Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandin E2 (PGE2), PTH, and epidermal growth factor (EGF) are potent regulators of osteoblast proliferation. In UMR 106-01 rat osteosarcoma cells with osteoblast-like features, PGE2 and PTH inhibit, while EGF stimulates, mitogenesis. Both PGE2 and PTH increase intracellular cAMP levels, cytosolic calcium, and inositol phosphate turnover. In a variety of cell types, EGF mediates its effects in part via activation of receptor protein-tyrosine kinase and other protein kinases, such as protein kinase-C. The nuclear mechanisms of PGE2, PTH, and EGF regulation of osteoblast proliferation are unknown. Accordingly, we have examined the effects of these agents on mitogenesis, second messenger generation, and primary response genes, which may link second messenger activation to subsequent alterations in gene expression. Northern blot analysis of mRNA from UMR 106-01 cells treated for 3 h with 2 microM PGE2, 10 nM PTH, or 10 ng/ml EGF in the presence of cycloheximide demonstrated that all three agents induced the expression of c-fos and c-jun mRNA. In contrast, only EGF stimulated cellular proliferation and induced Egr-1 mRNA. Also, unlike PGE2 and PTH, EGF did not increase intracellular cAMP levels. c-fos mRNA was induced by treatment with 50 ng/ml tetradecanoyl phorbol acetate or by 40 ng/ml forskolin, while induction of Egr-1 mRNA was stimulated by treatment with tetradecanoyl phorbol acetate, but not forskolin. Thus, EGF signal transduction differs from that of PGE2 and PTH in UMR 106-01 osteoblast-like cells, in that EGF does not stimulate the protein kinase-A second messenger system, but causes activation of Egr-1, a primary response gene that may play a role in the mitogenic effect of EGF.
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PMID:The effects of prostaglandin E2, parathyroid hormone, and epidermal growth factor on mitogenesis, signaling, and primary response genes in UMR 106-01 osteoblast-like cells. 133 Apr 91

Binding of beraprost sodium (sodium dl-4-[(1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro-2-hydroxy-1-[(3S, 4RS)- 3-hydroxy-4-methyl-oct-6-yne-(E)-1-enyl] -5- cyclopenta[b]benzofuranyl]butyrate, TRK-100), a new potent antithrombotic agent, to washed platelets of humans and rats was studied. [11-3H]-TRK-100 binding was rapid, reversible, saturable, and highly specific. Scatchard analysis of concentration-dependent binding to human platelets revealed a single class of specific binding sites with an equilibrium dissociation constant (Kd) of 133 nmol/l and a maximal concentration of binding sites (Bmax) of 46 fmol/10(8) platelets (275 sites/cell). Similar binding was observed on rat platelets. The Kd and Bmax were 66 nmol/l and 124 fmol/10(8) platelets (750 sites/cell), respectively. Competitive studies indicated that TRK-100 was 1.5 times less active than prostacyclin (epoprostenol, PGI2), but was 3 times more potent than PGE1 in displacing [3H]-TRK-100 from the binding sites on rat platelets. PGE2, PGD2, PGF2 alpha, and pinane thromboxane A2, a stable thromboxane A2 analogoue, had no affinity for the binding sites. The relative affinity of the four enantiomers of TRK-100--APS-314d, 315d, 3141 and 3151--for the binding sites was 100: 14: less than 1: less than 1, respectively. These results suggest that TRK-100 is a useful tool for studying biological roles of PGI2 as well as for use as an antithrombotic agent since TRK-100 mimics its actions via specific interaction with PGI2 receptors.
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PMID:Specific binding of the new stable epoprostenol analogue beraprost sodium to prostacyclin receptors on human and rat platelets. 266 58

The effects of the active principles of crude ginger (a traditional Sino-Japanese medicine), the gingerols, on the contractile responses to eicosanoids were compared using isolated mouse and rat blood vessels. Leukotrienes (LT) C4 and D4, a thromboxane (TX) A2 derivative (U-46619), prostaglandins (PG) F2 alpha, PGI2-Na, PGE2, the stable PGI2 derivative TRK-100, and PGD2 induced contraction in longitudinal segments of mouse mesenteric veins in that order of potency. Exogenous arachidonic acid and PGE1 did not cause contraction. The mesenteric veins also contracted in response to noradrenaline (NA) and phenylephrine (PhE), but not to clonidine. The gingerols alone relaxed the muscle transiently and then augmented the response to PGF2 alpha, PGE2, PGI2-Na, and TRK-100, but suppressed the response to PGD2, U-46619, LTC4, LTD4, NA and PhE. (+/-)-[6]-Gingerol also potentiated the PGF2 alpha-induced contraction in longitudinal segments of rat mesenteric vein and vena cava, but inhibited it in circular segments of rat aorta and longitudinal segments of mouse mesenteric arteries. These results showed that (+/-)-[6]- and (+/-)-[8]-gingerols potentiated the contraction induced by prostanoids (except PGD2) and inhibited that produced by PGD2, TXA2, and LT, suggesting the modulation of eicosanoids-induced responses by (+/-)-[6]- or (+/-)-[8]-gingerol.
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PMID:Modulation of eicosanoid-induced contraction of mouse and rat blood vessels by gingerols. 276 Nov 27

