a 161-nucleotide region located between positions 416 and 576 which was sufficient for P1 kinase activation. Treatment of reovirus s1 mRNA transcripts with either ssRNA- or dsRNA-specific ribonucleases, but not with heat, destroyed the ability of s1 mRNA transcripts to activate the kinase. These results suggest that P1 kinase autophosphorylation in vitro may be selectively activated by individual ssRNAs in a differential manner, and that a secondary or higher-ordered ssRNA structure(s) may be important in mediating the activation.
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PMID:Mechanism of interferon action. Activation of the human P1/eIF-2 alpha protein kinase by individual reovirus s-class mRNAs: s1 mRNA is a potent activator relative to s4 mRNA. 247 69

In this study the effect of interferon (IFN) on uninfected cells (H9-) and cells infected (H9+) with HIV-1 was investigated. In both H9- and H9+, IFN was unable to inhibit Sindbis virus replication. HIV-1 replication was inhibited by a maximum of 22% at 1000 U/ml of IFN. In both H9- and H9+ cells IFN exhibited a limited antiproliferative effect. There was activation of the 2'-5' oligo-A-synthetase (E enzyme) and the protein kinase enzyme systems, but low activation of the ribonuclease F was seen in both H9- and H9+ cells. From these results it can be concluded that IFN produces a limited antiviral and antiproliferative effect in both H9- and H9+ cells, and a defective ribonuclease F pathway might be responsible for this limited activity.
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PMID:The effect of interferon on cells persistently infected with HIV. 249 10

We investigated the possible translational regulatory roles played by the interferon-induced, double-stranded-RNA-activated protein kinase (P68) and its natural substrate, eucaryotic initiation factor 2 (eIF-2), in poliovirus-infected cells. We demonstrated that protein kinase P68 was both highly autophosphorylated and activated during poliovirus infection. In accordance with these results, immunoprecipitation analysis revealed that phosphorylation of the endogenous eIF-2 alpha subunit also increased in poliovirus-infected cells. We found that double-stranded RNA synthesized during infection likely induced the high levels of P68 autophosphorylation. To determine whether the increase in kinase activity also could be attributed to induction of P68 synthesis, physical levels of protein kinase were measured. It was unexpectedly found that P68 protein levels did not increase but rather dramatically declined in poliovirus-infected cells. Pulse-chase experiments confirmed that the protein kinase was significantly degraded during virus infection. We corroborated our in vivo observations by developing an in vitro assay for P68 degradation using cell extracts. The possible consequences of P68 degradation and increased eIF-2 alpha phosphorylation for protein synthesis regulation in poliovirus-infected cells are discussed.
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PMID:The cellular 68,000-Mr protein kinase is highly autophosphorylated and activated yet significantly degraded during poliovirus infection: implications for translational regulation. 253 16

The kinetics of induction of the antiviral state against two RNA viruses, vesicular stomatitis virus (VSV) and Sindbis virus, by human interferons (IFNs)-alpha, -beta, and -gamma was measured and compared with that of 2',5'-oligoadenylate (2-5A) synthetase and protein kinase in cells treated with IFNs. Both enzymes were induced in similar time courses and the induction by IFN-gamma was slower than IFN-alpha or beta. The time course of the induction of antiviral state against VSV almost paralleled with that of the enzyme induction by each IFN species. In contrast, the induction of antiviral state against Sindbis virus with IFN-gamma was as fast as that induced with IFN-alpha or beta, in spite of the slower enzyme induction by IFN-gamma. The addition of actinomycin D at the time of virus challenge did not substantially affect the induction of the antiviral state against VSV, but markedly retarded the establishment of IFN-gamma-induced antiviral state against Sindbis virus. These results suggest that the antiviral machinery against VSV is induced solely by IFN during the pretreatment, but the one against Sindbis virus involves additional cellular component(s) induced shortly after virus infection, especially in the case of IFN-gamma. Sindbis virus, but not VSV, induced a cellular double-stranded (ds) RNA-dependent protein kinase at an early stage of virus replication. The kinase appeared to phosphorylate the same protein as IFN-induced kinase in the IFN-gamma-treated and Sindbis virus-infected cells, leading to an increased phosphorylation level. These results are consistent with the idea that the Sindbis virus-induced protein kinase may be involved in the IFN-gamma-induced antiviral state against Sindbis virus.
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PMID:Possible involvement of virus-induced protein kinase in the antiviral state induced with interferon-gamma against Sindbis virus. 254 Dec 9

The signal transduction mechanisms involved in interferon (IFN) gamma induction in human peripheral mononuclear lymphocyte nylon-nonadherent cells (NNA cells) by stimulation with poly(I):poly(C) are investigated. Significant enhancement of IFN gamma production by poly(I):poly(C) is observed in the presence of the phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA, a protein kinase C (PKC) activator). Our study shows that in NNA cells, poly(I):poly(C) with or without TPA causes prolonged activation of cytosolic PKC of NNA cells for at least 120 min. The level of activation of PKC is quite remarkable in the case of the combined stimulation by poly(I):poly(C) and TPA as compared to poly(I):poly(C) alone. This demonstrates that prolonged activation of cytosolic PKC for at least 120 min is essential for high levels of production of IFN gamma. Moreover, inhibition experiments using the PKC inhibitor H-7 and cAMP-dependent protein kinase inhibitor H-8 suggest that the mechanism of signal transduction with regard to PKC is involved in stimulation of IFN gamma production in NNA cells by poly(I):poly(C) in the presence of TPA and that along with PKC, cAMP-dependent protein kinase is probably involved in induction of IFN gamma by stimulation with poly(I):poly(C) alone.
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PMID:The roles of protein kinase C and cyclic nucleotide dependent kinase in signal transduction in human interferon gamma induction by poly I:poly C. 254 91


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