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)

Ito cell mitogenesis occurs during liver injury and fibrogenesis in vivo coincident with the de novo expression of Ito cell PDGF beta receptor messenger RNA. PDGF-induced mitogenesis was studied in cultured rat hepatic Ito cells which resemble the myofibroblast associated with liver injury. Pretreatment with prostaglandin E markedly suppressed the PDGF response in a dose-dependent fashion. The PDGF-induced cascade was studied with or without PGE to determine the level of regulation which induced the observed suppression. PGE caused no apparent diminution in the abundance of the surface PDGF beta receptor nor its subsequent activation and tyrosine phosphorylation following PDGF stimulation. The cytoplasmic 'secondary messengers' mitogen-activated protein kinase pp42-44 and raf kinase, appeared to be comparably induced and therefore unaffected by PGE. Raf perinuclear translocation was also intact and comparable degrees of nuclear egr, fos, and jun expression occurred. Since other studies have suggested that many of these features of the PDGF cascade may be causally and sequentially linked, the data collectively suggests that the dominant PGE mitogenic suppressive effect resides at a raf-MAP parallel pathway or at a nuclear level distal to the induction of these early growth response genes.
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PMID:Prostaglandin E suppression of platelet-derived-growth-factor-induced Ito cell mitogenesis occurs independent of raf perinuclear translocation and nuclear proto-oncogene expression. 803 66

Osteoblasts produce prostaglandins in response to a wide variety of stimuli. Induced prostaglandin synthesis is generally the consequence of elevated cyclooxygenase-2 (COX-2) expression. Agents as diverse as serum, bFGF, PDGF, PGE(2), or [TNFalpha + IL1beta] rapidly induce expression of COX-2 protein in murine MC3T3-E1 osteogenic cells. Transient transfection studies using reporter constructs containing either wild-type COX-2 regulatory sequences or mutated cis-acting sequences linked to a luciferase reporter gene identify a CRE site and two NF-IL6 (C/EBP) sites which play important roles in the regulation of COX-2 expression in response to all these agents in osteoblasts. Induction of wild-type COX-2 reporter gene expression in MC3T3-E1 cells by all these agents involves signaling through the MEKK/JNK pathway and activation of both c-Jun and the C/EBP family of transcription factors.
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PMID:Transcriptional regulation of the cyclooxygenase-2 gene by diverse ligands in murine osteoblasts. 1054 22

We have previously reported that interleukin (IL)-1beta causes beta-adrenergic hyporesponsiveness in cultured human airway smooth muscle cells by increasing cyclooxygenase-2 (COX-2) expression and prostanoid formation. The purpose of this study was to determine whether extracellular signal-regulated kinases (ERKs) are involved in these events. Levels of phosphorylated ERK (p42 and p44) increased 8.3- and 13-fold, respectively, 15 min after treatment with IL-1beta (20 ng/ml) alone. Pretreating cells with the mitogen-activated protein kinase kinase inhibitor PD-98059 or U-126 (2 h before IL-1beta treatment) decreased ERK phosphorylation. IL-1beta (20 ng/ml for 22 h) alone caused a marked induction of COX-2 and increased basal PGE(2) release 28-fold (P < 0.001). PD-98059 (100 microM) and U-126 (10 microM) each decreased COX-2 expression when administered before IL-1beta treatment. In control cells, PD-98059 and U-126 had no effect on basal or arachidonic acid (AA; 10 microM)-stimulated PGE(2) release, but both inhibitors caused a significant decrease in bradykinin (BK; 1 microM)-stimulated PGE(2) release, consistent with a role for ERK in the activation of phospholipase A(2) by BK. In IL-1beta-treated cells, prior administration of PD-98059 caused 81, 92 and 40% decreases in basal and BK- and AA-stimulated PGE(2) release, respectively (P < 0.01), whereas administration of PD-98059 20 h after IL-1beta resulted in only 38 and 43% decreases in basal and BK-stimulated PGE(2) release, respectively (P < 0.02) and had no effect on AA-stimulated PGE(2) release. IL-1beta attenuated isoproterenol-induced decreases in human airway smooth muscle stiffness as measured by magnetic twisting cytometry, and PD-98059 or U-126 abolished this effect in a concentration-dependent manner. These results are consistent with the hypothesis that ERKs are involved early in the signal transduction pathway through which IL-1beta induces PGE(2) synthesis and beta-adrenergic hyporesponsiveness and that ERKs act by inducing COX-2 and activating phospholipase A(2).
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PMID:Role of ERK MAP kinases in responses of cultured human airway smooth muscle cells to IL-1beta. 1056 79