Purified interleukins 1 and 2 (IL-1 and IL-2) were used to investigate their role in the production of gamma-interferon (gamma-IFN). Macrophage depletion from human peripheral blood mononuclear leukocytes (PBML) inhibited gamma-IFN production. Addition of purified IL-1 partially restored IFN production of macrophage-depleted PBML induced by three T cell mitogens (phytohemagglutinin, PHA; concanavalin A, con A; and staphylococcal enterotoxin A, SEA), but had no effect on induction of IFN production by undepleted PBML. Therefore endogenous IL-1 production by macrophages is probably one of the mechanisms by which they act as accessory cells for IFN production by lymphocytes. A monoclonal antibody 9.6 which binds to the sheep erythrocyte (E) receptor found on human T cells inhibited IFN production. Addition of IL-2, but not IL-1, was found to reverse this inhibition. Prostaglandin E2, a macrophage product, inhibited gamma-IFN production induced by PHA, Con A, and OKT3 but usually not SEA. This inhibitory effect was reversible by the addition of IL-2 but not IL-1. In the absence of mitogen IL-1 alone rarely induced any IFN production, although some IFN was produced by PBML from a small minority of donors. Without mitogen IL-2 induced IFN production only at very high concentrations and the added presence of IL-1 did not enhance this induction.
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PMID:The regulation of gamma-interferon production by interleukins 1 and 2. 310 55

U46619, a thromboxane A2 analogue, and basic fibroblast growth factor (FGF-2) both induced the expression of the inducible cyclo-oxygenase (Cox)-2 in porcine aortic smooth-muscle cells. This induction was dose-dependent (submaximal at 300 nM for U46619 and 1 ng/ml for FGF-2) and time-dependent, with similar intensity and maximal expression at 2 h. Under these conditions, both inducers stimulated rapid activation of extracellular signal-regulated kinase (ERK2) at 5-10 min, a transient and lower intensity being induced by U46619 whereas that induced by FGF-2 was sustained (>1 h). PD98059, an inhibitor of the ERK pathway, inhibited the expression of Cox-2. In contrast, activation of Jun-N-terminal kinase (JNK1) was sustained with U46619 but poorly induced by FGF-2. Cox-2 expression induced by U46619 or FGF-2 was similarly reduced by prostaglandin (PGE2), forskolin or dibutyryl-cAMP, suggesting a regulatory effect of adenylate cyclase on Cox-2 expression. However, activation of ERK2 by FGF-2 was not affected by PGE2 whereas that of JNK1 by U46619 was inhibited, suggesting that inhibition of COX-2 expression by cAMP may be downstream of ERK2. The effects of PGE2 and forskolin on Cox-2 and phosphorylation of JNK1 were reversed with the protein kinase A inhibitor H89. In addition, endogenous PGE2 down-regulated the expression of Cox-2 by the two inducers, as stimulation of the cells in the presence of different Cox inhibitors increased the expression of the protein. Overall, these results suggest that exogenous and endogenous PGE2 exert negative inhibitory effects on Cox-2 expression mediated by stimulation of protein kinase A.
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PMID:Regulatory role of prostaglandin E2 in induction of cyclo-oxygenase-2 by a thromboxane A2 analogue (U46619) and basic fibroblast growth factor in porcine aortic smooth-muscle cells. 929 Nov 37

