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)

Delivery of IgA to the mucosal surface occurs via transcytosis of polymeric IgA (pIgA) across the epithelium, a process mediated by the pIgR. Several factors increase pIgR expression in human epithelial cells, including IL-4 and IFN-gamma. Using an RNase protection assay, we found that IL-4 and IFN-gamma increase steady state levels of pIgR mRNA in both human intestinal (HT29) and airway (Calu-3) epithelial cells. Time course studies in HT29 clone 19A cells showed that with each cytokine alone and with both together: 1) there was a significant lag before mRNA levels increased; 2) maximal levels were not reached until 48-72 h after the addition of cytokines; 3) mRNA levels remained elevated in the continued presence of cytokines; and 4) addition of actinomycin D or removal of cytokines led to decreases in mRNA levels with a half-life of approximately 20-28 h. Cytokine-dependent increases in steady state levels of pIgR mRNA were inhibited by cycloheximide and by protein tyrosine kinase inhibitors but not by inhibitors of protein kinase C or cAMP-dependent protein kinase A. Both IFN-gamma and IL-4 increased expression of the inducible transcription factor IFN regulatory factor-1 (IRF-1), but levels of IRF-1 only weakly correlated with levels of pIgR mRNA, suggesting that additional transcription factors are required. These studies provide additional insights into the mechanisms by which cytokines regulate expression of the pIgR, a central player in mucosal immunity.
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PMID:IL-4 and IFN-gamma increase steady state levels of polymeric Ig receptor mRNA in human airway and intestinal epithelial cells. 1022 81

One prominent effect of IFNs is their cell growth-inhibitory activity. The mechanism behind this inhibition of proliferation is still not fully understood. In this study, the effect of IFN-alpha treatment on cell cycle progression has been analysed in three lymphoid cell lines, Daudi, U-266 and H9. Examination of the growth-arrested cell populations shows that Daudi cells accumulate in a G0-like state, whereas U-266 cells arrest later in G1. H9 cells are completely resistant to IFN-alpha's cell growth-inhibitory effects. The G0/G1-phase arrest is preceded by a rapid induction of the cyclin-dependent kinase inhibitors (CKIs), p21 and p15. In parallel, the activities of the G1 Cdks are significantly reduced. In addition to p21/p15 induction, IFN-alpha regulates the expression of another CKI, p27, presumably by a post-transcriptional mechanism. In the G1 Cdk-complexes, there is first an increased binding of p21 and p15 to their respective kinases. At longer exposure times, when Cdk-bound p15 and p21 decline, p27 starts to accumulate. Furthermore, we found that IFN-alpha not only suppresses the phosphorylation of pRb, but also alters the phosphorylation and expression of the other pocket proteins p130 and p107. These data suggest that induction of p21/p15 is involved in the primary IFN-alpha response inhibiting G1 Cdk activity, whereas increased p27 expression is part of a second set of events which keep these Cdks in their inactive form. Moreover, elevated levels of p27 correlated with a dissociation of cyclin E/Cdk2-p130 or p107 complexes to yield cyclin E/Cdk2-p27 complexes. In resistant H9 cells, which possess a homozygous deletion of the p15/p16 genes and lack p21 protein expression, IFN-alpha causes no detectable changes in p27 expression and, furthermore, no effects are observed on either pocket proteins in this cell line. Taken together, these data suggest that the early decline in G1 Cdk activity, subsequent changes in phosphorylation of pocket proteins, and G1/G0 arrest following IFN-alpha treatment, is not primarily due to loss of the G1 kinase components, but result from the inhibitory action of CKIs on these complexes.
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PMID:Molecular mechanisms underlying interferon-alpha-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins. 1036 50

