Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons in vivo are exposed to a variety of different growth factors and cytokines. A principal signalling pathway for ciliary neurotrophic factor (CNTF)-like cytokines is the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) system of kinases and transcription factors. In the human cell line (SH-SY5Y), STAT1 and STAT3 activation by CNTF-like cytokines showed tyrosine phosphorylation peaking at 0.5 h and inactivating within 2 h. Tyrosine phosphorylation of the receptor-associated tyrosine kinases Jak1 and Jak2 showed a similar time course of activation and inactivation in response to CNTF. The STAT1 response to the non-CNTF-like cytokine, interferon-gamma (IFN-gamma) did not inactivate. Inactivation to CNTF was not due to a decrease in CNTF receptor subunit gp130 or in levels of Jak1 or Jak2. STAT inactivation was inhibited by the protein kinase blocker H7 and a tyrosine phosphatase blocker, but not by inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) kinase, mTOR-P70/S6 kinase or phosphatidyl inositol-3-kinase (PI-3 kinase). Surprisingly, CNTF caused only a minor increase in levels of suppressors of cytokine signalling, SOCS-1 and SOCS-3. CNTF pretreatment desensitized the cells to the CNTF-like cytokines, leukemia inhibitory factor and oncostatin-M but not to IFN-gamma. These results reveal a complex level of regulation of shared signalling pathways for cytokines that is dependent on both the type of cell and cytokine.
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PMID:Activation and inactivation of signal transducers and activators of transcription by ciliary neurotrophic factor in neuroblastoma cells. 1188 86

Crosstalk between interferons (IFNs) and several cytokines is likely to play an important role in viral clearance in chronic hepatitides B and C. We investigated the influence of this phenomenon on IFN-inducible antiviral gene expression in HuH-7 human hepatoma cells. HuH-7 cells were treated with IFN-alpha in the absence or presence of interleukin-1beta (IL-1beta) or IL-10 and the expression of antiviral genes such as 2(')5(')-oligoadenylate synthetase (2(')5(')-OAS) and double-stranded RNA-dependent protein kinase (PKR), as well as activation of signal transducer and activator of transcription 1 (STAT1), a key step for relaying the IFN-alpha signals, was analyzed by Northern blotting, Western blotting, and the reporter gene transfection assay. IL-1beta potentiated IFN-alpha-induced 2(')5(')-OAS and PKR gene expression, similar to expression of the transfected reporter genes containing the IFN-stimulated regulatory elements, while IL-10 suppressed IFN-alpha-stimulated gene expression. With regard to IFN-alpha signaling, IL-1beta enhanced both tyrosine and serine phosphorylation of STAT1 through p38 mitogen-activated protein kinase activation. In contrast, IL-10 inhibited IFN-alpha-mediated tyrosine phosphorylation of STAT1 by induction of a Janus kinase inhibitor, JAB. IL-1beta and IL-10 interact with IFN-alpha to up- and down-regulate antiviral gene expression, respectively, by modulating STAT1 activation induced by IFN-alpha.
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PMID:Involvement of IL-1beta and IL-10 in IFN-alpha-mediated antiviral gene induction in human hepatoma cells. 1205 28

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-gamma are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-gamma leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-gamma and calcium in the activation of ICER expression was identified. The IFN-gamma-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-gamma stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-gamma-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.
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PMID:Interferon-gamma stimulates the expression of the inducible cAMP early repressor in macrophages through the activation of casein kinase 2. A potentially novel pathway for interferon-gamma-mediated inhibition of gene transcription. 1260 74

The mechanisms by which lipopolysaccharide (LPS) is recognized, and how such recognition leads to innate immune responses, are poorly understood. Stimulation with LPS induces the activation of a variety of proteins, including mitogen-activated protein kinases (MAPKs) and NF-kappaB. Activation of protein tyrosine kinases (PTKs) is also necessary for a number of biological responses to LPS. We used a murine macrophage-like cell line, RAW264.7, to demonstrate that Janus kinase (JAK)2 is tyrosine phosphorylated immediately after LPS stimulation. Anti-Toll-like receptor (TLR)4 neutralization antibody inhibits the phosphorylation of JAK2 and the c-Jun NH2-terminal protein kinase (JNK). Both the JAK inhibitor AG490 and the kinase-deficient JAK2 protein reduce the phosphorylation of JNK and phosphatidylinositol 3-kinase (PI3K) via LPS stimulation. Pharmacological inhibition of the kinase activity of PI3K with LY-294002 decreases the phosphorylation of JNK. Finally, we show that JAK2 is involved in the production of IL-1beta and IL-6. PI3K and JNK are also important for the production of IL-1beta. These results suggest that LPS induces tyrosine phosphorylation of JAK2 via TLR4 and that JAK2 regulates phosphorylation of JNK mainly through activation of PI3K. Phosphorylation of JAK2 via LPS stimulation is important for the production of IL-1beta via the PI3K/JNK cascade. Thus JAK2 plays a pivotal role in LPS-induced signaling in macrophages.
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PMID:Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages. 1268 12

