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)

Proinflammatory agents were assessed for their capacity to stimulate the expression of the inducible cyclooxygenase isoform (COX-2) in human neutrophils. A number of agents, including PMA, opsonized bacteria and zymosan, LPS, GM-CSF, TNF-alpha, and fMLP, induced COX-2 protein expression through signaling pathways involving transcription and protein synthesis events. Northern blots showed that freshly isolated neutrophils expressed low levels of COX-2 mRNA, which rapidly increased after incubation with inflammatory agents. A characterization of the signal transduction pathways leading to COX-2 protein expression was initiated. In LPS-treated neutrophils, efficient induction of COX-2 required the presence of serum and involved ligand binding to the CD14 surface antigen. The specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB 203580, had little effect on the induction of COX-2 expression in neutrophils, in contrast to what had been previously observed with other inflammatory cell types. Depending on the agonist present, ethanol differentially blocked the stimulated expression of COX-2, raising the possibility that phospholipase D activation might take part in the process of COX-2 induction. Major COX-2-derived prostanoids synthesized by inflammatory neutrophils were identified by liquid-chromatography and tandem mass-spectrometry as TXA2 and PGE2. The agonist-induced synthesis of TXA2 and PGE2 was effectively blocked by cycloheximide and by the specific COX-2 inhibitor NS-398. These results show that COX-2 can be induced in an active state by different classes of inflammatory mediators in the neutrophil. They support the concept that, in these cells, the COX-2 isoform is preeminent over COX-1 for the stimulated-production of prostanoids, and also suggest that neutrophil COX-2 displays a distinct profile of expression among circulatory cells.
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PMID:Expression and activity of prostaglandin endoperoxide synthase-2 in agonist-activated human neutrophils. 973 14

Induction of the alpha-platelet-derived growth factor receptor (PDGF-Ralpha) by IL-1beta in lung myofibroblasts enhances mitogenic and chemotactic responses to PDGF, and this could be a mechanism of myofibroblast hyperplasia during lung fibrogenesis. Since the regulation of many genes by IL-1beta involves activation of NF-kappaB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Ralpha expression by IL-1beta in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-kappaB activation, completely blocked PDGF-Ralpha up-regulation by IL-1beta as assayed by [125I]PDGF-AA binding and PDGF-Ralpha mRNA expression, suggesting a role for NF-kappaB. However, while IL-1beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappaB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappaB-alpha (IkappaB-alpha) in the cytoplasm of myofibroblasts, only IL-1beta upregulated PDGF-Ralpha. These results suggest that NF-kappaB activation alone is not sufficient for up-regulation of PDGF-Ralpha. An investigation of MAP kinase signaling pathways revealed that IL-1beta or PDTC activated extracellular signal-regulated kinase-2 (ERK-2) and c-jun NH2 terminal kinase-1 (JNK-1) phosphorylation of PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked IL-1beta-induced activation of ERK-2 by more than 90% but enhanced IL-1beta-stimulated induction of PDGF-Ralpha expression fourfold. Taken together, these data suggest that IL-1beta activates both positive and negative signaling pathways that control the expression of PDGF-Ralpha. IL-1beta appears to mediate its negative effects on PDGF-Ralpha expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Ralpha remain to be elucidated.
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PMID:Role of nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways in IL-1 beta-mediated induction of alpha-PDGF receptor expression in rat pulmonary myofibroblasts. 975 65

Mast cells express the receptor tyrosine kinase kit/stem cell factor receptor (SCFR) which is encoded by the proto-oncogene c-kit. Ligation of SCFR induces its dimerization and activation of its intrinsic tyrosine kinase activity leading to activation of Raf-1, phospholipases, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases. However, little is known about the downstream signals initiated by SCFR ligation except for activation of extracellular signal-regulated kinases. The murine mast cell line, MC/9, synthesizes and secretes TNF-alpha following the aggregation of high affinity Fc receptors for IgE (Fc epsilonRI). Ligation of SCFR or Fc epsilonRI on MC/9 cells resulted in the activation of all three MAP kinase family members, extracellular signal-regulated kinases, c-Jun amino-terminal kinase (JNK), and p38. Stem cell factor (SCF)-induced activation of JNK and p38 was insensitive to wortmannin, cyclosporin A, and FK506 whereas activation of these kinases through Fc epsilonRI was sensitive to these drugs. Coligation of SCFR augmented Fc epsilonRI-mediated activation of MAP kinases, especially JNK activation, and SCF augmented Fc epsilonRI-mediated TNF-alpha production in MC/9 cells, although SCF alone did not induce TNF-alpha production. This augmentation by SCF was regulated at the level of transcription, at least in part, since the promoter activity of TNF-alpha was enhanced following addition of SCF. These results demonstrate that SCF can augment Fc epsilonRI-mediated JNK activation and cytokine gene transcription but via pathways that are regulated differently than the ones activated through Fc epsilonRI.
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PMID:Stem cell factor augments Fc epsilon RI-mediated TNF-alpha production and stimulates MAP kinases via a different pathway in MC/9 mast cells. 975 85