The cyclic AMP (cAMP) elevating agent PGE(2) and dibutyryl cyclic AMP (dBcAMP) affect T cell functions. Using human helper T cell clones, we examined effects of cAMP on c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), which are assumed to play a role in T cell regulation. When we analyzed the effects of dBcAMP on activities of mitogen-activated protein kinase (MAPK) family members ERK2, JNKp55 and JNKp46, dBcAMP did not inhibit the activities of ERK2 and JNKp55 induced by PMA/A23187 stimulation. JNKp46 activity was, however, inhibited by dBcAMP. JNK phosphorylates c-Jun on Ser-63 and Ser-73, the result being induction of its transcriptional activity. We found that dBcAMP inhibited the phosphorylation of c-Jun Ser-63 induced by PMA/A23187 stimulation. We suggest a different mechanism of regulation of JNKp55 and JNKp46 activities and that JNKp46 is a specific c-Jun kinase by which the activity of c-Jun is regulated in T lymphocytes.
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PMID:Cyclic AMP inhibits the activity of c-Jun N-terminal kinase (JNKp46) but not JNKp55 and ERK2 in human helper T lymphocytes. 1058 Nov 77

Angiotensin II (Ang II) stimulates the release of prostaglandins (PGs) in various cells and tissues. Recently, cyclooxygenase-2 (COX-2) emerged as a new key regulator for PG synthesis. In the present study, we investigated whether Ang II regulates COX-2 expression in cultured rat vascular smooth muscle cells (VSMCs). Ang II markedly increased the expression of COX-2 mRNA in a time- and dose-dependent manner. This effect was completely blocked by the Ang II type 1 receptor antagonist losartan but not by the Ang II type 2 receptor antagonist PD123319. The p42/44 mitogen-activated protein kinase (MAPK) kinase-1 inhibitor PD98059 and the p38 MAPK inhibitor SB203580 significantly suppressed Ang II-induced COX-2 mRNA and protein expression. Ang II did not increase transcription of the COX-2 gene, as examined with a COX-2 promoter/luciferase chimeric plasmid construct. Instead, it suppressed the degradation of COX-2 mRNA. PD98059 and SB203580 markedly enhanced the decay of COX-2 mRNA induced by Ang II, implying that p42/44 and p38 MAPK activated by Ang II play a role in the regulation of COX-2 through stabilization of its mRNA. The COX-2-specific inhibitor NS-398 attenuated Ang II-stimulated DNA and protein synthesis, as well as PGE(2) production by VSMCs. These results suggest that Ang II regulates COX-2 expression and PG production and modulates cell proliferation through MAPK-mediated signaling pathways in rat VSMCs.
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PMID:Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth muscle cells. 1064 77

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

The regulation of expression of cyclooxygenase 2 (COX-2) was investigated by treatment with PGE(2) in human endometrial adenocarcinoma cell line HEC-1B. One microM PGE(2) could stimulate the expression of COX-2 approximately twofold in this cell line. The same concentration of PGE(2) also stimulated activation of mitogen-activated protein kinase (MAP kinase) and protein kinase B (PKB). PGE(2)-induced MAP kinase activation was sensitive to a MAP kinase kinase (MEK) inhibitor, PD098059, and a protein kinase A inhibitor, H-89. PD098059 and H-89 also partially inhibited the expression of COX-2 stimulated by PGE(2). PGE(2) could stimulate the activation of PKB, which was sensitive to phosphatidylinositol-3-OH kinase (PI3K) inhibitor, wortmannin. Whereas wortmannin alone partially inhibited the expression of COX-2, a combination of wortmannin and PD098059 totally inhibited PGE(2)-mediated COX-2 expression. These results suggest that MAP kinase and PI3K pathways are stimulated with PGE(2), and that both of these pathways are involved in the expression of COX-2. In addition, they also suggest that protein kinase A remains upstream of PGE(2)-induced activation of MAP kinase in HEC-1B cells.
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PMID:Expression of cyclooxygenase 2 by prostaglandin E(2) in human endometrial adenocarcinoma cell line HEC-1B. 1095 41

