Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric mucosa responds to Helicobacter pylori-induced cell damage by increasing the expression of COX-2 and EGF-related peptides. We sought to investigate the bacterial virulence factor/s and the host cellular pathways involved in the upregulation of COX-2, HB-EGF and amphiregulin in MKN 28 and AGS gastric mucosal cells. H. pylori strain CCUG 17874 was grown in Brucella broth supplemented with 0.2% (2,6-dimethyl)-beta-cyclodextrins. The soluble proteins released in the culture medium by the bacterium were fractionated by exclusion size and anion exchange chromatography. A single peak retaining the ability to upregulate COX-2 and HB-EGF mRNA and protein expression was obtained. SDS-PAGE analysis of the peak showed two peptides with an apparent molecular weight of 38 and 22 kDa, which were identified by automated Edman degradation analysis as the N-terminal and C-terminal peptides of H. pylori gamma-glutamyltranspeptidase respectively. Acivicin, a selective gamma-glutamyltranspeptidase inhibitor, counteracted H. pylori-induced upregulation of COX-2 and EGF-related peptide mRNA expression. An H. pylori isogenic mutant gamma-glutamyltranspeptidase-deficient strain did not exert any effect on COX-2, HB-EGF and amphiregulin mRNA expression. Blockade of phosphatidylinositol-3 kinase and p38 kinase, but not MAP kinase kinase, inhibited H. pylori gamma-glutamyltranspeptidase-induced upregulation of COX-2 and EGF-related peptide mRNA expression.
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PMID:Helicobacter pylori gamma-glutamyltranspeptidase upregulates COX-2 and EGF-related peptide expression in human gastric cells. 1476 9

IL-1beta reduces the activity and protein expression of Na(+)-K(+)-ATPase in rat kidney cells. The aim of the present study was to elucidate the signalling pathway involved, using the LLC-PK(1) cell line. In these cells IL-1beta caused a time and concentration-dependent decrease in the protein expression of the Na(+)-K(+)-ATPase. Inhibition of extracellular signal-regulated kinase (ERK), nuclear factor-kappaB (NF-kappaB) and cyclooxygenase (COX), but not p38 mitogen-activated kinase (MAPK), abolished the effect of the cytokine on the pump. The activation of NF-kappaB by IL-1beta was maximal at 20 min and declined thereafter. Inhibition of the transcription factor by pyrrolidinediethyldithiocarbamate (PDTC) down-regulated the ATPase. The effects of IL-1beta on the pump and NF-kappaB were prevented by the COX inhibitor indomethacin. Exogenous PGE(2) reduced protein expression of the ATPase within 15 min, even in presence of an ERK inhibitor. It is concluded that IL-1beta stimulates the mitogen and extracellular signal regulated protein kinase kinase/extracellular signal regulated protein kinase (MEK/ERK) pathway. This activates NF-kappaB, thus leading to increased COX-2 expression and PGE(2) release. PGE(2) in turn inhibits NF-kappaB and reduces the protein expression of Na(+)-K(+)-ATPase.
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PMID:The signal transduction pathway that mediates the effect of interleukin-1 beta on the Na+-K+-ATPase in LLC-PK1 cells. 1498 81

Interleukin-1beta (IL-1beta) has been recognized as a potent stimulus for the synthesis of prostaglandin (PG), which has been implicated in inflammatory responses of the airways. However, the mechanisms underlying IL-1beta-induced cyclooxygenase (COX) expression and PGE(2) synthesis via activation of p42/p44 and p38 mitogen-activated protein kinases (MAPKs) in human tracheal smooth muscle cells (HTSMCs) are not completely understood. We found that IL-1beta increased COX-2 expression and PGE(2) synthesis in time- and concentration-dependent manners. Both specific phosphatidylcholine-phospholipase C inhibitor (D609) and protein kinase C inhibitor (GF109203X) attenuated IL-1beta-induced responses in HTSMCs. IL-1beta-induced COX-2 expression and PGE(2) synthesis were also inhibited by an inhibitor of MEK1/2 (PD98059) and inhibitors of p38 MAPK (SB203580 and SB202190), respectively, suggesting the involvement of p42/p44 and p38 MAPKs in these responses. This hypothesis was further supported by the transient activation of p42/p44 and p38 MAPKs induced by IL-1beta. Furthermore, IL-1beta-induced activation of nuclear factor-kappaB (NF-kappaB) was inversely correlated with the degradation of IkappaB-alpha in HTSMCs. IL-1beta-induced COX-2 expression and PGE(2) synthesis were inhibited by the NF-kappaB inhibitor pyrrolidinedithiocarbamate. These findings suggest that the expression of COX-2 is correlated with the release of PGE(2) from IL-1beta-challenged HTSMCs, which is mediated, at least in part, through p42/p44 and p38 MAPKs and NF-kappaB signaling pathways in HTSMCs.
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PMID:Induction of cyclooxygenase-2 expression in human tracheal smooth muscle cells by interleukin-1beta: involvement of p42/p44 and p38 mitogen-activated protein kinases and nuclear factor-kappaB. 1506 22

