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)

Human cells treated with trifluoperazine (TFP) or K252a prior to and/or during priming with human interferon-alpha (HuIFN-alpha) produce significantly more IFN on induction with poly(rI).poly(rC) than primed cells in the absence of the drug. Results suggest that calmodulin/protein kinase activity may be involved in priming activity of HuIFN-alpha.
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PMID:Role of calmodulin/protein kinase C in interferon production by poly(rI).poly(rC) in primed human cell cultures. 170 30

Using Northern analysis, we here show that the inducibility by double-stranded (ds) RNA of interferon-alpha/beta-inducible genes is not restricted to a few genes but extends to all the genes known to be stimulated by IFN type I in fibroblasts. Moreover, we show that some genes, preferentially regulated by IFN-gamma, are also activated by dsRNA. We present a series of arguments demonstrating that the induction by dsRNA is not mediated by IFN. In addition to the fact that this induction occurs in the presence of cycloheximide and/or anti-IFN-alpha/beta antibodies in fibroblasts, we observed that, in IFN-resistant Daudi cells, ISG15 and IP-10 genes which are not induced by IFN-beta, are still inducible by dsRNA. dsRNA is also still active on 2-5 AS and ISG15 genes in cells carrying homozygous deletions of IFN alpha/beta genes. Actinomycin D experiments and nuclear in vitro elongation assays reveal that the induction by dsRNA involves, as its early step, a transcriptional event. This induction was found not to require protein synthesis, suggesting that activation of preexisting cellular factors is involved. The opposite inducibility by dsRNA of IFN-beta and 2',5'-oligoadenylate (2-5A) synthetase genes in serum-deprived fibroblasts indicates that pathways of induction by dsRNA of these two genes are not identical. Inhibition by 2-aminopurine of the induction of IFN-inducible mRNAs by IFN-beta or dsRNA suggests the participation of a protein kinase in their mechanism of action.
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PMID:Direct induction of interferon-gamma- and interferon-alpha/beta-inducible genes by double-stranded RNA. 191 73

The antiproliferative effects of human recombinant interferon-alpha (rIFN-alpha A) and interferon-beta (rIFN-beta ser) were assessed in vitro against seven human glioma cell lines. Further analysis of one of these lines (EFC-2) in response to rIFN-alpha A demonstrated a minimum growth inhibition by day 6 of treatment, whereas a 50% inhibition of cell growth was observed with a dose of 50 U/ml of IFN-beta ser. No significant growth inhibition was seen by rIFN-alpha A at doses up to 500 U/ml. Addition of rIFN-alpha A to rIFN-beta ser-treated EFC-2 cells neither suppressed nor augmented the antiproliferative response to IFN-beta ser. The binding of 125I-labeled rIFN-alpha A or 125I-labeled rIFN-beta ser to EFC-2 cells was inhibited competitively by increasing concentrations of either unlabeled rIFN-alpha A or rIFN-beta ser. This suggests that the cellular receptors for both rIFN-alpha A and rIFN-beta ser appear to be intact and appear to bind both agents equally. Furthermore, incubation of EFC-2 cells for 72 h with either rIFN-alpha A or rIFN-beta ser resulted in an increase in 2',5'-oligoadenylate (2-5A) synthetase activity 5-fold with rIFN-alpha A and 50-fold with rIFN-beta ser. Similarly, the 68-kD IFN-induced protein kinase was induced substantially with rIFN-beta ser but only slightly induced with rIFN-alpha A treatment. These results suggest that EFC-2 human glioma cells demonstrate a differential sensitivity in terms of growth inhibition to rIFN-beta ser and to rIFN-alpha A which appears to correlate with a differential induction of both intracellular 2-5A synthetase and protein kinase activity. These results cannot be explained solely on the basis of surface receptor binding of rIFN-alpha A and rIFN-beta ser. These data do suggest that, for human glioma cells in culture, type I IFN receptors may display a subtle architectural variation that allows equivalent binding of both IFN-alpha and IFN-beta ser, but allows an enhanced signal transduction and biological effect only after binding a specific IFN subtype.
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PMID:Growth inhibitory effects of interferon-beta but not interferon-alpha on human glioma cells: correlation of receptor binding, 2',5'-oligoadenylate synthetase and protein kinase activity. 214 Mar 95