Previous studies of hepatocyte growth factor (HGF) in the stomach are briefly reviewed. Exogenous HGF has a strong effect on proliferation and migration of gastric epithelial cells. These effects of HGF are mediated by the specific receptor c-MET. Our previous immunohistochemical study revealed that the main source of endogenous HGF in human gastric ulcer is gastric fibroblasts. These findings suggest that HGF may play an important role in the repair of gastric ulcers through a paracrine mechanism. Therefore, regulation of HGF expression by gastric fibroblasts may be important. We have demonstrated that prostaglandins (PGs) E1 and E2 strongly stimulate HGF expression by gastric fibroblasts, indicating that the clinical efficacy of PGs is mediated by HGF, PGE1 actually facilitates restitution in an in vitro gastric mucosal model consisting of gastric epithelial cells and fibroblasts, which was completely inhibited by anti-HGF antibody. In this study we investigated the effect of an anti-ulcer drug, sofalcone, on PGE2 release and HGF expression by human gastric fibroblasts in primary culture. Sofalcone induced PGE2 release by human gastric fibroblasts in a dose-dependent manner. It also stimulated HGF expression by gastric fibroblasts, indicating that PGs induced by sofalcone increased HGF expression. These findings suggest that clinical efficacy of PGs and sofalcone might be mediated, at least in part, by HGF.
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PMID:Effect of sofalcone on the expression of hepatocyte growth factor (HGF) and a brief review of HGF in the stomach. 947 23

Oxytocin (OT) induces PG synthesis by both uterine endometrial and amnion cells. We showed previously that CHO cells stably transfected with the rat oxytocin receptor (CHO-OTR cells) also synthesize PGE2 in response to OT. In the present work we have demonstrated that OTRs are coupled to both Gi and Gq/11, using immunoprecipitation of solubilized OTR complexes and ADP ribosylation. OT treatment caused the rapid phosphorylation of extracellular signal-regulated protein kinase 2 (ERK2 or p42MAPK), which was partially inhibited by pertussis toxin (PTX), consistent with OTR-Gi coupling. The PTX-insensitive portion of ERK2 phosphorylation was linked to Gq, as inhibitors of both phospholipase C (U-73122) and protein kinase C (GF-109203X) blocked OT-induced ERK2 phosphorylation. OT-stimulated c-fos expression was also mediated by ERK2 phosphorylation. The ERK-c-fos pathway has been shown to be associated with cell proliferation, but OT had no effect on [3H]thymidine uptake by CHO-OTR cells. However, inhibition of OT-induced ERK2 phosphorylation with an ERK kinase inhibitor (PD-98059) markedly reduced OT-stimulated PGE2 synthesis, pointing to the importance of ERK2 activation in OT action.
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PMID:ERK2 mediates oxytocin-stimulated PGE2 synthesis. 957 24

Lipid metabolism can play an important role in the development and progression of human cancers. We have used Syrian hamster embryo (SHE) fibroblasts as a model system to study how lipid metabolites can alter cell proliferation and apoptosis. For example, the linoleic acid metabolite 13(S)-HpODE enhances EGF-dependent growth by inhibiting de-phosphorylation of the EGFR which leads to activation of the MAP kinase pathway. In contrast, the arachidonic acid metabolite, PGE2, inhibits EGF-dependent mitogenesis and the expression of the proto-oncogenes c-myc, c-jun, and jun-B. In this study, we have investigated the mechanism by which PGE2 attenuates these responses by studying the EGF signaling cascade in SHE cells. PGE2 pretreatment caused a concentration-dependent decrease in EGF-dependent phosphorylation of MAP kinase and a corresponding inhibition of EGF-stimulated MAP kinase activity. Pretreatment of the SHE cells with PGE2 had little effect on the magnitude of EGF-dependent receptor auto-phosphorylation and the phosphorylation of GAP suggesting a down-stream target. Treatment of cells with forskolin and EGF causes similar inhibition of MAP kinase phosphorylation as observed with PGE2 and EGF. Since PGE2 elevates cAMP in these cells, it may act by altering cAMP accumulation. Raf-1 activity can be inhibited by a cAMP-dependent process. Raf-1 activity, measured by phosphorylation of Mek-1, was attenuated by the addition of PGE2. To determine if inhibition of Raf-1 activity causes inhibition of the MAP kinase pathway, cells were concomitantly incubated with PGE2 and EGF. Inhibition of MAP kinase phosphorylation was observed. From these data, we propose that in SHE cells PGE2 increases cAMP levels, which in turn causes inhibition of Raf-1 activity. The MAP kinase pathway is thus downregulated which decreases mitogenesis and proto-oncogene expression. This study demonstrates that an arachidonic acid metabolite can modulate phosphorylation and activity of key signal transduction proteins in a growth factor mitogenic pathway.
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PMID:Inhibition of EGF-dependent mitogenesis by prostaglandin E2 in Syrian hamster embryo fibroblasts. 965

