Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A persistent infection with rabies virus (HEP-Flury) was established in the CNS-derived hybrid cell line 108CC15 which possesses specific membrane receptors for prostaglandins, catecholamines and acetylcholine. We report a differential virus influence on the specific receptor response to PGE, isoproterenol and acetycholine as indicated by typical changes of the intracellular cyclic AMP levels. As the adenylate cyclase activity was unchanged in infected cells in vitro, a selective virus influence on specific receptors themselves or their coupling to the cAMP synthesizing system must be considered.
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PMID:Rabies virus infection selectively impairs membrane receptor functions in neuronal model cells. 21 41

Progesterone priming of the ovariectomized rat, followed by a single injection of estradiol-17beta (10 mug) is followed by an increased uterine synthesis of both PGF and PGE. The administration of an estrogen antagonist (MER-25; 10 mg) concomitantly with estradiol had no effect on uterine prostaglandin synthesis. Similarly, the administration of either Actinomycin D or cycloheximide, antibiotics demonstrated to inhibit mRNA and protein synthesis, respectively, is without effect on estrogen-stimulated uterine prostaglandin synthesis. These results are considered with regard to the classic receptor theory of estrogen action and are a preliminary indication that estrogen-stimulated uterine prostaglandin synthesis may not require those receptor mediated events.
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PMID:Considerations into the mechanism of estrogen-stimulated uterine prostaglandin synthesis. 95 89

In the passive Heymann nephritis (PHN) model of membranous nephropathy, C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated via production of eicosanoids. Using rat GEC in culture, we demonstrated that sublytic C5b-9 induced tyrosine phosphorylation of the epidermal growth factor receptor (EGF-R), Neu, fibroblast growth factor receptor-2, and hepatocyte growth factor receptor. In addition, C5b-9 stimulated increases in tyrosine(204) phosphorylation of extracellular signal-regulated kinase-2 (ERK2), as well as free [(3)H]arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, Grb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [(3)H]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation of these pathways. Glomeruli isolated from rats with PHN demonstrated increases in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhibited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) production in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosine kinases may serve as scaffolds for assembly and/or activation of proteins, which then lead to activation of the ERK2 cascade and AA metabolism.
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PMID:Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells. 1055 Mar 26

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

Asthmatic airways are characterized by an increase in smooth muscle mass, due mainly to hyperplasia. Many studies suggest that extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2, respectively), one group of the mitogen-activated protein (MAP) kinase superfamily, play a key role in the signal transduction pathway leading to cell proliferation. PGE(2) and forskolin inhibited mitogen-induced ERK activation. Inhibition of MAP kinase kinases 1 and 2 (MEK1 and MEK2, respectively), which are upstream from ERK, with the specific MEK inhibitor U-0126 blocked both cell proliferation and ERK activation. In addition, U-0126 inhibited mitogen-induced activation of p90 ribosomal S6 kinase and expression of c-Fos and cyclin D1, all of which are downstream from ERK in the signaling cascade that leads to cell proliferation. Antisense oligodeoxynucleotides directed to ERK1 and -2 mRNAs reduced ERK protein and cell proliferation. These results indicate that ERK is required for human airway smooth muscle cell proliferation. Thus targeting the control of ERK activation may provide a new therapeutic approach for hyperplasia seen in asthma.
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PMID:ERK activation and mitogenesis in human airway smooth muscle cells. 1129 May 27

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

Prostaglandins play regulatory roles in a variety of physiological and pathological processes in immune response and inflammation. Epigallocatechin-3-gallate (EGCG) is known to potent antitumor agent with antioxidant property. We first investigated the effect of EGCG on the production of prostaglandin E(2) (PGE(2)) and the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of PGE(2), using macrophage cell line, Raw264.7. Our results showed that COX-2 expression and PGE(2) production are upregulated by EGCG treatment and that this induction of COX-2 is regulated in part at the transcriptional level. In addition, we demonstrated the signal transduction pathway of mitogen-activated protein kinase (MAP kinase) in EGCG-mediated COX-2 expression. The MEK inhibitor (PD098059) prevented EGCG-induced COX-2 expression, whereas sodium orthovanadate (protein-tyrosine phosphatase inhibitor) significantly enhanced COX-2 expression and PGE(2) production. These results suggest that EGCG mediated COX-2 expression and PGE(2) production is associated with the activation of both the ERK and protein-tyrosine phosphatase signaling pathways.
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PMID:Involvement of ERK and protein tyrosine phosphatase signaling pathways in EGCG-induced cyclooxygenase-2 expression in Raw 264.7 cells. 1152 57

Prostaglandin E(2) (PGE(2)) production involves the activity of a multistep biosynthetic pathway. The terminal components of this cascade, two PGE(2) synthases (PGES), have very recently been identified as glutathione-dependent proteins. cPGES is cytoplasmic, apparently identical to the hsp90 chaperone, p23, and associates functionally with prostaglandin-endoperoxide H synthase-1 (PGHS-1), the constitutive cyclooxygenase. A second synthase, designated mPGES, is microsomal and can be regulated. Here we demonstrate that mPGES and PGHS-2 are expressed at very low levels in untreated human orbital fibroblasts. Interleukin (IL)-1beta treatment elicits high levels of PGHS-2 and mPGES expression. The induction of both enzymes occurs at the pretranslational level, is the consequence of enhanced gene promoter activities, and can be blocked by dexamethasone (10 nm). SC58125, a PGHS-2-selective inhibitor, could attenuate the induction of mPGES, suggesting a dependence of this enzyme on PGHS-2 activity. IL-1beta treatment activates p38 and ERK mitogen-activated protein kinases. Induction of both mPGES and PGHS-2 was susceptible to either chemical inhibition or molecular interruption of these pathways with dominant negative constructs. These results indicate that the induction of PGHS-2 and mPGES by IL-1beta underlies robust PGE(2) production in orbital fibroblasts.
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PMID:Up-regulation of prostaglandin E2 synthesis by interleukin-1beta in human orbital fibroblasts involves coordinate induction of prostaglandin-endoperoxide H synthase-2 and glutathione-dependent prostaglandin E2 synthase expression. 1184 19


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