We characterized the tracheal and bronchial relaxation caused by proteinase-activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2-knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)) and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides, respectively, caused relaxation in the isolated ddY mouse trachea and main bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E(2)-induced relaxation. Inhibitors of cytosolic Ca(2+)-dependent phospholipase A(2) (PLA), Ca(2+)-independent PLA(2), diacylglycerol lipase, tyrosine kinase, and protein kinase C exhibited no or only minor inhibitory effects on the PAR-mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH(2), caused airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout mice, the peptide effects were absent and the potency of trypsin decreased. Desensitization of PAR-2 and/or PAR-1 greatly suppressed the relaxant effect of trypsin. The bronchial and tracheal tissues displayed distinct sensitivities toward trypsin and the PAR-2-activating peptides. Our data indicate an involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered relaxation of mouse airway tissue, and substantiate a role for PAR-2 in regulating both the trachea and bronchial responsiveness in the mouse lung.
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PMID:Proteinase-activated receptor-2-mediated relaxation in mouse tracheal and bronchial smooth muscle: signal transduction mechanisms and distinct agonist sensitivity. 1519 93

Pancreatic carcinogenesis is driven by multiple genetic and epigenetic changes. The epidermal growth factor receptor (EGFR) and its downstream signaling pathways, Ras-Raf-MEK-ERK axis, play important roles in pancreatic cancer development. The phosphoinositol 3 kinase (PI3 K)/Akt and the nuclear factor kappaB (NF-kappaB) pathways control both proliferation and resistance to apoptosis of pancreatic cancer. The role of cyclooxygenase (COX) and lipoxygenase (LOX) in the development of pancreatic cancer has been made known recently. The elucidation of these molecular events has led to several distinct therapeutic advances, including therapies that target EGFR, the Ras-Raf-MEK-ERK axis, the COX-2 and LOX pathways, and others. Many novel agents have been developed and are undergoing clinical investigation, such as monoclonal antibodies against EGFR, tyrosine kinase inhibitors (TKIs), farnesyl transferase inhibitors (FTIs), Bay43-9006, CI-1040, CCI-779, celecoxib, and LY293111. This review highlights recent advances in the development of these agents.
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PMID:Molecular targeting therapy for pancreatic cancer. 1531 51

Elevated levels of prostaglandins (PGs), products of cyclooxygenases (COXs), are found in the plasma and stool of rotavirus-infected children. We sought to determine the role of COXs, PGs, and the signal transduction pathways involved in rotavirus infection to elucidate possible new targets for antiviral therapy. Human intestinal Caco-2 cells were infected with human rotavirus Wa or simian rotavirus SA-11. COX-2 mRNA expression and secreted PGE2 levels were determined at different time points postinfection, and the effect of COX inhibitors on rotavirus infection was studied by an immunofluorescence assay (IFA). To reveal the signal transduction pathways involved, the effect of MEK, protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), and NF-kappaB inhibitors on rotavirus infection was analyzed. In infected Caco-2 cells, increased COX-2 mRNA expression and secreted PGE2 levels were detected. Indomethacin (inhibiting both COX-1 and COX-2) and specific COX-1 and COX-2 inhibitors reduced rotavirus infection by 85 and 50%, respectively, as measured by an IFA. Indomethacin reduced virus infection at a postbinding step early in the infection cycle, inhibiting virus protein synthesis. Indomethacin did not seem to affect viral RNA synthesis. Inhibitors of MEK, PKA, p38 MAPK, and NF-kappaB decreased rotavirus infection by at least 40%. PGE2 counteracted the effect of the COX and PKA inhibitors but not of the MEK, p38 MAPK, and NF-kappaB inhibitors. Conclusively, COXs and PGE2 are important mediators of rotavirus infection at a postbinding step. The ERK1/2 pathway mediated by PKA is involved in COX induction by rotavirus infection. MAPK and NF-kappaB pathways are involved in rotavirus infection but in a PGE2-independent manner. This report offers new perspectives in the search for therapeutic agents in treatment of severe rotavirus-mediated diarrhea in children.
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PMID:Inhibition of cyclooxygenase activity reduces rotavirus infection at a postbinding step. 1533 5

The nonsteroidal anti-inflammatory drug (NSAID) sulindac prevents experimental colon cancer and can regress precancerous polyps in humans. Sulindac sulfide inhibits cyclooxygenase (COX)-mediated prostaglandin synthesis and retards the growth of cultured colon cell lines primarily by inducing apoptosis. Given the known role of mitogen-activated protein kinase (MAPK) in signal transduction and the regulation of cell survival and death, we determined the effect of sulindac sulfide on MAPK activation, COX-2 expression, and apoptosis induction in HCA-7 human colon cancer cells. Sulindac sulfide treatment was associated with activation of ERKp44/42 and p38 MAPK in a dosage- and time-dependent manner, and also activated upstream MEK. Similar results were seen in HCT-15 cells and also with the selective COX-2 inhibitor NS398. ERKp44/42 and p38 activation were accompanied by an induction of COX-2 protein expression. Selective inhibitors of sulindac sulfide-induced ERKp44/42 (PD98059) and p38 MAPK (SB203580) activation also suppressed the induction of COX-2 by this NSAID. Furthermore, both MAPK inhibitors significantly augmented sulindac sulfide-induced apoptosis, as did suppression of constitutive COX-2 using antisense oligonucleotides. In conclusion, MEK/ERK and p38 MAPK activation mediate COX-2 induction by sulindac sulfide. Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer.
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PMID:Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. 1565 53

