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)

Prostaglandin H2 synthase (PGHS)-1 and PGHS-2 expression was examined in primary cultures of human amnion cells, an in vitro model of amnion tissue. Epidermal growth factor (EGF), the protein kinase C (PKC) activating phorbol ester TPA, and the protein phosphatase inhibitor, okadaic acid (OA), stimulated PGHS activity and the level of PGHS-2 mRNA, but did not affect the level of PGHS-1 mRNA. In situ hybridization suggested that the same population of cells responded to EGF, TPA and OA. Okadaic acid promoted PGHS activity independently of PKC. EGF stimulated the activity of extracellular signal-regulated protein kinase (Erk) and N-terminal c-Jun kinase (Jnk). OA increased Jnk activity but had no effect on Erk activity, while TPA had no influence on either Erk or Jnk activity. PD098059, a selective inhibitor of the Erk-activating kinase MEK, blocked the stimulation of PGHS expression by EGF, but did not decrease stimulation in response to OA. Herbimycin A, a tyrosine kinase inhibitor, suppressed the stimulation of PGHS activity and PGHS-2 mRNA abundance by all three stimulants, and blocked signalling via the Erk and Jnk mitogen-activated protein kinase pathways. Thus, growth factor stimulation, PKC activation and protein phosphatase inhibition induced the expression of PGHS-2 in primary amnion cells by distinct regulatory mechanisms involving tyrosine kinase(s). Tyrosine kinase inhibitors may constitute a new category of PGHS-2 inhibitors that act by blocking the expression of the enzyme.
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PMID:Regulation of prostaglandin H2 synthase-2 expression in primary human amnion cells by tyrosine kinase dependent mechanisms. 951 44

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

Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 microM H2O2 for 10 min or doxorubicin at 10 and 100 micrograms/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-kappaB-2 but not the NF-kappaB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation.
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PMID:Oxidative damage of cardiomyocytes is limited by extracellular regulated kinases 1/2-mediated induction of cyclooxygenase-2. 998 50

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

The possible participation of phosphatidylinositol (PI) 3-kinase, p44/42 mitogen-activated protein (MAP) kinases and protein kinase C (PKC) in staurosporine-induced prostaglandin E(2) (PGE(2)) production was investigated pharmacologically in rat peritoneal macrophages. When the cells were incubated in the presence of staurosporine (63 nM), phosphorylation of p44/42 MAP kinases and cytosolic phospholipase A(2) (cPLA(2)) was induced at 15 min and increased until 60 min, whereas PGE(2) production and expression of cyclooxygenase-2 (COX-2) protein began to increase at 2 h and increased thereafter. Both PD98059 and U0126, MAP kinase/extracellular signal-regulated kinase (ERK) kinase inhibitors, and LY294002, a PI 3-kinase inhibitor, inhibited staurosporine-induced phosphorylation of p44/42 MAP kinases and cPLA(2) and PGE(2) production. Moreover, U0126 inhibited staurosporine-induced arachidonic acid release at 1 h. Although PD98059 and U0126 at 30 microM partially inhibited staurosporine-induced COX-2 protein expression, they completely inhibited staurosporine-induced PGE(2) production. LY294002 at 100 microM did not inhibit staurosporine-induced expression of COX-2 protein. In contrast, Ro-31-8220, a PKC inhibitor, completely inhibited staurosporine-induced PGE(2) production and COX-2 protein expression at 8 h but did not inhibit staurosporine-induced phosphorylation of p44/42 MAP kinases and cPLA(2). These findings suggest that staurosporine induces PGE(2) production by two mechanisms. One is cPLA(2) phosphorylation through a signal transduction pathway from PI 3-kinase to p44/42 MAP kinases, by which arachidonic acid, a substrate for COX-1 and COX-2, is increased. The other is COX-2 protein expression, which is induced mainly by activation of PKC and partially by activation of p44/42 MAP kinases; thus, arachidonic acid is metabolized to PGE(2).
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PMID:Signal transduction cascade in staurosporine-induced prostaglandin E(2) production by rat peritoneal macrophages. 1073 71

Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) induced a transient increase in vascular smooth muscle cell (VSMC) cyclooxygenase-2 (COX-2) mRNA accumulation, without affecting COX-1 mRNA levels. The kinetics of COX-2 mRNA accumulation were similar in VSMCs challenged with either TNF-alpha or Ang II; mRNA accumulation peaked at 2 hours and decreased to control levels by approximately 6 hours. Accumulation of COX-2 mRNA was associated with a time-dependent increase of COX-2 protein expression that displayed similar kinetics in response to either TNF-alpha or Ang II. Both the increase in COX-2 mRNA accumulation and protein expression in response to either TNF-alpha or Ang II were inhibited by the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD098059. In addition, the AT(1)-selective receptor antagonist losartan attenuated the Ang II-mediated increase in COX-2 mRNA accumulation; the AT(2)-selective antagonist PD123319 had no effect. Prostacyclin I(2) synthesis was tightly coupled to expression of COX-2, whereas prostaglandin E(2) and thromboxane A(2) (TXA(2)) synthesis may be associated with differential usage of COX-1 and COX-2. The COX-2-selective inhibitors NS-398 and nimesulide and the TXA(2) receptor antagonist BMS 180,291 inhibited TNF-alpha- and Ang II-mediated increases in DNA content and cell number by approximately 95%. These findings suggest that a prostanoid derived from COX-2, possibly TXA(2), may contribute to VSMC hyperplasia in vessel injury or pathophysiological conditions associated with elevated levels of either TNF-alpha or Ang II.
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PMID:Cyclooxygenase-2 is required for tumor necrosis factor-alpha- and angiotensin II-mediated proliferation of vascular smooth muscle cells. 1078 14

Group B streptococcal (GBS) infections are associated with high morbidity and mortality. The molecular pathways mediating the pathophysiological events in GBS infection are not fully delineated. Cyclooxygenases (COX) are the enzymes that convert arachidonate to active eicosanoids. To identify the effects of GBS on eicosanoid metabolism and regulatory mechanisms, we exposed human monocytes to GBS and found that they secreted prostaglandin E2, prostacyclin, and thromboxane A2. Exposure to GBS caused monocytes to express COX-2 mRNA and protein in both a time- and concentration-dependent manner that correlated with eicosanoid production. COX-1 protein was unchanged. Addition of the anti-inflammatory cytokines interleukin (IL)-4 or IL-10 markedly attenuated GBS-induced COX-2 protein accumulation after GBS exposure, as did inhibition of p38 MAPK. Our experiments are the first to show that exposure of monocytes to a gram-positive bacterium (GBS) results in induction of functional COX-2, suggesting that eicosanoids may play important roles in the pathogenesis of GBS infections.
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PMID:Induction of cyclooxygenase-2 by human monocytes exposed to group B streptococci. 1081 Oct

In response to the bacterial endotoxin, LPS, Kupffer cells are induced to express NO and TNF-alpha. These compounds are involved in hepatic inflammation/injury, especially that associated with endotoxic shock. In this study, we demonstrate that ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one), a selenoorganic compound, blocks LPS-induced NO and TNF-alpha production by cultured rat liver Kupffer cells. LPS can activate both the NF-kappaB signaling pathway and MAPK signal transduction pathways such as JNK and p38 MAPK. We find that ebselen inhibits LPS-induced NF-kappaB nuclear translocalization, and also suppresses the LPS-induced phosphorylation of JNK, but not the phosphorylation of p38 MAPK. This inhibition of signal transduction leads to a decrease in the transcription of TNF-alpha and the inducible isoform of NO. Furthermore, ebselen inhibits LPS-induced COX-2 expression, which is responsible for proinflammatory prostaglandin production, without affecting constitutive COX-1 expression. These data suggest the mechanism by which ebselen acts as an antiinflammatory agent, and also suggest that ebselen may be potent in preventing hepatic injury such as endotoxic shock, in which Kupffer cell activation has been implicated.
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PMID:Selenoorganic compound, ebselen, inhibits nitric oxide and tumor necrosis factor-alpha production by the modulation of jun-N-terminal kinase and the NF-kappab signaling pathway in rat Kupffer cells. 1086 57

