Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C-theta (PKC-theta) plays important roles in the activation and survival of lymphocytes and is the predominant PKC isoform expressed in T-cells. Interferons regulate T-cell function and activation, but the precise signaling mechanisms by which they mediate such effects have not been elucidated. We determined whether PKC-theta is engaged in interferon (INF) signaling in T-cells. Both Type I (alpha, beta) and Type II (gamma) IFNs induced phosphorylation of PKC-theta in human T-cell lines and primary human T-lymphocytes. Such phosphorylation of PKC-theta resulted in activation of its kinase domain, suggesting that this kinase plays a functional role in interferon signaling. Consistent with this, inhibition of PKC-theta protein expression using small interfering RNAs (siRNA) abrogated IFN-alpha- and IFN-gamma-dependent gene transcription via GAS elements. Similarly, blocking of PKC-theta kinase activity by overexpression of a dominant-negative PKC-theta mutant also blocked GAS-driven transcription, further demonstrating a requirement for PKC-theta in IFN-dependent transcriptional activation. The effects of PKC-theta on IFN-dependent gene transcription were not mediated by regulation of the IFN-activated STAT pathway, as siRNA-mediated PKC-theta knockdown had no effects on STAT1 phosphorylation and binding of STAT1-containing complexes to SIE/GAS elements. On the other hand, siRNA-mediated PKC-theta inhibition blocked phosphorylation/activation of MKK4, suggesting that interferon-dependent PKC-theta activation regulates downstream engagement of MAP kinase pathways. Altogether, these findings demonstrate that PKC-theta is an interferon-inducible kinase and strongly suggest that it plays an important role in the generation of interferon-responses in T-cells.
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PMID:Engagement of protein kinase C-theta in interferon signaling in T-cells. 1515 Feb 72

The gp130-like receptor (GPL) is a recently cloned member of the family of type I cytokine receptors. The name reflects its close relationship to gp130, the common receptor subunit of the interleukin (IL)-6-type cytokines. Indeed, the recently proposed ligand for GPL, IL-31, is closely related to the IL-6-type cytokines oncostatin M, leukemia inhibitory factor, and cardiotrophin-1. The second signal transducing receptor for IL-31 seems to be the oncostatin M receptor beta (OSMRbeta). The present study characterizes in depth the molecular mechanisms underlying GPL-mediated signal transduction. GPL is a strong activator of STAT3 and STAT5, whereas STAT1 is only marginally tyrosine-phosphorylated. We identify tyrosine residues 652 and 721 in the cytoplasmic region of the longest isoform of GPL (GPL(745)) as the major STAT5- and STAT3-activating sites, respectively. Additionally, we demonstrate Jak1 binding to GPL and its activation in heteromeric complexes with the OSMRbeta but also in a homomeric receptor complex. Most interesting, unlike OSMRbeta and gp130, GPL is insufficient to mediate ERK1/2 phosphorylation. We propose that this is due to a lack of recruitment of the tyrosine phosphatase SHP-2 or the adaptor protein Shc to the cytoplasmic domain of GPL.
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PMID:Characterization of the signaling capacities of the novel gp130-like cytokine receptor. 1519

A characteristic of many enteropathies is increased epithelial permeability, a potentially pathophysiological event that can be evoked by T helper (Th)-1 (i.e., IFN-gamma) and Th2 (i.e., IL-4) cytokines and bacterial infection [e.g., enteropathogenic Escherichia coli (EPEC)]. The green tea polyphenol (-)-epigallocatechin gallate (EGCG) has immunosuppressive properties, and we hypothesized that it would ameliorate the increased epithelial permeability induced by IFN-gamma, IL-4, and/or EPEC. EGCG, but not the related epigallocatechin, completely prevented the increase in epithelial (i.e., T84 cell monolayer) permeability caused by IFN-gamma exposure as gauged by transepithelial resistance and horseradish peroxidase flux; EGCG did not alleviate the barrier disruption induced by IL-4 or EPEC. IFN-gamma-treated T84 and THP-1 (monocytic cell line) cells displayed STAT1 activation (tyrosine phosphorylation on Western blot analysis, DNA binding on EMSA) and upregulation of interferon response factor-1 mRNA, a STAT1-dependent gene. All three events were inhibited by EGCG pretreatment. Aurintricarboxylic acid also blocked IFN-gamma-induced STAT1 activation, but it did not prevent the increase in epithelial permeability. Additionally, pharmacological blockade of MAPK signaling did not affect IFN-gamma-induced epithelial barrier dysfunction. Thus, as a potential adjunct anti-inflammatory agent, EGCG can block STAT1-dependent events in gut epithelia and monocytes and prevent IFN-gamma-induced increased epithelial permeability. The latter event is both a STAT1- and MAPK-independent event.
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PMID:Green tea polyphenol (-)-epigallocatechin gallate blocks epithelial barrier dysfunction provoked by IFN-gamma but not by IL-4. 1523 86