While classical interactions of bacterial superantigens (SAgs) with antigen presenting cells and T cells have been studied intensively, the potential interactions of SAgs with granulocytes (PMNs) have gained much less attention. We investigated if in the bovine system SAgs have any direct or indirect influence on the fate of granulocytes, which are among those cells primarily responsible for the elimination of superantigen-producing bacteria. The tested SAgs (SEA, SEB) had no apparent direct effect on PMN viability (neutrophils and eosinophils). However, in the presence of blood mononuclear cells (MNCs), SAgs led to an accelerated death of neutrophils but not of eosinophils. Compared to medium controls, in SAg-stimulated cultures only about 20-50% of the neutrophils survived after 24 hours in vitro. Accelerated death of neutrophils required the presence of at least 10% MNC and started between 2.5-24 h after initiation of the co-culture between MNC and PMN. Minimal effective SEA concentrations ranged between 10-100 pg/l (SEB 0.1-10 ng/l). The effect could be mimicked by culture supernatants of SAg-stimulated MNCs, suggesting that direct cell-cell interactions are not required for the killing. In the human system, where we tested the role of TNF-alpha, an antibody specific for this cytokine was not able to abolish the death of human neutrophils. Brefeldin A, an inhibitor of golgi transport and cytokine secretion, which blocked the SAg-induced activation of bovine MNC did not abolish the killing of neutrophils. Blocking of nitric oxide generation or PGE2 synthesis also could not alter the SAg-induced killing of bovine neutrophils. The observed indirect negative effects of SAgs on neutrophils may provide new insights in mechanisms by which superantigens modulate the hosts immune response.
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PMID:Superantigen-dependent accelerated death of bovine neutrophilic granulocytes in vitro is mediated by blood mononuclear cells. 1120 77

Two experiments were conducted to determine the luteotropin of pregnancy in sheep and to examine autocrine and paracrine roles of progesterone and estradiol-17 beta on progesterone secretion by the ovine corpus luteum (CL). Secretion of progesterone per unit mass by day-8 or day-11 CL of the estrous cycle was similar to day-90 CL of pregnancy (P > or = 0.05). In experiment 1, secretion of progesterone in vitro by slices of CL from ewes on day-8 of the estrous cycle was increased (P < or = 0.05) by LH or PGE2. Secretion of progesterone in vitro by CL slices from day-90 pregnant ewes was not affected by LH (P > or = 0.05) while PGE2 increased (P < or = 0.05) secretion of progesterone. Day 8 ovine CL of the estrous cycle did not secrete (P > or = 0.05) detectable quantities of PGF2alpha or PGE while day-90 ovine CL of pregnancy secreted PGE (P < or = 0.05) but not PGF2alpha. Secretion of progesterone and PGE in vitro by day-90 CL of pregnancy was decreased (P < or = 0.05) by indomethacin. The addition of PGE2, but not LH, in combination with indomethacin overcame the decreases in progesterone by indomethacin (P < or = 0.05). In experiment 2, secretion of progesterone in vitro by day-11 CL of the estrous cycle was increased at 4-h (P < or = 0.05) in the absence of treatments. Both day-11 CL of the estrous cycle and day-90 CL of pregnancy secreted detectable quantities of PGE and PGF2alpha (P < or = 0.05). In experiment 1, PGF2alpha secretion by day-8 CL of the estrous cycle and day-90 ovine CL of pregnancy was undetectable, but was detectable in experiment 2 by day-90 CL. Day 90 ovine CL of pregnancy also secreted more PGE than day-11 CL of the estrous cycle (P < or = 0.05), whereas day-8 CL of the estrous cycle did not secrete detectable quantities of PGE (P > or = 0.05). Trilostane, mifepristone, or MER-25 did not affect secretion of progesterone, PGE, or PGF2alpha by day- 11 CL of the estrous cycle or day-90 CL of pregnancy (P > or = 0.05). It is concluded that PGE2, not LH, is the luteotropin at day-90 of pregnancy in sheep and that progesterone does not modify the response to luteotropins. Thus, we found no evidence for an autocrine or paracrine role for progesterone or estradiol-17 36 on luteal secretion of progesterone, PGE or PGF2alpha.
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PMID:Effects of indomethacin, luteinizing hormone (LH), prostaglandin E2 (PGE2), trilostane, mifepristone, ethamoxytriphetol (MER-25) on secretion of prostaglandin E (PGE), prostaglandin F2alpha (PGF2alpha) and progesterone by ovine corpora lutea of pregnancy or the estrous cycle. 1130 96


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