Interleukin-1 (IL-1) is an important mediator of immunoinflammatory responses in the brain. In the present study, we examined whether prostaglandin E(2) (PGE(2)) production after IL-1beta stimulation is dependent upon activation of protein kinases in astroglial cells. Astrocyte cultures stimulated with IL-1beta or the phorbol ester, PMA significantly increased PGE(2) secretion. The stimulatory action of IL-1beta on PGE(2) production was totally abolished by NS-398, a specific inhibitor of cyclo-oxygenase-2 activity, as well as by the protein synthesis inhibitor cycloheximide, and the glucocorticoid dexamethasone. Furthermore, IL-1beta induced the expression of COX-2 mRNA. This occurred early at 2 h, with a maximum at 4 h and declined at 12 h. IL-1 beta treatment also induced the expression of COX-2 protein as determined by immunoblot analysis. In that case the expression of the protein remained high at least up to 12 h. Treatment of cells with protein kinase C inhibitors (H-7, bisindolylmaleimide and calphostin C) inhibited IL-1beta stimulation of PGE(2). In addition, PKC-depleted astrocyte cultures by overnight treatment with PMA no longer responded to PMA or IL-1. The ablation of the effects of PMA and IL-1beta on PGE(2) production, likely results from down-regulation of phorbol ester sensitive-PKC isoenzymes. Immunoblot analysis demonstrated the translocation of the conventional isoform cPKC-alpha from cytosol to membrane following treatment with IL-1beta. In addition, IL-1beta treatment led to activation of extracellular signal-regulated kinase (ERK1/2) and p38 subgroups of MAP kinases in astroglial cells. Interestingly, the inhibition of ERK kinase with PD 98059, as well as the inhibition of p38 MAPK with SB 203580, prevented IL-1beta-induced PGE(2) release. ERK1/2 activation by IL-1beta was sensitive to inhibition by the PKC inhibitor bisindolylmaleimide suggesting that ERK phosphorylation is a downstream signal of PKC activation. These results suggest key roles for PKC as well as for ERK1/2 and p38 MAP kinase cascades in the biosynthesis of PGE(2), likely by regulating the induction of cyclo-oxygenase-2, in IL-1beta-stimulated astroglial cells.
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PMID:Induction of COX-2 and PGE(2) biosynthesis by IL-1beta is mediated by PKC and mitogen-activated protein kinases in murine astrocytes. 1096 82

Reducing luminal NaCl concentration in the macula densa region of the nephron stimulates renin secretion, and this response is blocked by a specific inhibitor of cyclooxygenase-2 (COX-2) (Traynor, T. R., Smart, A., Briggs, J. P., and Schnermann, J. (1999) Am. J. Physiol. Renal Physiol. 277, F706-710). To study whether low NaCl activates COX-2 activity or expression we clonally derived a macula densa cell line (MMDD1 cells) from SV-40 transgenic mice using fluorescence-activated cell sorting of renal tubular cells labeled with segment-specific fluorescent lectins. MMDD1 cells express COX-2, bNOS, NKCC2, and ROMK, but not Tamm-Horsfall protein, and showed rapid (86)Rb(+) uptake that was inhibited by a reduction in NaCl concentration and by bumetanide or furosemide. Isosmotic exposure of MMDD1 cells to low NaCl (60 mm) caused a prompt and time-dependent stimulation of prostaglandin E(2) (PGE(2)) release that was prevented by the COX-2 specific inhibitor NS-398 (10 microm). Reducing NaCl to 60 and 6 mm for 16 h increased COX-2 expression in a chloride-dependent fashion. Low NaCl phosphorylated p38 kinase within 30 min and ERK1/2 kinases within 15 min without changing total MAP kinase levels. Low NaCl-stimulated PGE(2) release and COX-2 expression was inhibited by SB 203580 and PD 98059 (10 microm), inhibitors of p38 and ERK kinase pathways. We conclude that low chloride stimulates PGE(2) release and COX-2 expression in MMDD1 cells through activation of MAP kinases.
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PMID:Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. 1098 5

1. We have investigated the contribution of specific PLA(2)s to eicosanoid release from A549 cells by using specific inhibitors of secretory PLA(2) (ONO-RS-82 and oleyloxyethylphosphocholine), cytosolic PLA(2) (AACOCF(3) and MAFP) and calcium-independent PLA(2) (HELSS, MAFP and PACOCF(3)). Similarly, by using specific inhibitors of p38 MAPK (SB 203580), ERK1/2 MAPK (Apigenin) and MEK1/2 (PD 98059) we have further evaluated potential pathways of AA release in this cell line. 2. ONO-RS-82 and oleyloxyethylphosphocholine had no significant effect on EGF or IL-1beta stimulated (3)H-AA or PGE(2) release or cell proliferation. AACOCF(3), HELSS, MAFP and PACOCF(3) significantly inhibited both EGF and IL-1beta stimulated (3)H-AA and PGE(2) release as well as cell proliferation. Apigenin and PD 98509 significantly inhibited both EGF and IL-1beta stimulated (3)H-AA and PGE(2) release and cell proliferation whereas, SB 203580 had no significant effect on EGF or IL-1beta stimulated (3)H-AA release, or cell proliferation but significantly suppressed EGF or IL-1beta stimulated PGE(2) release. 3. These results confirm that the liberation of AA release, generation of PGE(2) and cell proliferation is mediated largely through the actions of cPLA(2) whereas, sPLA(2) plays no significant role. We now also report a hitherto unsuspected contribution of iPLA(2) to this process and demonstrate that the stimulating action of EGF and IL-1beta in AA release and cell proliferation is mediated in part via a MEK and ERK-dependent pathway (but not through p38MAPK). We therefore propose that selective inhibitors of MEK and MAPK pathways may be useful in controlling AA release, eicosanoid production and cell proliferation.
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PMID:Investigation into the involvement of phospholipases A(2) and MAP kinases in modulation of AA release and cell growth in A549 cells. 1099 18


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