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)

The transcription factor IRF-1 (interferon regulatory factor 1) is an activator of type I interferon and interferon-inducible genes. IRF-1 manifests tumor suppressor activity. Its overexpression results in inhibition of cell growth, and deletions of the IRF-1 gene were demonstrated in a number of human leukemias and myelodysplasias. Although the mechanism by which IRF-1 affects cell growth is unknown, it is believed that IRF-1 activates a set of genes that negatively regulate cell growth. The double-stranded RNA-dependent protein kinase (PKR), which is an interferon-inducible gene, contains a promoter element for the binding of IRF-1 and exhibits antiproliferative properties. Consequently, we investigated the role of IRF-1 in PKR expression. Here, we show that in IRF-1-deficient embryonic fibroblasts, PKR expression is reduced relative to wild-type cells. This result predicts diminished expression of PKR as a potential consequence of deletion of the IRF-1 gene in human leukemias. We show that cells of the human leukemic U937 cell line contain a deletion of one IRF-1 gene and express low levels of PKR. We demonstrate that upregulation of IRF-1 expression in U937 cells by transfection is sufficient to induce PKR expression. We also found a marked reduction in the expression of PKR in blood samples from two patients with myelodysplasias, carrying a deletion of chromosome 5q, a locus to which IRF-1 was mapped. These results show that IRF-1 activates PKR expression and suggest that loss of one allele of the IRF-1 gene is sufficient to affect PKR expression. Therefore, PKR is a strong candidate for a mediator of the tumor suppressor activity of IRF-1.
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PMID:Expression of the protein kinase PKR in modulated by IRF-1 and is reduced in 5q- associated leukemias. 862 78

Constitutive expression of the type I interferon-inducible human cytoplasmic MxA protein has been shown to interfere with primary transcription of vesicular stomatitis virus (VSV) in tissue culture cells. As phosphorylation of the VSV P protein has been linked to its ability to stimulate viral transcription, we analyzed the phosphorylation status of this protein in human brain cells (U-87) stably transfected with MxA. We observed a general increase in cellular kinase activity in the presence of MxA, affecting both cellular proteins and VSV P protein. Phosphorylation of the latter was up to threefold higher both in vivo and in vitro. In vitro phosphorylation of recombinant VSV P protein could be enhanced in MxA-negative cell extracts after exogenous addition of recombinant His-MxA. Biochemical evidence and phosphorylation of a mutant P protein lacking the recognized casein kinase II (CKII) sites suggested that hyperphosphorylation of VSV P protein was not due to a stimulation of CKII. We thus propose that expression of MxA in human brain cells is associated with the stimulation of a cellular kinase that is active in phosphorylating both cellular target proteins and VSV P protein.
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PMID:Expression of the human MxA protein is associated with hyperphosphorylation of VSV P protein in human neural Cells. 865 21

The interferon-inducible, double-stranded RNA-dependent protein kinase PKR has been implicated in anti-viral, anti-tumor, and apoptotic responses. Others have attempted to examine the requirement of PKR in these roles by targeted disruption at the amino terminal-encoding region of the Pkr gene. By using a strategy that aims at disruption of the catalytic domain of PKR, we have generated mice that are genetically ablated for functional PKR. Similar to the other mouse model of Pkr disruption, we have observed no consequences of loss of PKR on tumor suppression. Anti-viral response to influenza and vaccinia also appeared to be normal in mice and in cells lacking PKR. Cytokine signaling in the type I interferon pathway is normal but may be compromised in the erythropoietin pathway in erythroid bone marrow precursors. Contrary to the amino-terminal targeted Pkr mouse, tumor necrosis factor alpha-induced apoptosis and the anti-viral apoptosis response to influenza is not impaired in catalytic domain-targeted Pkr-null cells. The observation of intact eukaryotic initiation factor-2alpha phosphorylation in these Pkr-null cells provides proof of rescue by another eukaryotic initiation factor-2alpha kinase(s).
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PMID:Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. 1002 21