Atopic asthma is a chronic inflammatory disorder of the airways where upon exposure to allergens, the body mounts an immune response. This disease is associated with an increase in the number of Th2 (T helper type 2) cells and Th2 cytokines and a decrease in the number of Th1 (T helper type 1) cells and Th1 cytokines. Histamine plays an important role in the pathogenesis of atopic asthma through differential regulation of T helper lymphocytes. Histamine enhances the secretion of Th2 cytokines such as IL-4 (interleukin-4), IL-5, IL-10 and IL-13 and inhibits the production of Th1 cytokines IL-2 and IFNgamma (interferon-gamma) and monokine IL-12. It has been shown that histamine can modulate the cytokine network through upregulation of PGE(2) (prostaglandin E(2)) and NO (nitric oxide). Histamine also affects cytokine production via H2 receptors and through the activation of PKA (protein kinase A). We have also demonstrated that the Jak-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in histamine-mediated regulation of Th2 cytokines IL-5, IL-10, IL-13 and Th1 cytokine IFNgamma. While standard treatment of asthma consists of beta-receptor agonists and inhaled corticosteroids, the elucidation of histamine's control over the cytokine network and the Th1/Th2 balance provides a basis for the potential use of antihistamines in the prevention and treatment of atopic asthma. Several other anti-allergic agents to modulate the Th1/Th2 balance are under current investigation based on this paradigm. These include cytokines, cytokine antagonists, anti-IgE, and vaccinations. As more advances are made in our understanding of histamine and its control over the Th1/Th2 balance, the use of new therapeutic targets such as these will play a prominent role in disease management.
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PMID:Effects of histamine on Th1/Th2 cytokine balance. 1281 Mar 48

Mice that exhibit characteristics of physical dependence following ethanol exposure serve as useful models of alcoholism in humans. The DBA/2J and C57BL/6J inbred strains differ in their behavioral response to ethanol withdrawal. Alterations in gene expression are believed to underlie neuroadaptation to ethanol dependence and tolerance. Therefore, the differences in ethanol withdrawal severity observed between the DBA/2J and C57BL/6J strains may be related to differential regulation of gene expression. We have used cDNA microarrays to determine the gene expression profile in the hippocampus of DBA/2J and C57BL/6J mice during withdrawal after chronic and acute ethanol exposure. Of the 7634 genes surveyed, approximately 2% were consistently differentially expressed by at least 1.4-fold in DBA/2J mice during chronic ethanol withdrawal. Less than 1% of the genes showed altered expression in C57BL/6J mice under the same conditions, or in DBA/2J mice during acute ethanol withdrawal. Strain- and treatment-specific patterns of altered expression were observed for multiple genes associated with the Janus kinase/signal transducers and activators of transcription and the mitogen activated protein kinase pathways. Genes associated with both pathways are regulated in DBA/2J mice during chronic ethanol withdrawal, and to a lesser extent during acute ethanol withdrawal. Only those genes associated with the mitogen-activated protein kinase (MAPK) pathway exhibited changes in expression in C57BL/6J mice during ethanol withdrawal. Furthermore, genes associated with retinoic acid-mediated signaling show differential expression exclusively in C57BL/6J mice. These findings represent significant differences in cellular adaptation to ethanol between the DBA/2J and C57BL/6J strains.
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PMID:Expression profiling identifies strain-specific changes associated with ethanol withdrawal in mice. 1288 48

Novel neurotrophin-1/B cell stimulating factor-3 (NNT-1/BSF-3) is a gp130 cytokine potently stimulating corticotroph proopiomelanocortin gene expression and ACTH secretion by a Janus kinase-signal transducer and activator of transcription (JAK-STAT)-dependent mechanism. In the current study, we examined the regulation of NNT-1/BSF-3 mRNA expression in murine pituitary folliculostellate TtT/GF cells using Northern blot technique. A 5- to 9-fold and a 4- to 7-fold induction in NNT-1/BSF-3 mRNA expression was observed between 2 and 6 h stimulation with the protein kinase C (PKC) stimulus phorbol-12-myristate-13-acetate (100 nm) and the protein kinase A (PKA) stimulus Bu(2)cAMP (5 mm), respectively. Pituitary adenylate cyclase-activating polypeptide (PACAP-38, 50 nm) and vasoactive intestinal peptide (VIP, 50 nm) also stimulated NNT-1/BSF-3 mRNA expression 5- to 9-fold between 2 and 6 h. Preincubation with PKC and PKA inhibitors such as H-7 (20 microm), GF109203X (50 microm), and H-89 (50 microm) decreased the stimulatory effects of PACAP and VIP. Both PACAP-38 and VIP also rapidly induced ERK1/2 phosphorylation and their stimulatory effect on NNT-1/BSF-3 mRNA expression was reduced by the MAPK kinase/ERK kinase (MEK) inhibitor U0126 (10 microm). Dexamethasone (10(-7) m) was a potent inhibitor of phorbol-12-myristate-13-acetate-induced NNT-1/BSF-3 expression. RT-PCR analysis demonstrated TtT/GF cells to express the short and the hop variant but not the hip variant of the PACAP-1 receptor (PAC1-R). In addition, TtT/GF cells express the VIP/PACAP-2 receptor (VPAC2-R). In summary, NNT-1/BSF-3 is expressed in pituitary folliculostellate TtT/GF cells and induced by PKC-, PKA-, and ERK1/2-dependent mechanisms. The novel gp130 cytokine NNT-1/BSF-3 derived from folliculostellate cells might act as a paracrine neuroimmunoendocrine modulator of pituitary corticotroph function.
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PMID:Expression of novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) in murine pituitary folliculostellate TtT/GF cells: pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide-induced stimulation of NNT-1/BSF-3 is mediated by protein kinase A, protein kinase C, and extracellular-signal-regulated kinase1/2 pathways. 1460 1

