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)

Double-stranded RNA (dsRNA)-dependent protein kinase (p68) has been shown to be induced by alpha-interferon (IFN-alpha) in mammalian cells. It binds to dsRNA, and is believed to be a factor in the control of both cellular and viral protein synthesis. This report describes the use of a new monoclonal antibody (MAb) TJ4C4, to monitor levels of p68 in a patient with AIDS-associated Kaposi's sarcoma. Using a novel immunoperoxidase/iron staining method, we examined formalin-fixed, paraffin-embedded biopsies prior to, and 4 months after the initiation of IFN therapy. Immunostaining showed low levels (1+ staining) of p68 in the pretreatment tissue, whereas a marked increase (4+ staining) was noted during interferon treatment. This staining suggests an increased level of intracellular p68 expression. This patient has subsequently remained on IFN-alpha therapy and is alive with no evidence of Kaposi's sarcoma, 6 1/2 years after diagnosis. The use of MAb TJ4C4 will greatly facilitate the study of p68 kinase in clinical tissues, and may provide a way to monitor the effects of IFN therapy.
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PMID:Immunohistochemical detection of double-stranded-RNA-dependent protein kinase (p68) with a novel monoclonal antibody TJ4C4. A case report of an AIDS-associated Kaposi's sarcoma treated with alpha-interferon. 128 28

Treatment of human HeLa and amnion U cells with gamma interferon (IFN-gamma), either alone or in combination with alpha interferon (IFN-alpha), reduced the steady-state level of mRNA encoding the catalytic (C) subunit of protein kinase A (PKA) as measured by Northern gel-blot (RNA) analysis. In addition, IFN-gamma treatment increased the ratio of C alpha to C alpha 2 (the two splice-site variants of PKA C alpha subunit mRNA produced in HeLa cells) as measured by a polymerase chain reaction assay. IFN-gamma greatly reduced the amount of a novel splice-site variant of PKA, C alpha 2, which retains introns G and H, relative to the amount of C alpha, which lacks introns G and H. IFN-alpha treatment in combination with IFN-gamma did not further reduce the level of PKA C alpha transcripts beyond that of IFN-gamma alone, as measured by Northern blots; however, IFN-alpha in combination with IFN-gamma did cause a synergistic increase in the level of human Mx transcripts.
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PMID:Mechanism of interferon action: alpha and gamma interferons differentially affect mRNA levels of the catalytic subunit of protein kinase A and protein Mx in human cells. 154 77

DFMO and IFN have both been shown to suppress the intracellular activity of ornithine decarboxylase in rapidly proliferating tissues. In addition, both agents demonstrate antiproliferative activity against human lymphoblastoid (Daudi) cells in culture. Treatment of log-phase Daudi cells with doses of 6 U/ml of IFN or 1 mM DFMO resulted in a 50% reduction of cell number 72 h after drug addition. Combination of IFN with DFMO against DAUDI cells using the isobologram method showed that the two demonstrate true antiproliferative synergy. Analysis of 2',5'-oligoadenylate synthetase (2,5A) activity in treated cells showed that both IFN alone and IFN/DFMO combination result in equivalent 2,5A induction (1800 mmol/mg/20 h) compared to control (300 mmol/mg/20 h). While 2,5A activity decreased by 50% at 48 h in cells after treatment with IFN alone, the IFN/DFMO combination remained elevated (1700 mmol/mg/20 h). Phosphodiesterase (PdE) activity in these cells showed no substantial changes with IFN, DFMO, or IFN/DFMO treatment over 72 h compared to control values. In contrast, the activity of the 68-kDa interferon induced protein kinase (PK) in IFN/DFMO-treated cells was 1.6-fold greater at 48 and 72 h than that found for IFN alone. These studies demonstrate that the synergistic antiproliferative activity of IFN/DFMO combination may be due, in part, to modification of the activity of IFN-inducible enzymes.
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PMID:Biochemical effects of human alpha interferon in combination with alpha-difluoromethylornithine on human lymphoblastoid (DAUDI) cells in culture. 165 71

A complex system of cis regulatory elements exists by which induction of IFN gene expression is initiated in response to a variety of inducers; cis elements also appear to be involved in the down-regulation of IFN production. IFN gene activation or inhibition of expression may be tightly regulated by the specific binding of newly synthesized or modified proteins to be regulatory regions of the IFN genes. IFN itself acts as a potent modulator of multiple cellular activities. By binding to specific cell surface receptors and probable internalization via receptor-mediated endocytosis and transport into the dense chromatin, IFN treatment leads to activation of numerous genes, some of which possess known antiviral or immunoregulatory functions, whereas the function of others remains to be identified. As with the IFN genes themselves, many of the IFN-inducible genes appear to possess complex regulatory mechanisms, including domains for binding of specific trans-acting proteins. To add to this molecular complexity some viruses have successfully developed methods to circumvent, among other mechanisms, the 2',5'-A-mediated system and the P1 protein kinase system.
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PMID:Recent progress in interferon research: molecular mechanisms of regulation, action, and virus circumvention. 169 Apr 91