There is increasing evidence suggesting that chondrocyte death may contribute to the progression of osteoarthritis (OA). This study focused on the characterization of signaling cascade during NO-induced cell death in human OA chondrocytes. The NO generator, sodium nitroprusside (SNP), promoted chondrocyte death in association with DNA fragmentation, caspase-3 activation, and down-regulation of Bcl-2. Both caspase-3 inhibitor Z-Asp(OCH3)-Glu(OCH3)-Val-Asp(OCH3)-CH2F and caspase-9 inhibitor Z-Leu-Glu(OCH3)-His-Asp(OCH3)-CH2F prevented the chondrocyte death. Blocking the mitogen-activated protein kinase pathway by the mitogen-activated protein kinase kinase 1/2 inhibitor PD98059 or p38 kinase inhibitor SB202190 also inhibited the SNP-mediated cell death, suggesting possible requirements of both extracellular signal-related protein kinase 1/2 and p38 kinase for the NO-induced cell death. Furthermore, the selective inhibition of cyclooxygenase (COX)-2 by NS-398 or the inhibition of COX-1/COX-2 by indomethacin blocked the SNP-induced cell death. The chondrocyte death induced by SNP was associated with an overexpression of COX-2 protein (as determined by Western blotting) and an increase in PGE2 release. PD98059 and SB202190, but neither Z-DEVD FMK nor Z-LEHD FMK completely inhibited the SNP-mediated PGE2 production. Analysis of interactions between PGE2 and the cell death showed that PGE2 enhanced the SNP-mediated cell death, whereas PGE2 alone did not induce the chondrocyte death. These data indicate that NO-induced chondrocyte death signaling includes PGE2 production via COX-2 induction and suggest that both extracellular signal-related protein kinase 1/2 and p38 kinase pathways are upstream signaling of the PGE2 production. The results also demonstrate that exogenous PGE2 may sensitize human OA chondrocytes to the cell death induced by NO.
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PMID:The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. 1097 59

Prostaglandin endoperoxide synthase (PGHS) catalyses the rate-limiting step in the formation of prostaglandin and thromboxane eicosanoids from arachidonic acid released by phospholipase A(2). Two forms of PGHS exist, PGHS-1 and PGHS-2. PGHS-2, normally absent from cells, is rapidly expressed in response to a wide variety of stimuli and has been implicated in the pathogenesis of colon cancer and several inflammatory diseases. The three principal mitogen-activated protein kinase (MAPK) pathways are the extracellular signal-regulated protein kinase (ERK), the c-Jun N-terminal kinase (JNK) cascade and the p38-MAPK cascade. The present study was undertaken to investigate the putative involvement of the MAPK cascades in PGHS-2 induction. The potential role of ERK in PGHS-2 up-regulation was assessed by using cell lines expressing, both stably and after adenoviral infection, constitutively active forms of its upstream activator MAPK/ERK kinase (MEK1). The possible involvement of JNK and p38-MAPK in positively modulating PGHS-2 transcription was investigated by using adenovirus-mediated transfer of active forms of their respective specific upstream kinases, mitogen-activated protein kinase kinase (MKK) 7 and MKK3/MKK6. ERK activation promoted the induction of PGHS-2 mRNA and protein. Similarly, activation of JNK by Ad-MKK7D and p38-MAPK by Ad-MKK3bE/Ad-MKK6bE resulted in the increased expression of PGHS-2. These results provide evidence that activation of all three of the major mammalian MAPK leads to the induction of PGHS-2 mRNA and protein. Because PGHS-2 is up-regulated by a diverse range of stimuli, both mitogenic and stress-evoking, these results provide evidence that the convergence point of these stimuli could be the activation of one or more MAPK cascade(s).
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PMID:Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades. 1108 35


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