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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For understanding the mechanism(s) relating inflammation to corticosteroid action, the effect of tumour necrosis factor-alpha (TNF-alpha) on 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the enzyme regulating access of 11beta-hydroxycorticosteroids to receptors, was studied in LLC-PK(1) cells. We observed (i) NAD-dependent enzyme activity and mRNA for 11beta-HSD2, but not 11beta-HSD1, (ii) increasing 11beta-HSD2 activity with increasing degree of differentiation and (iii) a concentration-dependent down-regulation by TNF-alpha, phorbol myristate acetate (PMA) or glucose of activity and mRNA of 11beta-HSD2. The decrease of activity and mRNA by glucose and PMA, but not that by TNF-alpha, was abrogated by the protein kinase C inhibitor GF-109203X. The effect of TNF-alpha on 11beta-HSD2 was reversed by inhibiting the mitogen-activated protein kinases ERK with PD-098050 and p38 by SB-202190, or by activating protein kinase A with forskolin. Overexpression of MEK1, an ERK activator, down-regulated the 11beta-HSD2 activity. In conclusion, TNF-alpha decreases 11beta-HSD2 activity and thereby enhances glucocorticoid access to glucocorticoid receptors to modulate the inflammatory response.
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PMID:TNF-alpha enhances intracellular glucocorticoid availability. 1169 70

Helicobacter pylori and proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-alpha and IL-1 significantly increased gastrin mRNA in canine G cells to 181 +/- 18% and 187 +/- 28% of control, respectively, after 24 h of treatment. TNF-alpha and IL-1 stimulated gastrin promoter activity to a maximal level of 285 +/- 12% and 415 +/- 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-alpha and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.
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PMID:TNF-alpha and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms. 1170 45

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are a group of kinases that play an important role in proliferation and differentiation. In megakaryocyte-like human erythroleukemia (HEL) cells, ERK2 was found to be predominantly expressed and strongly activated by prostaglandin (PG) E(2), thrombin, and epinephrine. On the other hand, adenosine, ADP, ATP, and UTP did not significantly increase ERK1/2 phosphorylation. However, of the agonists tested, only ADP was able to stimulate thymidine uptake. Pretreatment with pertussis toxin abolished the PGE(2) response but had less of an effect on thrombin. PGE(2)- and thrombin-induced ERK1/2 activation was mimicked by 4-beta-phorbol-12-myristate-13-acetate and ionomycin and blocked by mitogen-activated protein kinase kinase inhibitor 1,4 diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene but displayed differential sensitivity to protein kinase C inhibitor bisindolylmaleimide I and Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Analogs of cAMP or agents that stimulate cAMP production were either weak or ineffective activators. Further studies indicate that the effect of thrombin was blocked by the phosphoinositide 3-kinase inhibitor wortmannin but not by agents inhibiting tyrosine kinase activity. On the contrary, herbimycin, but not wortmannin, attenuated the effect of PGE(2). Collectively, these results indicate that ERK1/2 are selectively activated by G protein-coupled receptors and not functionally associated with proliferation in HEL cells. ERK1/2 activation in response to PGE(2) and thrombin is mediated by distinctive types of G proteins and is differentially regulated by multiple pathways, including calcium mobilization, protein kinase C, phosphoinositide 3-kinase, and tyrosine kinases.
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PMID:Extracellular signal-regulated kinases and g protein-coupled receptors in megakaryocytic human erythroleukemia cells: selective activation, differential regulation, and dissociation from mitogenesis. 1175 34

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.
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PMID:Angiotensin II type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. 1179 93