Type I interferon system is an important part of host's innate defense mechanisms against viral infections. The type I interferons mediate in part their antiviral effect via induction of various proteins. Among them the most widely known are 2'-5' oligoadenylate synthetase (2'-5' OAS) and a protein kinase (PKR). MxA, an other antiviral protein, is specifically induced by the type I interferons. The MxA protein contains the dynamin signature, which is implicated in transport processes. The MxA protein appears to block the replication of certain viruses at poorly defined steps. There are substantial differences in the antiviral activity of MxA between virus types. Indeed, the replication of vesicular stomatitis virus and influenza virus is inhibited by MxA, but not the one of type I herpes simplex virus. Measurements of interferon alpha and MxA levels may be of high value in clinical practice. Interferon alpha can be detected by using a bioassay based on the interferon alpha ability to protect cultured cells from the cytopathic effect caused by a selected challenged virus, or by using immunological techniques. The current bioassays are the most sensitive methods but they are cumbersome and lengthy, even though simplifications have been proposed. Immunological techniques are easier, however they do not explore the biological activity of the circulating interferon. The presence of type I interferon in biological samples (serum, plasma, cerebro-spinal fluid, cultured cell supernatants) can be indirectly assessed by capability of interferon alpha to induce in vitro the synthesis of MxA in a dose dependent manner in cultured cells. Following to the lysis of the cells, the induced MxA can be quantitated and hence the type I-interferon concentration can be determinated in samples. The quantitation of MxA protein in peripheral blood lysates can be useful as a specific marker of acute viral infections. A minute amount of whole blood (15 mul) is sufficient which facilitates its use in pediatrics. The specifically type-I-interferons inducible MxA protein is also a potential useful marker in the management of interferon alpha-treatment. Moreover, the detection of interferon alpha and antiviral proteins constitute an indirect approach for investigating the hypothesis of the role of viruses in chronic diseases with suspected infectious aetiology.
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PMID:[Alpha interferon, antiviral proteins and their value in clinical medicine]. 1057 14

Virus infection triggers innate responses to host cells including production of type I interferon (IFN). Since IFN production is also induced by treatment with poly(I:C), viral double-stranded (ds) RNA has been postulated to play a direct role in the process. In the present study, we investigated the effect of dsRNA binding proteins on virus-induced activation of the IFN-beta gene. We found that PACT, originally identified as protein activator for dsRNA-dependent protein kinase (PKR) and implicated in the regulation of translation, augmented IFN-beta gene activation induced by Newcastle disease virus. Concomitantly with the augmented activity of IFN-beta enhancer, increased activity of NF-kappaB and IRF-3 and IRF-7 was observed. For the observed effect, the dsRNA-binding activity of PACT was essential. We identified residues of PACT that interact with a presumptive target molecule to exert its function. Furthermore, PACT colocalized with viral replication complex in the infected cells. Thus the observed effect of PACT is novel and PACT is involved in the regulation of viral replication and results in a marked increase of cellular IFN-beta gene expression.
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PMID:PACT, a double-stranded RNA binding protein acts as a positive regulator for type I interferon gene induced by Newcastle disease virus. 1140 90

We isolated a UL13 gene-deleted mutant of the herpes simplex virus type 1 (HSV-1) strain VR3 (VRDelta13) and its revertant virus (VRDelta13R). This deletion mutant still had virus host shutoff (vhs) activity, although a previous report had suggested the possibility of a functional relation between the UL13 product, that is protein kinase (PK), and vhs activity. We compared the in vivo growth of these viruses in BALB/c mice. VRDelta13 was cleared in the early period of intraperitoneal infection. VRDelta13 had a higher sensitivity to the mouse type I interferon (IFN) and showed a higher level of IFN induction in the study period of infection than did VR3 and VRDelta13R. These results suggest that a nonspecific antiviral response (i.e., the IFN system) may contribute to this rapid inhibition of viral replication in vivo.
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PMID:Participation of type I interferon in the decreased virulence of the UL13 gene-deleted mutant of herpes simplex virus type 1. 1142 58

Double-stranded RNA (dsRNA) plays a role in the regulation of cell growth and apoptosis as well as in the cellular antiviral responses. However, it remains unknown if dsRNA-activated signaling systems are functional in the thyroid. Here we report the presence of the dsRNA-dependent protein kinase (PKR) in FRTL-5 rat thyroid cells. In poly(I)-poly(C) (pIC)-stimulated cells, activation of nuclear factor-kappa B (NF kappa B) binding was clearly induced. Incubation of FRTL-5 cells with pIC resulted in a marked increase in interferon regulatory factor-1 (IRF-1) mRNA and phosphorylated signal transducer and activator of transcription-1 (STAT1) levels. Addition of pIC to cells led to type I interferon (IFN) gene expression, especially IFN beta, which can induce STAT1 phosphorylation, suggesting that dsRNA indirectly induced STAT1 phosphorylation through expression of type I IFN. Thus, our results suggest that the dsRNA-activated signaling pathway may be involved in the regulation of IFN-inducible genes in the thyroid.
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PMID:Double-stranded RNA-induced interferon regulatory factor-1 gene expression in FRTL-5 rat thyroid cells. 1169 43