The transient expression of hepatitis B virus (HBV) surface and "eJ" antigens caused by transfection of human hepatoblastoma HepG2 cells with HBV DNA was markedly inhibited by cotransfection with poly(I):poly(C). Cotransfection with poly(I):poly(C) also inhibited the expression of bacterial chloramphenicol acetyltransferase (CAT) gene which was under the control of either the HBV core promoter or the human immunodeficiency virus (HIV-1) long terminal repeat. This inhibition was much more pronounced on the expression of HBV-promoted CAT than HIV-promoted CAT. The uptake of reporter plasmid was not affected by cotransfected poly(I):poly(C). The inhibition was found to be at the steady-state CAT mRNA level and appeared to be specific for HBV and HIV regulatory sequences since CAT expression directed by other viral and cellular regulatory sequences was not inhibited. Cotransfection with a mixture of equal amounts of poly(I) and poly(C) had similar inhibitory effects whereas cotransfection with poly(l) or poly(C) alone, or other double-stranded ribo- or deoxyribonucleotides, did not have such strong effects. The addition of poly(l):poly(C) to the culture medium of cells transfected with these reporter plasmids caused little inhibition. Transfection with poly(l):poly(C) induced a minimal amount of intracellular interferon-alpha in HepG2 cells which may be involved in selective inhibition of HBV-and HIV-1-directed gene expression. 2-Aminopurine, an inhibitor of double-stranded RNA activated protein kinase known to block interferon gene induction by poly(l):poly(C), partially reversed the poly(l):poly(C)-induced inhibitory effect on HBV-CAT expression.
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PMID:Selective inhibition of hepatitis B virus and human immunodeficiency virus sequence-promoted gene expression by cotransfected poly(I):poly(C). 221 31

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

Fourteen of 18 proteins induced by interferon-alpha (IFN-alpha) in HeLa S3 cells were labeled with [35S]methionine, resolved by two-dimensional electrophoresis, and assigned coordinates corresponding to HeLa proteins previously mapped by Bravo and Celis (Clin. Chem. 28, 766-781, 1982). Proteins phosphorylated with [gamma-32P]ATP in response to polyinosinic:polycytidylic acid [poly(I):poly(C)] were mapped similarly. Multiple phosphorylated species of a 72-kD protein were labeled in response to poly(I):poly(C) by extracts from IFN-treated cells but not by extracts from control cells. These are likely phosphorylated forms of the IFN-induced poly(I):poly(C)-dependent protein kinase, the enzyme responsible for the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF-2 alpha). Two phosphorylated forms of eIF-2 alpha were labeled in extracts of IFN-treated cells. One of these is a new phosphorylated product of the double-stranded (ds) RNA-activated protein kinase.
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PMID:The mapping of interferon-induced proteins and phosphoproteins from HeLa S3 cells. 271 69

RD-114 is a human sarcoma-derived cell line which is chronically infected with the RD-114 retrovirus. In a previous study, we found that treatment of these cells with human interferon-alpha or human interferon-gamma causes a marked inhibition of RD-114 virus production, but that the replication of exogenous vesicular stomatitis or encephalomyocarditis virus is not impaired. In the present study, we report that neither type of interferon has strong inhibitory effects on DNA synthesis or on multiplication of the cells. We also failed to detect a double-stranded RNA-dependent protein kinase activity in extracts of both interferon-treated and untreated cells. However, a low level of 2',5'-oligoadenylate [2,5(A)] synthetase activity was detectable in extracts of interferon-treated cells. 2,5(A)-dependent endonuclease L activity was detectable in extracts of both untreated and interferon-treated cells. This was probably responsible for the inhibition of protein synthesis observed upon introduction of 2,5(A) to RD-114 cells. In many cells, interferon has been found to induce synthesis of several proteins demonstrable by autoradiographic analysis of slab gels on which extracts of interferon-treated and radiolabelled cells are separated. Using a similar method, no such induced protein synthesis was detectable in interferon-treated RD-114 cells. Our results indicate that RD-114 cells are resistant to most known actions of interferons except for the antiretroviral action to which they are as sensitive as any other cell line.
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PMID:Antiviral, anticellular and enzyme-inducing activities of interferons in RD-114 cells. 619 49

