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)

Salicylates inhibit signaling by tumor necrosis factor (TNF), including TNF-induced activation of mitogen-activated protein kinases (MAPKs). On the other hand, we recently showed that in normal human diploid fibroblasts sodium salicylate (NaSal) elicits activation of p38 MAPK but not activation of c-Jun N-terminal kinase (JNK). Here we show that NaSal treatment of COS-1 or HT-29 cells produced a sustained c-Jun N-terminal kinase (JNK) activation. Activation of JNK or p38 MAPK by NaSal (or aspirin) was not due to a nonspecific hyperosmotic effect because much higher molar concentrations of sorbitol or NaCl were required to produce a similar activation. Three structurally unrelated nonsteroidal antiinflammatory drugs (ibuprofen, acetaminophen, and indomethacin) failed to induce significant activation of JNK or p38 MAPK, suggesting that cyclooxygenase inhibition is not the underlying mechanism whereby salicylates induce p38 MAPK and JNK activation. Activation of JNK and p38 MAPKs may be relevant for some antiinflammatory actions of salicylates.
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PMID:Cell-type-specific activation of c-Jun N-terminal kinase by salicylates. 1008 38

5-Hydroxytryptamine (5-HT, 'serotonin') is a potent inducer of the early response gene cyclo-oxygenase 2 (Cox-2; prostaglandin G/H synthase) in mesangial cells. Protein kinase C (PKC), Ca2+-dependent enzymes and mitogen-activated protein kinase (p42/44 MAPK) have previously been shown to be essential modules of the signalling pathway leading from the pertussis-insensitive 5-HT2A receptor to the induction of Cox-2 mRNA expression. In the present study, PKC activation was linked to the 5-HT-mediated phosphorylation and thus the activation of p42/44 MAPK: the inhibition of PKC by the specific inhibitor GF109203x prevented p42/44 MAPK activation. Ca2+/calmodulin-dependent (CaM) kinase II delta2 was detected in mesangial cells by Western blot analysis. The inhibition of CaM kinase by the inhibitors KN62 or KN93 led to a partial inhibition of 5-HT-induced Cox-2 mRNA expression and decreased basal, but not PMA-mediated, Cox-2 expression. The 5-HT-mediated activation of MAPK was not decreased by KN62 or KN93, excluding CaM kinase as a signalling module upstream of p42/44 MAPK. Taken together, these results indicate a modulatory involvement of CaM kinase in the regulation of 5-HT-mediated Cox-2 mRNA expression in addition to the main pathway that consists of the activation of PKC and p42/44 MAPK.
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PMID:Independent regulation of cyclo-oxygenase 2 expression by p42/44 mitogen-activated protein kinases and Ca2+/calmodulin-dependent kinase. 1019 Dec 63

Arachidonic acid (AA) is generated via Rac-mediated phospholipase A2 (PLA2) activation in response to growth factors and cytokines and is implicated in cell growth and gene expression. In this study, we show that AA activates the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in a time- and dose-dependent manner. Indomethacin and nordihydroguaiaretic acid, potent inhibitors of cyclooxygenase and lipoxygenase, respectively, did not exert inhibitory effects on AA-induced SAPK/JNK activation, thereby indicating that AA itself could activate SAPK/JNK. As Rac mediates SAPK/JNK activation in response to a variety of stressful stimuli, we examined whether the activation of SAPK/JNK by AA is mediated by Rac1. We observed that AA-induced SAPK/JNK activation was significantly inhibited in Rat2-Rac1N17 dominant-negative mutant cells. Furthermore, treatment of AA induced membrane ruffling and production of hydrogen peroxide, which could be prevented by Rac1N17. These results suggest that AA acts as an upstream signal molecule of Rac, whose activation leads to SAPK/JNK activation, membrane ruffling and hydrogen peroxide production.
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PMID:Arachidonic acid induces the activation of the stress-activated protein kinase, membrane ruffling and H2O2 production via a small GTPase Rac1. 1038 21