We previously demonstrated that Poly (IC) decreased the growth of C6 cultures in association with reduced IGF-I synthesis and secretion. In this study we characterized the mechanism(s) by which Poly (IC) decreased IGF-I mRNA in C6 cells. Both Poly (IC) and type I interferon (IFN) decreased IGF-I mRNA. Cycloheximide and a blocking antibody against IFN did not alter the Poly (IC)-mediated inhibition of IGF-I mRNA, but prevented IFN from reducing IGF-I mRNA. Poly (IC) did not alter the stability of IGF-I mRNA. Poly (IC) decreased the abundance of IGF-I pre-mRNA in C6 nuclei, but did not inhibit proximal IGF-I exon 1 promoter/luciferase fusion constructs in transient transfection assays. Poly (IC) activated double-stranded RNA-activated protein kinase (PKR) at 5 min and increased PKR protein levels at 48 and 72 h. Exogenous IGF-I did not prevent Poly (IC) from activating PKR, but inhibited the Poly (IC)-mediated increase in PKR protein levels. The PKR inhibitor 2-aminopurine prevented the Poly (IC) stimulation of eIF2-alpha phosphorylation and the Poly (IC)-mediated decrease in IGF-I mRNA. We conclude that Poly (IC) decreases IGF-I gene transcription in a mechanism that requires the activation of preexisting PKR, but not the induction of IFN or PKR proteins in C6 cells.
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PMID:Double-stranded RNA decreases IGF-I gene expression in a protein kinase R-dependent, but type I interferon-independent, mechanism in C6 rat glioma cells. 1179 7

The type I interferon-alpha (IFN-alpha) family is a family of natural small proteins that have clinically important anti-infective and antitumor activity. We have developed a semisynthetic protein-polymer conjugate of IFN-alpha2b (Intron A) by attaching a 12,000-Da monomethoxypolyethylene glycol (PEG-12000) polymer to the protein. PEG conjugation is thought to increase the serum half-life and thereby prolong patient exposure to IFN-alpha2b without altering the biologic potency to the protein. Matrix-assisted laser desorption ionization/mass spectrometry (MALDI-MS), high-performance size exclusion chromatography (HPSEC), circular dichroism (CD) analysis and tryptic digestion peptide analysis of PEG Intron demonstrated that the IFN-alpha2b protein was approximately 95% monopegylated and that the primary, the secondary, and the tertiary structures were unaltered. Pegylation did not affect the epitope recognition of antibodies used for Intron A quantitation. An extensive analysis of the pegylated positional isomers revealed that approximately 50% of PEG Intron was monopegylated on the His(34) residue of the IFN-alpha2b protein. The highest antiviral activity of the pegylated positional isomers for PEG Intron was associated with the His(34) pegylated isomer. The specific activity for PEG Intron in an antiviral cytopathic protection assay was 28%, relative to Intron A. However, the potency of PEG Intron, defined as bioactivity independent of protein concentration, was comparable to Intron A at both the molecular and cellular levels in a battery of in vitro assays. Equivalent units of PEG Intron and Intron A were indistinguishable for the induction of several key IFN-induced genes, including 2',5'-oligoadenylate synthetase (2',5'-OAS) and protein kinase R (PKR), in Molt 4 cells. The antiviral dose-response curves revealed that there were no significant differences between PEG Intron and Intron A. This demonstrated that the introduction of more IFN-alpha2b protein associated with equivalent unit dosing of PEG Intron did not create any antagonism or agonism in the antiviral assay. In assays for the immune response, PEG Intron and Intron A displayed comparable potency for both natural-killer (NK) and lymphokine-activated killer (LAK) cell cytolytic activity and for the induction of class I major histocompatibility protein. These results demonstrate that PEG Intron maintains an in vitro biologic potency profile for both antiviral and immunotherapeutic activity that is highly comparable to that of Intron A.
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PMID:Structural and biologic characterization of pegylated recombinant IFN-alpha2b. 1179 69

We previously reported that reduction of autocrine IGF-I by polyinosinic-polycytidylic acid [poly(IC)] was permissive for the poly(IC)-mediated decrease in C6 rat glioma cell number. We now report that poly(IC) caused a block in G(1) to S transition in confluent C6 cultures, whereas in subconfluent cultures, poly(IC) decreased the percentage of cells in the G(2)/M phase. Addition of IGF-I to poly(IC)-treated cells decreased the percentage of cells in G(0)/G(1) phase and increased the percentage of cells in G(2)/M phase in confluent and subconfluent C6 cultures, indicating the reversal of cell cycle blocks. Inhibition of protein kinase R (PKR) activation partially prevented the poly(IC)-mediated cytostasis of C6 cells. Poly(IC) induced interferon-alpha in C6 cells. Both IGF-I and a blocking antibody against type I interferon (IFN) prevented the increase in PKR levels and the decrease in cell proliferation caused by poly(IC). We conclude that poly(IC) induces IFN, which mediates the cytostatic effect of poly(IC) on C6 cells at least in part through PKR. IGF-I prevents IFN from inducing PKR, thus explaining the ability of IGF-I to reverse the cell cycle blocks and the decreased C6 proliferation caused by poly(IC).
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PMID:Double-stranded ribonucleic acid decreases c6 rat glioma cell proliferation in part by activating protein kinase R and decreasing insulin-like growth factor I levels. 1202 Nov 78


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