Treatment of Rous sarcoma virus-transformed rat cells with rat interferon-alpha (specific activity, 10(6) U/mg of protein) for 24 h caused a 50% reduction in intracellular pp60src-associated protein kinase activity. Staphylococcus aureus V8 protease digestion of pp60src, derived from 32P-labeled monolayer cultures incubated with or without interferon, revealed no differences either in the phosphopeptide pattern or in the phosphoserine-phosphotyrosine ratio. However, [3H]leucine pulse-labeling experiments showed that the synthesis of pp60src was reduced by 42 to 48%, relative to the level of bulk protein synthesis, in the interferon-treated cultures. Rat interferon-alpha also reduced the growth rate of Rous sarcoma virus-transformed rat cells in a dose-dependent manner over a 72-h period. The decrease in growth rate was accompanied by increases in the thickness and number of actin fibers per cell and by a decline in intracellular tyrosine phosphorylation by pp60src. The results suggest that interferon can inhibit the expression of the transformation-related phenotype by selectively reducing the synthesis of the Rous sarcoma virus transforming gene product. However, the interferon effects on the cytoskeletal organization and proliferation of Rous sarcoma virus-transformed cells may be due at least in part to the predominance of interferon-induced phenotypic changes over those caused by pp60src.
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PMID:Reduced synthesis of pp60src and expression of the transformation-related phenotype in interferon-treated Rous sarcoma virus-transformed rat cells. 631 24

B-HIV1, an oligoclone of immortalized cells derived from human peripheral B lymphocytes infected in vitro with the TIIIB isolate of HIV-1, produces low levels of replication-competent HIV when propagated in 1% serum, but increases production > or = 5-fold after phorbol myristate acetate (PMA) exposure. Electron microscopy reveals budding of mature virions from the plasma membrane, without concentration in endocytotic spaces. The PMA effect is specific for protein kinase activation, occurring upon exposure of B-HIV1 to those congeners capable of upregulating calcium and phospholipid dependent protein kinase C and susceptible to inhibition by the protein kinase antagonists H-7 and staurosporine. Induction could also be effected by another viral activator, 5-azacytidine, which acts via an alternate mechanism, and blocked by high doses of interferon-alpha but not the anti-viral nucleoside analog zidovudine (AZT). B-HIV1 may provide a model system for study of the regulation of chronic HIV infection in cells of B lymphocyte lineage.
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PMID:A model system for regulation of chronic HIV-1 infection in peripheral B lymphocytes. 769 May

The polymerase chain reaction (PCR) was used to introduce a phosphorylation site into human interferon-alpha B2 (Hu-IFN-alpha B2) and the chimeric human interferon-alpha A/D (Hu-IFN-alpha A/D). The phosphorylation sites were created by adding an amino acid consensus sequence for phosphorylation by the cAMP-dependent protein kinase to the carboxyl termini of the IFNs. The resultant modified IFNs (Hu-IFN-alpha B2-P and Hu-IFN-alpha A/D-P) were expressed in Escherichia coli and purified. The purified proteins exhibited antiviral activities similar to that of unmodified Hu-IFN-alpha B2 and Hu-IFN-alpha A/D. The Hu-IFN-alpha B2-P and Hu-IFN-alpha A/D-P can be phosphorylated by the catalytic subunit of the cAMP-dependent protein kinase and [gamma-32P]ATP with retention of biological activities. The introduction of phosphorylation sites into Hu-IFN-alpha B2 and Hu-IFN-alpha A/D provides new reagents for studies of receptor binding, pharmacokinetics, and other studies where labeled IFNs are useful.
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PMID:Construction and activity of phosphorylatable human interferon-alpha B2 and interferon-alpha A/D. 802 92


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