Imatinib mesylate is a novel anti-tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy. Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including BCR-ABL, platelet-derived growth factor receptor and c-kit kinases, resulting in the collapse of downstream signaling cascades important for transformation. In some patients, unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target. In this report, we investigated the effects of imatinib on squamous carcinoma cell signaling. Imatinib induced expression of COX-2 in a dose-dependent manner with concomitant accumulation of prostaglandin E2. COX-2 induction by imatinib was initiated through epidermal growth factor (EGF) receptor kinase activation and downstream signaling through mitogenic-activated protein kinase. COX-2 induction by imatinib was blocked by MEK1 or EGF receptor inhibition. Imatinib did not activate stressor cytokine-signaling pathways (p38 kinase, nuclear factor-kB nuclear translocation) or affect COX-1 expression. Imatinib failed to activate EGF receptor signals in other tumor types, suggesting that COX-2 induction in imatinib-treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors. COX-2 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target-specific agents and may represent one of the unintended toxic effects of imatinib described in some patients.
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PMID:Cyclooxygenase-2 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate. 1584 61

Combination studies of celecoxib and chemotherapeutic agents suggest that combining cyclooxygenase-2 inhibitors with other agents may have supra-additive or synergistic effects on tumor growth inhibition. Carboxyamido-triazole (CAI), a voltage-independent calcium channel inhibitor, has been shown to induce growth inhibition and apoptosis in cancer cells. We found that continuous exposure to cytostatic doses of CAI and LM-1685, a celecoxib analogue, reduced the proliferation and survival of seven human cancer cell lines by at least one log (P < or = 0.001) over either agent alone. To explore the mechanism of action of this combination, we further studied the effects of LM-1685/CAI on CCL-250 colorectal carcinoma cells. We found that the supra-additive antiproliferative effects occurred throughout a range of LM-1685 doses (5-25 micromol/L) and paralleled a decrease in COX-2 activity as measured by prostaglandin E2 production. In these cells, treatment with LM-1685/CAI suppressed the extracellular signal-regulated kinase pathway within the first hour but ultimately results in high, sustained activation of ERK over a 9-day period (P = 0.0005). Suppression of cyclin D1 and phospho-AKT, and cleavage of caspase-3 and PARP were concomitant with persistent ERK activation. Addition of PD98059, a MEK-1 inhibitor, suppressed ERK activation and significantly but incompletely reversed these signaling events and apoptosis. Flow cytometry experiments revealed that the CAI/LM-1685 combination induced a 3-fold increase in apoptosis over control (P = 0.005) in 3 days. We show that the combination of CAI and LM-1685 produces a cytotoxic effect by suppressing proliferation and triggering apoptosis.
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PMID:Supra-additive growth inhibition by a celecoxib analogue and carboxyamido-triazole is primarily mediated through apoptosis. 1586 84

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used as analgesics. They inhibit cyclooxygenases (COX), preventing the formation of prostaglandins, including prostacyclin and thromboxane. A serious side effect of COX-1 and COX-2 inhibitors is renal damage. To investigate the molecular basis of the renal injury, we evaluated the expression of the stress marker, heme oxygenase-1 (HO-1), in celecoxib-stimulated mesangial cells. We report here that a COX-2 selective NSAID, celecoxib, induced a concentration- and time-dependent increase of HO-1 expression in glomerular mesangial cells. Celecoxib-induced HO-1 protein expression was inhibited by actinomycin D and cycloheximide, suggesting that de novo transcription and translation are required in this process. N-acetylcysteine, a free radical scavenger, strongly decreased HO-1 expression, suggesting the involvement of reactive oxygen species (ROS). Celecoxib-induced HO-1 expression was attenuated by pretreatment of the cells with SP 600125 (a specific JNK inhibitor), but not SB 203580 (a specific p38 MAPK inhibitor), or PD 98059 (a specific MEK inhibitor). Consistently, celecoxib activated c-Jun N-terminal kinase (JNK) as demonstrated by kinase assays and by increasing phosphorylation of this kinase. N-acetylcysteine reduced the stimulatory effect of celecoxib on stress kinase activities, suggesting an involvement of JNK in HO-1 expression. On the other hand, LY 294002, a phosphatidylinositol 3-kinase (PI-3K)-specific inhibitor, prevented the enhancement of HO-1 expression. This effect was correlated with inhibition of the phosphorylation of the PDK-1 downstream substrate Akt/protein kinase B (PKB). In conclusion, our data suggest that celecoxib-induced HO-1 expression in glomerular mesangial cells may be mediated by ROS via the JNK-PI-3K cascade.
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PMID:Celecoxib induces heme-oxygenase expression in glomerular mesangial cells. 1596 68


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