Human acute leukemia and myelodysplasia are often associated with an interstitial deletion in chromosome arm 5q. The deleted region is hypothesized to contain tumor suppressor loci that are critical to the maintenance of normal hematopoiesis. We have identified NKIAMRE, a novel cyclin-dependent kinase-related molecule that is closely related to the rat serine/threonine kinase NKIATRE. Human NKIAMRE localizes to chromosome band 5q31.1, centromeric to the interleukin 9 locus and telomeric to IFN response factor-1. NKIAMRE was deleted at both alleles in 9 of 18 leukemic samples with chromosome band 5q31 abnormalities studied by fluorescence in situ chromosomal hybridization. NKIAMRE loss may be an important determinant of dysmyelopoiesis.
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PMID:Identification of NKIAMRE, the human homologue to the mitogen-activated protein kinase-/cyclin-dependent kinase-related protein kinase NKIATRE, and its loss in leukemic blasts with chromosome arm 5q deletion. 1046 9

Persistent infections by viruses such as HIV-1 and hepatitis B virus can pose long-term health hazards. Because establishment of persistent infections involves close interactions and adjustments in both host and virus, it would be informative to establish a paradigm with which a normally cytolytic viral infection can be easily converted to persistent infection, so that the different stages in developing persistent infection can be examined. Such a model system is described in this paper. Highly cytolytic encephalomyocarditis virus (EMCV) infection was shifted to persistent infection as a result of repressed expression of the double-stranded RNA-dependent protein kinase (PKR) in the promonocytic U937 cells. Because of the apoptogenic potential of PKR, a deficiency of PKR resulted in a delay in virus-induced apoptosis in EMCV-infected U937 cells, allowing the eventual establishment of persistent EMCV infection in these cells (U9K-AV2). That this was a bona fide persistent infection was demonstrated by the ability of infected cells to propagate as long-term virus-shedding cultures; electron microscopy studies showing presence of intracellular EMCV virions and chromatin condensation; detection of virus-induced chromosomal DNA fragmentation and sustained expression of apoptogenic p53 and IL-1beta converting enzyme; and demonstration of active EMCV transcription by reverse transcription-PCR. In addition, a host-virus coevolution was observed in U9K-AV2 cultures over time: U9K-AV2 cells exhibited slower growth rates, resistance to viral super-infection, and cessation of IFN-alpha synthesis, whereas the infectivity of EMCV was drastically attenuated. Finally, data are presented on the suitability of this model to study establishment of persistent infection by other viruses such as Sendai virus and reovirus.
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PMID:Inhibitory role of the host apoptogenic gene PKR in the establishment of persistent infection by encephalomyocarditis virus in U937 cells. 1051 10

Tumors interact with their environment, reprogramming host cells to induce responses such as angiogenesis, inflammation, immunity and immune suppression. To understand these processes, it is important to identify and isolate new genes whose expression is induced in host tissues in response to tumors. Ascites tumors offer an attractive model for isolating such genes, because responding host peritoneal lining tissues can be cleanly separated from tumor cells growing in suspension within the peritoneal cavity. We here report the cloning by differential display of a novel gene, DLM-1, that is highly up-regulated in the peritoneal lining tissue of mice bearing MOT ascites tumors. Mouse peritoneal macrophages, stimulated by IFN-gamma or LPS, also expressed significant amounts of DLM-1. Up-regulation of DLM-1 became evident by 4h after stimulation with IFN-gamma and was not blocked by cycloheximide, suggesting the presence of IFN responding elements in its transcription regulation region. DLM-1 RNA was detected at significant levels in normal mouse lung, intestinal epithelium, liver and thymus by Northern blot analysis. In situ hybridization of MOT and HT-29 mouse subcutaneous transplanted solid tumors revealed strong DLM-1 expression in the host reactive stromal cells, but not the tumor cells. Sequence analysis of the full-length cDNA clone revealed that it encodes a protein of approx. M(r) 44330 with multiple potential protein kinase C and casein kinase II phosphorylation sites. Our data suggest that DLM-1 plays a role in such important processes as host response in neoplasia.
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PMID:Cloning of DLM-1, a novel gene that is up-regulated in activated macrophages, using RNA differential display. 1056 22