The ability of interferon-gamma (IFN gamma) to increase class II major histocompatibility complex (class II MHC) gene products in murine macrophages involves activation of Na+/H+ exchange (Prpic V., Yu, S. F., Figueiredo, F., Hollenbach, P. W., Gawdi, G., Herman, B., Uhing, R. J., and Adams, D. O. (1989) Science 244, 469-471). The ability of IFN gamma to increase class II MHC gene product expression is inhibited by a variety of agents. In the present studies, the involvement of cAMP-dependent protein kinase in modulating IFN gamma-induced expression of MHC gene products and the mechanism of regulation were assessed in macrophages treated with agents which activated cAMP-dependent protein kinase by different molecular mechanisms. Prostaglandin E2 (PGE2) produced a rapid (within 30 s) dose-dependent elevation of cAMP which was paralleled by the activation of cAMP-dependent protein kinase. The elevation of cAMP by PGE2 was still evident at 1 h and maintained through a 4-h incubation. Concentrations of PGE2 which activated the protein kinase produced a dose-dependent inhibition of surface expression of I-A and transcription of class II MHC genes. Inhibition of IFN gamma-induced class II MHC gene product expression was also observed in macrophages treated with agents which activated cAMP-dependent protein kinase by postreceptor mechanisms. Dibutyryl-cAMP (0.01-1 mM), 25 microM forskolin, 0.1 micrograms/ml cholera toxin, and 3-isobutyl-1-methylxanthine (0.1-1 mM) each suppressed IFN gamma-induced cell surface I-A expression, class II MHC gene transcription, and 22Na+ influx. The results are consistent with the suggestion that activation of cAMP-dependent protein kinase regulates an early transductional event initiated by IFN gamma, perhaps Na+/H+ exchange, which is involved in regulating transcription of class II MHC genes and their subsequent expression.
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PMID:Activation of the cAMP cascade inhibits an early event involved in murine macrophage Ia expression. 169 28

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

Previous studies have implicated protein kinase C (PKC) as a mediator in the activation of macrophages by interferons. In order to probe further into the suspected role of protein kinase C in mouse peritoneal macrophage activation, the effects of protein kinase inhibitors in macrophage Fc gamma R and Ia Ag expression were studied. The protein kinase inhibitor, H7, reduced basal levels, and inhibited IFN-alpha-induced expression of Fc gamma R significantly. The concentration of H7 required to inhibit 50% of the Fc gamma R induction was approximately 12 microM, which reflects the previously reported affinity of this compound for PKC in vitro. H7 had only a minimal effect on IFN-gamma-induced Fc gamma R, suggesting different pathways of Fc gamma R induction by the two types of IFN. Ia induction by IFN-gamma was also inhibited by H7, indicating that both types of IFN can utilize PKC to mediate at least part of the signal required for Fc gamma R or Ia expression. HA-1004, a derivative of H7 which possesses high affinity for cyclic nucleotide-dependent protein kinases, but low affinity for PKC, did not alter induction, while H8, a slightly less effective PKC inhibitor than H7, was effective at higher concentrations. Another structurally distinct PKC antagonist, staurosporine, was also effective inhibiting IFN-alpha-induced Fc gamma R and IFN-gamma-induced Ia Ag expression, providing additional evidence that PKC is important. H7 was found to be effective when added as late as several hours after IFN treatment, indicating a prolonged or delayed requirement of PKC for optimal induction of Ia and Fc gamma R by IFN.
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PMID:Pharmacologic evidence for the requirement of protein kinase C in IFN-induced macrophage Fc gamma receptor and Ia antigen expression. 170 Sep 95