The replication of hepatitis B virus (HBV) in hepatocytes is strongly inhibited in response to IFN-alpha/beta and IFN-gamma. Although it has been previously demonstrated that IFN-alpha/beta eliminates HBV RNA-containing capsids from the cell in a proteasome-dependent manner, the precise cellular pathway that mediates this antiviral effect has not been identified. Because IFN-induced signal transduction involves kinase-mediated activation of gene expression, we used an immortalized hepatocyte cell line that replicates HBV in an IFN-sensitive manner to investigate the role of cellular kinase activity and the cellular transcription and translation machinery in the antiviral effect. Our results indicate that Janus kinase activity is required for the antiviral effect of IFN against HBV, but that phosphatidylinositol 3-kinase, cyclin-dependent kinase, mitogen-activated protein kinase, and NF-kappaB activity are not. Additionally, we found that inhibitors of cellular transcription and translation completely abolish the antiviral effect, which also appears to require cellular kinase activity downstream of signal transduction and gene expression. Collectively, these results identify IFN-regulated pathways that interrupt the HBV replication cycle by eliminating viral RNA-containing capsids from the cell, and they provide direction for discovery of the terminal effector molecules that ultimately mediate this antiviral effect.
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PMID:Signal transduction pathways that inhibit hepatitis B virus replication. 1475 13

Heat shock protein (hsp) 56 (hsp56) is an immunophilin that acts as a cofactor with hsp90 and exhibits both peptidyl-prolyl isomerase activity and chaperone activity. Previous studies have shown that the hypertrophic effect of cardiotrophin-1 (CT-1) in cardiac cells is dependent on hsp56 induction. CT-1 activates a number of signal-transduction pathways. Therefore, we sought to determine whether these pathways were also important for hsp56-induced hypertrophy using overexpression with transiently transfected plasmid vectors in rat neonatal cardiomyocytes. Here we show that multiple signalling pathways are involved in hsp56-induced hypertrophy, namely the Janus kinase-signal-transducer and activator of transcription, extracellular signal-regulated protein kinase and PI3-kinase/Akt signalling pathways. Dominant-negative mutants and inhibitors of these pathways were able to block the hypertrophy observed as a result of hsp56 overexpression. However, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway was not able to block the hypertrophic effect of hsp56 overexpression. Furthermore, we show that domains I, II and IV of the hsp56 protein may be involved in its hypertrophic effect. These studies show for the first time that multiple signalling pathways are involved in the hypertrophic effect of hsp56 and that overexpression of hsp56 itself is able to activate the necessary signalling pathways, which induce hypertrophy.
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PMID:Signal-transduction pathways involved in the hypertrophic effect of hsp56 in neonatal cardiomyocytes. 1501 Feb 77

We recently provided evidence that interleukin-15 (IL-15) is expressed lowly in the pig adipocyte and that interferon-gamma (IFN-gamma) markedly increases this expression through a pathway regulated in part by protein kinase C. In the present study, we tested the hypothesis that IL-15 acts directly on the adipocyte to regulate lipid accretion by enhancing lipolysis or suppressing lipogenesis. Using recombinant porcine IL-15, we determined that this cytokine stimulates lipolysis in a dose-dependent manner (P < 0.001). Furthermore, comparative studies with other cytokines showed that IL-15 is more potent in its acute stimulation of lipolysis than either TNF-alpha, IL-6, or LPS (P < 0.001). When specific inhibitors of protein kinase A or Janus kinase are present, the lipolytic effect of IL-15 is attenuated (P < 0.01). These data indicate that, in addition to its regulation of muscle protein accretion and T-cell growth and development, IL-15 also targets the adipocyte directly to alter stimulate lipolysis. Thus, when induced by IFN-gamma or other inflammatory mediators, IL-15 may be a significant homeorhetic factor that mobilizes and directs energy away from the adipocyte to other cells during the acute phase of the inflammatory response.
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PMID:Direct regulation of lipolysis by interleukin-15 in primary pig adipocytes. 1515 79


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