Persistent infections with mumps virus were established in human B-lymphoid cell line Akata and in the human chronic myelogenous leukaemia cell line K562. Even after IFN treatment a drastic decrease in STAT-1alpha (signal transducers and activators of transcription-1alpha), STAT-2 and p48 (ISGF-3gamma: IFN-stimulated gene factor-3gamma), which are closely correlated with the IFN-signaling pathway, was found in these persistently infected cells (Akata-MP1 and K-MTP). Therefore, the IFN-signaling pathway is thought to be defective in these persistently infected cells. In other words, most of the IFN-inducible genes in these cells persistently infected with mumps virus may not be able to respond to IFN treatment. Indeed, poor induction of 2',5'-oligoadenylate synthetase (2-5AS), dsRNA activated protein kinase (PKR), and MxA protein mRNAs were demonstrated in these cell lines after IFN treatment. Expression of MHC class-I antigen was also significantly reduced in the persistently infected cell lines as compared with that of uninfected control cells. HLA antigen was augmented by IFN-alpha in Akata and K562 cells, but not in persistently infected cells. Furthermore, suppression of IFN-induced 2-5AS induction and MHC class-I expression was restored by treatment of persistently infected cells with ribavirin through inhibition of virus replication. The result of restoration was also confirmed by IFN-induced STAT-1 induction in persistently infected cells treated with ribavirin.
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PMID:Suppression of interferon response gene expression in cells persistently infected with mumps virus, and restoration from its suppression by treatment with ribavirin. 1058 90

The presence of protein kinase activity and its phosphorylated products has been demonstrated on the outer surface of the plasma membrane of endothelial cells. Extracellular phosphorylation was detected by incubation of primary endothelial cells (HUVEC's) and endothelial cell line EA.hy 926 with [gamma-32P]ATP. The reaction products were subjected to SDS/PAGE, autoradiography and scanning densitometry. Under the experimental conditions, five proteins with apparent molecular masses of 19, 23, 55, 88, and 110 kDa were prominently phosphorylated in both types of cells. Phosphorylation of the 19 kDa protein was the most rapid reaching maximum after 60 s and then the protein became dephosphorylated. Ecto-protein kinases responsible for the surface labeling of membrane proteins were characterized by using (a) protein kinase C inhibitors: K-252b, chelerythrine chloride, and [Ala113] myelin basic protein (104-118), (b) protein kinase A inhibitor Kemptide 8334, and (c) casein kinase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB). Stimulation of endothelial cells with tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) is associated with 20-80% reduction of extracellular phosphorylation of all membrane proteins. IFN gamma bound to membrane receptors becomes rapidly phosphorylated. Only in the case of IFN gamma it was associated with the appearance of a strongly phosphorylated band of 17 kDa corresponding to IFN gamma itself. Phosphorylation of this 17 kDa exogenous substrate was prevented by an ecto-kinase inhibitor K-252b. The existence of ecto-phosphoprotein phosphatase activity in endothelial cells was evidenced by testing the effect of microcystin LR--a membrane impermeable reagent that inhibits both PP-1 and PP-2a phosphoprotein phosphatases. The extent of phosphorylation of 19 kDa and 110 kDa phosphoproteins significantly increased in the presence of microcystin. Our results suggest the presence of at least two ecto-kinase activities on endothelial cells that may play a significant role(s) in the regulation of cytokines function.
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PMID:Interferon gamma bound to endothelial cells is phosphorylated by ecto-protein kinases. 1069 77