Studies on chemoprevention of colorectal cancer have generated increasing interest. The mechanisms involved in NSAIDs chemopreventive action are not fully elucidated. In this study, we examined in human colon cancer cells the effect of indomethacin and NS-398 (a pre-clinical selective COX-2 inhibitor) on expression of 96 genes of the EGF/PDGF signaling pathways essential for cell proliferation, migration, and survival. We found that indomethacin and NS-398 treatment significantly upregulated expression of the tumor suppressor gene, PTEN, the MAP kinase phosphatase-3, MKP-3, and the protein tyrosine phosphatase, SHP2. Additionally, NS-398 treatment increased expression of apoptotic genes such as BAD, STAT1, and CASP3. These results suggest that as a consequence of increased expression of phosphatases such as PTEN and the resulting dephosphorylation of kinases, NSAIDs can negatively regulate the EGF/PDGF pathways in colon cancer cells-a novel mechanism for NSAIDs' chemopreventive actions.
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PMID:NSAIDs activate PTEN and other phosphatases in human colon cancer cells: novel mechanism for chemopreventive action of NSAIDs. 1524 Jan 29

Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells.
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PMID:Redox regulation of glial inflammatory response to lipopolysaccharide and interferongamma. 1526 24

This study evaluated the effects of human interferon-gamma (IFN-gamma) on Na(+)-K(+)-ATPase activity and the intracellular signaling pathways involved in human intestinal epithelial Caco-2 cells. Na(+)-K(+)-ATPase activity was determined as the difference between total and ouabain-sensitive ATPase. p38 MAP kinase activity was analyzed by Western blotting using the p38 MAP kinase assay kit. Total and phosphorylated STAT1 protein levels were detected using the PhosphoPlus Stat1. IFN-gamma decreased Na(+)-K(+)-ATPase activity in a time- and concentration-dependent manner. The IFN-gamma-induced decrease in Na(+)-K(+)-ATPase activity was accompanied by no changes in the abundance of alpha(1) subunit Na(+)-K(+)-ATPase. Downregulation of protein kinase C (PKC) with phorbol-12,13-dibutyrate (PDBu) prevented the inhibitory effect of IFN-gamma on Na(+)-K(+)-ATPase activity. Inhibition of Raf-1, mitogen-activated protein kinase kinase (MAPKK/MEK), p38 MAPK and STAT1 with, respectively, GW 5074, PD 98059, SB 203580 and epigallocatechin gallate prevented inhibition of Na(+)-K(+)-ATPase activity by IFN-gamma. Treatment with IFN-gamma markedly increased the expression of total and phospho-STAT1, this being accompanied by activation of p38 MAPK. Activation of phospho-STAT1 by IFN-gamma was almost abolished by epigallocatechin gallate and markedly reduced by SB 203580, but insensitive to downregulation of PKC. The increase in short circuit current (I(sc)) by 1.0 and 2.5 micrograms ml(-1) amphotericin B was markedly attenuated in IFN-gamma-treated cells. However, the inhibitory effect of PDBu on the amphotericin B-induced increase in I(sc) was of similar magnitude in vehicle- and IFN-gamma-treated cells. It is concluded that IFN-gamma markedly attenuates Na(+)-K(+)-ATPase activity. The transduction mechanisms set into motion by IFN-gamma involve the activation of PKC downstream STAT1 phosphorylation and Raf-1, MEK, ERK2 and p38 MAPK pathways, in a complex sequence of events.
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PMID:Intestinal Na+-K+-ATPase activity and molecular events downstream of interferon-gamma receptor stimulation. 1527 14