Levels of the pro-inflammatory cytokine interleukin-1beta are known to be elevated in patients with chronic disorders such as Alzheimer's disease. We have investigated the effects of interleukin-1beta on long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials in the rat dentate gyrus in vitro utilizing field extracellular recordings obtained from the middle third of the molecular layer of the dentate gyrus. Presynaptic stimulation was applied to the commissural/association pathway at a frequency of 0.05 Hz and at a distance of 50 microm from the granule cell body layer. As previously reported, interleukin-1beta (1 ng/ml) caused an inhibition of long-term potentiation (108+/-2% of baseline 1 h following application of tetanic stimulation compared with 145+/-5% in vehicle control slices). This action of interleukin-1beta on long-term potentiation, as well as an inhibition of N-methyl-D aspartate receptor-mediated field potentials, was attenuated by pre-treatment of slices with the p38 mitogen-associated protein kinase inhibitor SB203580 (1 microM). SB203580 alone had no significant affect on long-term potentiation, but did cause an increase in baseline synaptic transmission [107+/-2% of baseline, 1 h after SB203580 (1 microM) treatment]. The p42/44 mitogen-activated protein kinase cascade inhibitor PD98059 (50 microM) did not inhibit the interleukin-1beta-induced inhibition of N-methyl-D-aspartate receptor-mediated field potentials. The cyclooxygenase inhibitor indomethacin (50 microM) was found to attenuate the interleukin-1beta-induced effects on both long-term potentiation and N-methyl-D-aspartate receptor-mediated field potentials. The lipid second messenger analogue C2 ceramide (20 microM) was found to attenuate the expression of long-term potentiation (108+/-3% of baseline 1 h following tetanic stimulation), and this effect was not blocked by pre-treatment with SB203580. To investigate a possible role for interleukin-1beta in the normal expression of long-term potentiation, the interleukin-1 receptor antagonist (25 ng/ml) was applied during the maintenance phase of long-term potentiation. This was found to depress the sustained expression of long-term potentiation (116+/-6% of baseline 1 h following tetanic stimulation). Our results indicate possible signalling mechanisms by which interleukin-1beta at pathophysiological concentrations may serve to inhibit long-term potentiation, and also suggests a role for IL-1beta in the physiological expression of synaptic plasticity in the rat dentate gyrus in vitro.
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PMID:The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro. 1043 Apr 70

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.
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PMID:Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. 1058 Oct 68

Although it is established that growth factors and prostaglandins function in the maintenance of gastric mucosal integrity and in the healing of gastric mucosal injury and ulceration, the regulatory relationship between growth factors and prostaglandins in the gastric mucosa is not well characterized. Therefore, we investigated whether hepatocyte growth factor (HGF) affects expression of COX-2 (the inducible form of the prostaglandin synthesizing enzyme, cyclooxygenase) in gastric epithelial cells and whether this action is mediated through the MAP (ERK) kinase signaling pathway. In RGM1 cells (an epithelial cell line derived from normal rat gastric mucosa), HGF caused an increase in COX-2 mRNA and protein by 236% and 175%, respectively (both P<0.05). This induction of COX-2 expression was abolished by pretreatment with the MAPK kinase (MEK) inhibitor PD98059. HGF also triggered a 13-fold increase in c-Met/HGF receptor phosphorylation (P<0.005) and increased ERK2 activity by 684% (P<0.01). Pretreatment with PD98059 abolished the HGF-induced increase in ERK2 activity, but not c-Met/HGF receptor phosphorylation. The specific inhibitor of p38 MAP kinase, SB203580, had no effect on HGF-induced COX-2 expression. Thus, HGF triggers activation of the COX-2 gene in gastric epithelial cells through phosphorylation of c-Met/HGF receptor and activation of the ERK2 signaling pathway.-Jones, M. K., Sasaki, E., Halter, F., Pai, R., Nakamura, T., Arakawa, T., Kuroki, T., Tarnawski, A. S. HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: action mediated through the ERK2 signaling pathway.
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PMID:HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: action mediated through the ERK2 signaling pathway. 1059 66

Multiple enzymes may stimulate ROS production in VSMC and endothelial cells. These include NADH/NADPH oxidase, xanthine oxidase, lipoxygenases, cyclooxygenase, P-450 monooxygenases, and the enzymes of mitochondrial oxidative phosphorylation. In addition to generation of intracellular O2- by these enzymes, extracellular stimuli including lipophilic substrates, membrane permeant oxidants (e.g., H2O2), cytokines, and growth factors may modulate cellular redox state. Both intracellular and extracellular ROS act as second-messengers to activate tyrosine and serine-threonine kinases, such as the MAP kinase family. As discussed in the previous sections, regulation of the MAP kinases is one example of the complexity of ROS-dependent signal transduction. Although the complexity of ROS-mediated signal transduction is daunting, the diversity offers multiple therapeutic targets for pharmacologic intervention.
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PMID:Redox signals that regulate the vascular response to injury. 1060 87

In renal mesangial cells, activation of protein tyrosine kinase receptors may increase the activity of mitogen-activated protein (MAP) kinases and subsequently induce expression of prostaglandin G/H synthase-2 (PGHS-2, cyclo-oxygenase-2). As examples, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) were shown to transiently enhance p42/44 MAP kinase activity, which was an essential step in the induction of PGHS-2 mRNA and protein. Inhibitors of receptor kinase activities, tyrphostins AG1296 and AG1478, specifically inhibited the effects of PDGF and EGF respectively. Activation of p42/44 and p38 MAP kinases and PGHS-2 induction were also mediated by lysophosphatidic acid (LPA), which binds to pertussis-toxin-sensitive G-protein-coupled receptors. LPA stimulation was inhibited by AG1296, but not AG1478, indicating involvement of the PDGF receptor kinase in LPA-mediated signalling. This was confirmed by pertussis-toxin-sensitive tyrosine phosphorylation of the PDGF receptor by LPA, whereas no phosphorylation of the EGF receptor was detected. For comparison, 5-hydroxytryptamine ('serotonin')-mediated signalling was only partially inhibited by AG1296, and also not affected by AG1478. A strong basal AG1296-sensitive tyrosine phosphorylation of the PDGF receptor and a set of other proteins was observed, which by itself was not sufficient to induce p42/44 MAP kinase activation, but played an essential role not only in LPA- but also in phorbol ester-mediated activation. Taken together, the PDGF receptor, but not the EGF receptor, is involved in LPA-mediated MAP kinase activation and PGHS-2 induction in primary mesangial cells, where both protein kinase receptors are present and functionally active.
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PMID:The platelet-derived-growth-factor receptor, not the epidermal-growth-factor receptor, is used by lysophosphatidic acid to activate p42/44 mitogen-activated protein kinase and to induce prostaglandin G/H synthase-2 in mesangial cells. 1062 Apr 97