Recent studies indicate that reactive oxygen intermediates (ROI) serve as second messengers in cell signaling. ROI have been implicated in the activation of NF-kappaB as well as c-Jun N-terminal kinase (JNK) in response to IL-1 and TNF-alpha stimulation. In this report we examine whether intracellular ROI are involved in CD40 receptor signaling. We show that CD40 engagement on resting splenic B lymphocytes and murine B lymphoma WEHI 231 cells generates ROI. Blocking ROI production by preincubation with the antioxidant N-acetyl-L-cysteine inhibits JNK activation, NF-kappaB-driven luciferase activity, and IL-6 secretion following CD40 ligation, suggesting a role for ROI in CD40-mediated signaling events. Furthermore, transfection of WEHI 231 cells with a plasmid encoding Mn-superoxide dismutase interferes with CD40-induced NF-kappaB activation, providing further support for ROI involvement in this pathway. Collectively, these data demonstrate that ROI may serve as second messengers linking CD40 engagement on B cells to important downstream activation events.
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PMID:Production of reactive oxygen intermediates following CD40 ligation correlates with c-Jun N-terminal kinase activation and IL-6 secretion in murine B lymphocytes. 986 55

Extracellular signal-regulated kinases (ERK, also known as mitogen-activated protein kinases) are serine-threonine kinases transducing signals elicited upon ligand binding to several tyrosine kinase-associated receptors. We have reported that ERK2 phosphorylation and activation follows engagement of the low affinity receptor for the Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced TNF-alpha mRNA expression. Here, we analyzed the involvement of ERK in NK cell-mediated cytotoxicity and IFN-gamma expression induced upon stimulation with targets cells, coated or not with Abs. Our data indicate that, as with immune complexes, ERK2 phosphorylation occurs in human primary NK cells upon interaction with target cells sensitive to granule exocytosis-mediated spontaneous cytotoxicity, and that this regulates both target cell- and immune complex-induced cytotoxicity and IFN-gamma mRNA expression. A specific inhibitor of mitogen-activated protein kinase kinase reduced both spontaneous and Ab-dependent cytotoxicity in a dose-dependent manner involving, at least in part, inhibition of granule exocytosis without affecting effector/target cell interaction and rearrangement of the cytoskeleton proteins actin and tubulin. Involvement of ERK in the regulation of Ca2+-dependent cell-mediated cytotoxicity was confirmed, using a genetic approach, in primary NK cells infected with a recombinant vaccinia virus encoding an ERK inactive mutant. These data indicate that the biochemical pathways elicited in NK cells upon engagement of receptors responsible for either spontaneous or Ab-dependent recognition of target cells, although distinct, utilize ERK as one of their downstream molecules to regulate effector functions.
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PMID:Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases. 986 93

In response to oxidant stress, the cardiovascular system is known to express a number of genes, which could occur owing to the participation of mitogen-activated protein kinases such as MAPKs, ERK and JNK (SAPK) followed by stimulation of at least two well-defined transcription factors NF-KB and AP-1 (c-Fos and c-Jun). Oxidants activate cytosolic and membrane-bound PLA2 activities with the subsequent production of AA metabolites such as HETEs, which subsequently stimulate ERK and JNK (SAPK) activities leading to the activation of transcriptional factors and the ultimate stimulation of the transcription of several mitogen-stress-responsive genes. LacCer, a ceramide analogue present in atherosclerotic plaques, has been found to induce proliferation of aortic smooth muscle cells. LacCer is involved in Ras-GTP loading, activation of kinase cascades (MEK, Raf, p44 MAPK) and c-fos expression. TNF-alpha, on the other hand, induces c-fos, c-myc and c-jun expression. Recent investigations link ceramide and its analogues to the extracellular signal-regulated kinase (ERK) cascade, stress-activated protein kinase-c-Jun kinase (SAPK/JNK) cascade and apoptotic responses. These critical steps in the signalling pathways are sensitive to intracellular thiol-redox and protease(s)-antiprotease(s) status, both of which can be modified by oxidants. Because mobilisation of intracellular Ca2+ caused by a variety of signals also plays a role in the activation of the signalling pathways, an important aspect of future work will be to ascertain the roles of oxidants and Ca2+ individually and in combination in the activation of the signalling pathways. The following two important questions also deserve future attention: (1) How does NF-kB shield cells from apoptotic death? and (2) By what mechanisms does the activated NF-kB cause cellular transformation? Furthermore, the role of AP-1 acting as transcriptional activator seems clear, but the target genes remain to be defined.
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PMID:Oxidant-mediated activation of mitogen-activated protein kinases and nuclear transcription factors in the cardiovascular system: a brief overview. 988 18