Considerable progress has been made in the understanding of the molecular biology of the human interferon system. The genes encoding the interferons, their receptors, and the proteins that mediate many of their biological effects have been molecularly cloned and characterized. The availability of complete cDNA clones of components of the interferon systems has contributed significantly to our understanding of both the biology and the biochemistry of the antiviral actions of interferons. At the biological level, the antiviral effects of interferon may be viewed to be virus-type nonspecific. That is, treatment of cells with one type or even subspecies of interferon often leads to the generation of an antiviral state effective against a wide array of different RNA and DNA animal viruses. However, at the biochemical level, the antiviral action of interferon is often virus-type selective. That is, the apparent molecular mechanism which is primarily responsible for the inhibition of virus replication may differ considerably between virus types, and even host cells. For example, the IFN-regulated Mx protein selectively inhibits influenza virus but not other viruses when constitutively expressed in mouse cells. The IFN-regulated 2',5'-oligoadenylate synthetase selectively inhibits EMC and mengo viruses, two picornaviruses, but not viruses of other families when constitutively expressed in transfected cells. Some viruses are typically insensitive to the antiviral effects of interferon, both in cell culture and in intact animals. This lack of sensitivity to IFN may result from a virus-mediated direct antagonism of the interferon system. For example, in the case of adenovirus, the activation of the IFN-regulated RNA-dependent P1/elF-2 protein kinase is blocked by the virus-associated VA RNA. The relative sensitivity to interferon of different animal viruses varies appreciably. All three of the basic components required to measure an antiviral response may play a role in determining the relative effectiveness of the antiviral response: the species of interferon administered; the kind of cell treated; and, the type of virus used to challenge the interferon-treated host cell. Thus, the relative sensitivity to interferon observed for a particular interferon-cell-virus combination is likely the result of the equilibrium between the many agonists and antagonists which contribute to the overall response. That is, the relative sensitivity of a virus to the inhibitory action of IFN is governed by the qualitative nature and quantitative amount of the individual IFN-regulated cell proteins that may collectively contribute to the inhibition of virus replication.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. 171 Dec 53

IFN play a central role in the activation of macrophages by inducing the expression of several proteins which, in turn, result in increased functional capabilities. Homologous interferon responsive sequences have been found in many IFN-inducible genes, and the gene for a protein that binds these sequences (interferon consensus sequence binding protein, ICSBP) has recently been cloned. In this study, the regulation of ICSBP mRNA induction by IFN-gamma was characterized in murine thioglycolate-elicited peritoneal macrophages. Northern blot analysis revealed two ICSBP mRNA species from these cells. Steady-state levels of both of these species were elevated by IFN-gamma at doses consistent with many IFN-gamma-induced macrophage functional responses. ICSBP mRNA levels increased within 1 h of IFN-gamma treatment, peaked between 4 and 6 h, and subsequently declined to approach baseline levels by approximately 24 h. IFN-alpha, at a concentration shown previously to modulate macrophage surface markers and functions, had no effect on ICSBP message levels alone, but antagonized the IFN-gamma-induction of ICSBP mRNA. IFN-gamma-induction of ICSBP mRNA is resistant to cycloheximide but sensitive to protein kinase inhibitors (H7, H8, HA-1004, staurosporine) at doses that suggest that protein kinase C is a likely target. ICSBP mRNA induction is also inhibited by dexamethasone, a synthetic glucocorticoid, well known as an anti-inflammatory drug capable of influencing gene expression in macrophages. The characterization of ICSBP mRNA regulation should help identify functions for this putative IFN trans-acting factor in macrophage activation.
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PMID:Modulation of interferon consensus sequence binding protein mRNA in murine peritoneal macrophages. Induction by IFN-gamma and down-regulation by IFN-alpha, dexamethasone, and protein kinase inhibitors. 173 Aug 73

Interferon-alpha (IFN alpha) induces an immediate transcriptional response of a restricted set of genes in target cells. Specific transcription is mediated by the cytoplasmic activation of a transcription factor complex termed ISGF3. ISGF3 is a multimeric protein complex composed of a regulatory component (ISGF3 alpha), which is activated following IFN alpha treatment, and a DNA-binding component (ISGF3 gamma), which recognizes the IFN alpha-stimulated response element (ISRE). Following activation, ISGF3 alpha translocates to the nucleus where ISGF3 assembles as a high affinity complex on the ISRE. The biochemical basis for receptor-mediated activation of ISGF3 is unknown. We report that two potent protein kinase inhibitors, staurosporine and K-252a, ablated the transcriptional response to IFN alpha treatment. These inhibitors prevented the activation of the ISGF3 alpha component without affecting the ISGF3 gamma component, resulting in no accumulation of mature ISGF3 in nuclei of treated cells. Although these agents are potent inhibitors of protein kinase C (PKC), PKC does not mediate ISGF3 alpha activation. Down-regulation of PKC by chronic exposure of cells to 12-O-tetradecanoylphorbol-13-acetate, which led to complete loss of PKC-immunoreactive material, failed to ablate the transcriptional response to IFN alpha or the activation of ISGF3 alpha. The PKC-specific inhibitor calphostin C did not perturb activation or nuclear accumulation of ISGF3. We conclude that a novel, staurosporine/K-252a-sensitive kinase is required for ISGF3 activity and may participate in receptor-mediated signal transduction.
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PMID:Protein kinase activity required for an early step in interferon-alpha signaling. 174 40


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