We have previously shown that exposure to diesel exhaust particles (DEPs) stimulates human airway epithelial cells to secrete the inflammatory cytokines interleukin-8, interleukin-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) involved in allergic diseases. In the present paper, we studied the mechanisms underlying the increase in GM-CSF release elicited by DEPs using the human bronchial epithelial cell line 16HBE14o-. RT-PCR analysis has shown an increase in GM-CSF mRNA levels after DEP treatments. Comparison of the effects of DEPs, extracted DEPs, or extracts of DEPs has shown that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and not to the metals present on the DEP surface because the metal chelator desferrioxamine had no inhibitory effect. Furthermore, radical scavengers inhibited the DEP-induced GM-CSF release, showing involvement of reactive oxygen species in this response. Moreover genistein, a tyrosine kinase inhibitor, abrogated the effects of DEPs on GM-CSF release, whereas protein kinase (PK) C, PKA, cyclooxygenase, or lipoxygenase inhibitors had no effect. PD-98059, an inhibitor of mitogen-activated protein kinase, diminished the effects of DEPs, whereas SB-203580, an inhibitor of p38 mitogen-activated protein kinase, had a lower effect, and DEPs did actually increase the active, phosphorylated form of the extracellular signal-regulated kinase as shown by Western blotting. In addition, cytochalasin D, which inhibits the phagocytosis of DEPs, reduced the increase in GM-CSF release after DEP treatment. Together, these data suggest that the increase in GM-CSF release is mainly due to the adsorbed organic compounds and that the effect of native DEPs requires endocytosis of the particles. Reactive oxygen species and tyrosine kinase(s) may be involved in the DEP-triggered signaling of the GM-CSF response.
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PMID:Mechanisms of GM-CSF increase by diesel exhaust particles in human airway epithelial cells. 1064 87

Oxygen derived free radicals and other reactive oxygen species (ROS) are involved in a variety of disease states, which can have cardiac and vascular implications. The present study was performed to investigate the mechanism of ROS-induced vasoconstriction and the influence of ROS on the functional integrity of isolated rat thoracic aorta. ROS were generated by means of electrolysis (30 mA, during 0.5, 1, 2 or 3 min) of the organ bath fluid. ROS induced a transient (approximately 60 min) vasoconstriction and the maximally induced contraction was dependent on the duration of electrolysis. Dimethyl sulfoxide (DMSO) diminished the ROS-induced vasoconstriction almost completely, indicating a major influence of hydroxyl radicals on contractility. The dual cyclooxygenase/lipoxygenase inhibitor, meclofenamate, completely prevented the ROS-induced vasoconstriction. The phospholipase A2 (PLA2) inhibitor, oleyloxyethyl phosphorylcholine, was able to reduce the vasoconstriction elicited by ROS by approximately 70%. Conversely, the specific cytoplasmic PLA2 inhibitor arachidonyl trifluoromethylketone proved ineffective in this respect. By using the specific mitogen-activated protein kinase (MAPkinase) kinase inhibitor PD98059, it was shown that the activation of extracellular-regulated kinase (ERK) MAPkinase contributes to the ROS-induced vasoconstriction. The effects of ROS on the functional integrity of the aortae were investigated, in particular with respect to receptor (alpha1-adrenoceptor) and non-receptor-mediated contractile responses (high potassium solution). In addition, both the endothelium dependent (methacholine) and endothelium independent (sodium nitroprusside) vasorelaxation were investigated before and after ROS exposure. Electrolysis periods of 0.5 and 1 min induced a modest leftward shift of the concentration response curves for the alpha1-adrenoceptor agonist methoxamine. Longer electrolysis periods of 2 and 3 min additionally decreased the maximal response to (alpha1-adrenoceptor stimulation. Methacholine-induced vasorelaxation proved diminished in aortae subjected to electrolysis (0.5, 1, 2 and 3 min), whereas relaxation to sodium nitroprusside was nearly complete in all groups. KCl-induced contractions proved attenuated only after longer electrolysis periods of 2 and 3 min. This ROS-induced deterioration of functional integrity was almost completely prevented by 0.6% DMSO. From these results we may conclude that ROS induce an eicosanoid and ERK MAPkinase-mediated vasoconstriction in isolated rat thoracic aorta. In addition, exposure to ROS leads to a deterioration of functional integrity characterized by endothelial dysfunction and decreased contractile function.
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PMID:Reactive oxygen species-induced aortic vasoconstriction and deterioration of functional integrity. 1068 67


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