Cardiotrophin (CT-1) is a naturally occurring protein member of the interleukin (IL)-6 cytokine family and signals through the gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. The formation of gp130/LIFR complex triggers the auto/trans-phosphorylation of associated Janus kinases, leading to the activation of Janus kinase/STAT and MAPK (ERK1 and -2) signaling pathways. Since adipocytes express both gp130 and LIFR proteins and are responsive to other IL-6 family cytokines, we examined the effects of CT-1 on 3T3-L1 adipocytes. Our studies have shown that CT-1 administration results in a dose- and time-dependent activation and nuclear translocation of STAT1, -3, -5A, and -5B as well as ERK1 and -2. We also confirmed the ability of CT-1 to induce signaling in fat cells in vivo. Our studies revealed that neither CT-1 nor ciliary neurotrophic factor treatment affected adipocyte differentiation. However, acute CT-1 treatment caused an increase in SOCS-3 mRNA in adipocytes and a transient decrease in peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA that was regulated by the binding of STAT1 to the PPARgamma2 promoter. The effects of CT-1 on SOCS-3 and PPARgamma mRNA were independent of MAPK activation. Chronic administration of CT-1 to 3T3-L1 adipocytes resulted in a decrease of both fatty acid synthase and insulin receptor substrate-1 protein expression yet did not effect the expression of a variety of other adipocyte proteins. Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo, and our current efforts are focused on determining the role of this cardioprotective cytokine on adipocyte physiology.
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PMID:Effects of cardiotrophin on adipocytes. 1533 20

This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum alpha(1)-acid glycoprotein (AG), TNF-alpha (TNF), and IL-1beta (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.
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PMID:Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats. 1537 Dec 80

LIGHT is a member of tumor necrosis factor (TNF) superfamily, and previous studies have indicated that in the presence of interferon-gamma (IFN-gamma), LIGHT through LTbetaR signaling can induce cell death with features unlike classic apoptosis. In present study, we investigated the mechanism of LIGHT/IFN-gamma-induced cell death in HT-29 cells, where the cell death was profoundly induced when sub-toxic concentrations of LIGHT and IFN-gamma were co-treated. LIGHT/IFN-gamma-induced cell death was accompanied by DNA fragmentation and slight LDH release. This effect was not affected by caspase, JNK nor cathepsin B inhibitors, but was partially prevented by p38 mitogen-activated protein kinase (MAPK) and poly (ADP-ribose) polymerase (PARP) inhibitors, and abolished by aurintricarboxylic acid (ATA), which is an inhibitor of endonuclease and STATs signaling of IFN-gamma. Immunobloting reveals that LIGHT/IFN-gamma could induce p38 MAPK activity, Bak and Fas expression, but down-regulate Mcl-1. Besides, LIGHT/IFN-gamma could not activate caspase-3 and -9, but decreased mitochondrial membrane potential. Although LIGHT could not affect IFN-gamma-induced STAT1 phosphorylation and transactivation activity, which was required for the sensitization of cell death, survival NF-kappaB signaling of LIGHT was inhibited by IFN-gamma. These data suggest that co-presence of LIGHT and IFN-gamma can induce an integrated interaction in signaling pathways, which lead to mitochondrial dysfunction and mix-type cell death, not involving caspase activation.
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PMID:Mechanism of LIGHT/interferon-gamma-induced cell death in HT-29 cells. 1548 69

Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal-regulated kinase (Erk) signaling, which was integrated to interferon regulatory factor 3 activation and type I interferon induction. We further show that Erk inactivation or disruption of interferon signaling mediated by the transcription factor STAT1 broke the cellular blockade to myxoma virus multiplication. Moreover, STAT1 deficiency rendered mice highly susceptible to lethal myxoma virus infection. Thus, the Erk-interferon-STAT1 signaling cascade elicited by myxoma virus in nonpermissive primary mouse embryo fibroblasts mediates an innate cellular barrier to poxvirus infection.
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PMID:Disruption of Erk-dependent type I interferon induction breaks the myxoma virus species barrier. 1554 19


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