Several signaling pathways are activated by interferon alpha (IFNalpha) in hematopoietic cells, including the Jak-Stat and the insulin receptor substrate (IRS) pathways. It has been previously shown that IFNalpha activates the phosphatidylinositol (PI) 3'-kinase via an interaction of the p85 subunit of PI 3'-kinase with IRS proteins. Other studies have proposed that Stat-3 also functions as an adapter for p85. We sought to identify the major pathway that regulates IFNalpha activation of the PI3'-kinase in hematopoietic cells. Our data demonstrate that IFNalpha induces the interaction of p85 with IRS-1 or IRS-2, but not Stat-3, in various hematopoietic cell lines in which IRS-1 and/or IRS-2 and Stat-3 are activated by IFNalpha. In addition, inhibition of PI 3'-kinase activity by preincubation of cells with the PI 3'-kinase inhibitor LY294002 does not affect IFN-dependent formation of SIF complexes that contain Stat-3. To determine whether phosphorylation of tyrosine residues in the IFN receptor is required for activation of the PI 3'-kinase, we performed studies using mouse L929 fibroblasts transfected with mutated human IFNAR1 and/or IFNAR2 subunits of the Type I IFN receptor, lacking tyrosine phosphorylation sites. The serine kinase activity of the PI-3K was activated by human IFNalpha in these cells, suggesting that phosphorylation of the Type I IFN receptor is not essential for PI3K activation. We then determined whether IFNalpha activates the Akt kinase, a known downstream target for PI 3'-kinase that mediates anti-apoptotic signals. Akt was activated by insulin or IGF-1, but not IFNalpha, in the IFNalpha-sensitive U-266 myeloma cell line. Altogether, our data establish that the IRS pathway and not the Stat pathway, is the major pathway regulating engagement of PI 3'-kinase in hematopoietic cells. Furthermore, the selective activation of Akt by insulin/IGF-1 suggests the existence of distinct regulatory activities of PI3'-kinase in growth factor versus interferon signaling.
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PMID:Interferon-dependent activation of the serine kinase PI 3'-kinase requires engagement of the IRS pathway but not the Stat pathway. 1073 21

The hepatitis C virus (HCV) interferon-alpha (IFN-alpha) sensitivity-determining region (ISDR) has been shown to suppress double-stranded RNA-dependent protein kinase (PKR) activity in vitro in a yeast PKR expression system. Since variability of ISDR was shown to correlate with nonresponsiveness to IFN-alpha therapy in chronically HCV-infected patients, it has been suggested that prototype ISDR might be a viral inhibitor of cellular PKR. The present study evaluates the biological significance of ISDR variability in situ, relating it to PKR-mediated cellular antiviral responses within the liver. ISDR variability was determined in patients chronically infected with HCV genotypes 1a, 1b, and 3a by direct sequencing using liver-derived RNA preparations as starting material. As surrogate parameters for PKR-mediated cellular responses, hepatic endogenous IFN-alpha gene expression as well as MxA expression were analysed by a competitive, quantitative reverse transcription-polymerase chain reaction technique. Irrespectively of intra- or intergenotypic ISDR amino acid substitutions, ISDR variability was found not to correlate with endogenous hepatic IFN-alpha or with hepatic MxA gene expression. The data suggest that at least two prominent PKR-mediated cellular responses might be largely unaffected by HCV ISDR variability.
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PMID:Lack of clinical evidence for involvement of hepatitis C virus interferon-alpha sensitivity-determining region variability in RNA-dependent protein kinase-mediated cellular antiviral responses. 1074 29

To produce disease, viruses must enter the host, multiply locally in host tissues, spread from the site of entry, and overcome or evade host immune responses. At each stage in this infectious process, specific microbial and host genes determine the ultimate virulence of the virus. Genetic approaches have identified many viral genes that play critical roles in virulence and are presumed to target specific components of the host innate and acquired immune response. However, formal proof that a virulence gene targets a specific protein in a host pathway in vivo has not been obtained. Based on cell culture studies, it has been proposed that the herpes simplex virus type 1 gene ICP34.5 (ICP, infected cell protein) enhances neurovirulence by negating antiviral functions of the IFN-inducible double-stranded RNA-dependent protein kinase R or PKR [Chou, J., Chen, J.J., Gross, M. & Roizman, B. (1995) Proc. Natl. Acad. Sci. USA 92, 10516-10520]. Herein, we show that a virus that has been attenuated by deletion of ICP34.5 exhibits wild-type replication and virulence in a host from which the PKR gene has been deleted. We show that restoration of virulence is specific to ICP34.5 and PKR by using additional host and viral mutants. The use of recombinant viruses to infect animals with null mutations in host defense genes provides a formal genetic test for identifying in vivo mechanisms and targets of microbial virulence genes.
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PMID:Specific phenotypic restoration of an attenuated virus by knockout of a host resistance gene. 1082 27


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