The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma.
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PMID:Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages. 988 15

The yeast serine/threonine kinase STE20 activates a signaling cascade that includes STE11 (mitogen-activated protein kinase kinase kinase), STE7 (mitogen-activated protein kinase kinase), and FUS3/KSS1 (mitogen-activated protein kinase) in response to signals from both Cdc42 and the heterotrimeric G proteins associated with transmembrane pheromone receptors. Using degenerate polymerase chain reaction, we have isolated a human cDNA encoding a protein kinase homologous to STE20. This protein kinase, designated HPK/GCK-like kinase (HGK), has nucleotide sequences that encode an open reading frame of 1165 amino acids with 11 kinase subdomains. HGK was a serine/threonine protein kinase that specifically activated the c-Jun N-terminal kinase (JNK) signaling pathway when transfected into 293T cells, but it did not stimulate either the extracellular signal-regulated kinase or p38 kinase pathway. HGK also increased AP-1-mediated transcriptional activity in vivo. HGK-induced JNK activation was inhibited by the dominant-negative MKK4 and MKK7 mutants. The dominant-negative mutant of TAK1, but not MEKK1 or MAPK upstream kinase (MUK), strongly inhibited HGK-induced JNK activation. TNF-alpha activated HGK in 293T cells, as well as the dominant-negative HGK mutants, inhibited TNF-alpha-induced JNK activation. These results indicate that HGK, a novel activator of the JNK pathway, may function through TAK1, and that the HGK --> TAK1 --> MKK4, MKK7 --> JNK kinase cascade may mediate the TNF-alpha signaling pathway.
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PMID:A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. 989 Sep 73

p38 mitogen-activated protein kinase (MAPK) (p38) is involved in various cellular responses, including LPS stimulation of monocytes, resulting in production of proinflammatory cytokines such as TNF-alpha. However, the function of p38 during antigenic stimulation of T cells is largely unknown. Stimulation of the human Th cell clone HA-1.70 with either the superantigen staphylococcal enterotoxin B (SEB) or with a specific antigenic peptide resulted in p38 activation and the release of TNF-alpha. MAPK-activated protein kinase-2 (MAPKAPK-2), an in vivo substrate for p38, was also activated by T cell signaling. SB 203580, a selective inhibitor of p38, blocked p38 and MAPKAPK-2 activation in the T cell clone but did not completely inhibit TNF-alpha release. PD 098059, a selective inhibitor of MAPK kinase 1 (MEK1), blocked activation of extracellular signal-regulated kinase (ERK) and partially blocked TNF-alpha production by the clone. In human peripheral T cells, p38 was not activated by SEB, but rather by CD28 cross-linking, whereas in the human leukemic T cell line Jurkat, p38 was activated by CD3 and CD28 cross-linking in an additive fashion. TNF-alpha production by peripheral T cells in response to SEB and anti-CD28 mAb correlated more closely with ERK activity than with p38 activity. Therefore, various forms of T cell stimulation can activate the p38 pathway depending on the cells examined. Furthermore, unlike LPS-stimulated monocytes, TNF-alpha production by T cells is only partially p38-dependent.
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PMID:T cell activation signals up-regulate p38 mitogen-activated protein kinase activity and induce TNF-alpha production in a manner distinct from LPS activation of monocytes. 991 83

Nitric oxide production by macrophages is principally regulated by the calcium-independent enzyme, inducible nitric oxide synthase (iNOS). Both lipopolysaccharide and TNF-alpha synergize with IFN-gamma in the expression of iNOS with subsequent production of nitric oxide. Previous work has shown that IL-4 downregulates iNOS and nitric oxide expression by macrophages stimulated with LPS and IFN-gamma. In this study, we found that IL-4 also downregulated iNOS and nitric oxide expression induced by IFN-gamma and TNF-alpha and in mouse macrophages. Because various members of the mitogen-activated protein kinases and their upstream kinases have been shown to directly or indirectly activate a number of transcription factors including AP-1 and NFkappaB, we examined the effects of IL-4 on TNF-alpha activation of the MAPKs. Our results show that IL-4 modestly inhibited JNK/SAPK and ERK activation by TNF-alpha. Previously, we showed that selective pharmacologic inhibition of the ERK and/or p38mapk pathway did not affect NO2- expression. Treatment of cells with the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) showed a dose-response inhibition of NO2- expression. NPPB was also found to inhibit ERK and JNK/SAPK activation but not p38mapk with TNF-alpha stimulation. The discordance between the marked degree of inhibition of iNOS transcript by IL-4 and the modest inhibition of JNK/SAPK and ERK suggests that the mechanism by which IL-4 inhibits iNOS transcription appears more complex than a mere inhibition of these MAPKs.
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PMID:Potential role of the JNK/SAPK signal transduction pathway in the induction of iNOS by TNF-alpha. 991 6


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