The elevated level of thrombin has been detected in the airway fluids of asthmatic patients and shown to stimulate cell proliferation in tracheal smooth muscle cells (TSMCs). However, the implication of thrombin in the cell proliferation was not completely understood. In this study, thrombin stimulated [3H]thymidine incorporation and p42/p44 mitogen-activated protein kinase (MAPK) phosphorylation in a time- and concentration-dependent manner in TSMCs. Pretreatment of TSMCs with pertussis toxin (PTX) significantly inhibited [3H]thymidine incorporation and phosphorylation of MAPK induced by thrombin. These responses were attenuated by tyrosine kinase inhibitors genistein and herbimycin A, phosphatidyl inositide (PI)-phospholipase C (PLC) inhibitor U73122, protein kinase C inhibitor GF109203X, removal of Ca2+ by addition of BAPTA/AM plus EGTA, PI 3-kinase inhibitors wortmannin and LY294002, and inhibitor of MEK1/2 PD98059. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed p42/p44 MAPK activation induced by thrombin and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. These results conclude that the mitogenic effect of thrombin was mediated through the activation of Ras/Raf/MEK/MAPK pathway. Thrombin-mediated MAPK activation was modulated by PI-PLC, Ca2+, PKC, tyrosine kinase, and PI 3-kinase associated with cell proliferation in canine cultured TSMCs.
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PMID:Thrombin-stimulated cell proliferation mediated through activation of Ras/Raf/MEK/MAPK pathway in canine cultured tracheal smooth muscle cells. 1181 55

Monoamine oxidases (MAO) A and B deaminate a number of biogenic amines. Aberrant expression of MAO is implicated in several psychiatric and neurogenerative disorders. In this study, we have shown that phorbol 12-myristate 13-acetate (PMA) increases human MAO B, but not MAO A, gene expression. The sequence between -246 and -225 bp consists of overlapping binding sites (Sp1/Egr-1/Sp1) that are recognized by Sp1, Sp3, and PMA-inducible Egr-1 is essential for PMA activation. PMA transiently increases egr-1 and c-jun gene expression. Mutation studies show that Egr-1 and c-Jun transactivate the MAO B promoter and increase endogenous MAO B transcripts via the Sp1/Egr-1/Sp1 overlapping binding sites. Sp3 inhibits Sp1 and Egr-1 activation of MAO B gene expression. c-fos gene expression was increased by PMA but not involved in MAO B gene transcription. Furthermore, protein kinase C inhibitor blocks the PMA-dependent activation of MAO B. Co-transfection of the MAO B promoter with dominant negative forms of Ras, Raf-1, MEKK1, MEK1, MEK3, MEK7, ERK2, JNK1, and p38/RK inhibit the PMA-dependent activation of the MAO B promoter. These results indicate that MAO B expression is selectively induced by the activation of protein kinase C and MAPK signaling pathway and that c-Jun and Egr-1 appear to be the ultimate targets of this regulation.
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PMID:Activation of human monoamine oxidase B gene expression by a protein kinase C MAPK signal transduction pathway involves c-Jun and Egr-1. 1195 20

In response to oxidative stress, the pathogenesis of a number of cardiovascular events and several genes are stimulated by extracellular signal-regulated kinases (ERK1/2). Biphasic (early, 10 min; and delayed, 120 min) ERK1/2 activation by H(2)O(2), a reactive oxygen species, was observed in cultured neonatal rat cardiomyocytes. We investigated the hypothesis that the delayed activation of ERK1/2 depends on a factor secreted by oxidative stress (FSO). The delayed activation was inhibited by calphostin C, a protein kinase C inhibitor. Conditioned medium (CM) obtained from cells stimulated with H(2)O(2) induced rapid and monophasic ERK1/2 activation, which was not inhibited by calphostin C. In contrast, calphostin C-pretreated CM did not activate ERK1/2. Macrophage migration inhibitory factor (MIF) was one of the candidate FSOs activating ERK1/2. The existence of MIF in CM, the recombinant MIF-stimulated ERK1/2 rapid activation, and anti-MIF neutralizing antibody-induced inhibition of the delayed activation implied that MIF could be the FSO. Pretreatment of cardiomyocytes with a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor did not suppress the MIF secretion, although it prevented the ERK1/2 activation by H(2)O(2). These results indicate that MIF is secreted from cardiomyocytes as a result of oxidative stress and activates ERK1/2 through a MEK1/2-dependent mechanism, although the secretion is not regulated by ERK1/2 but by protein kinase C.
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PMID:Contribution of macrophage migration inhibitory factor to extracellular signal-regulated kinase activation by oxidative stress in cardiomyocytes. 1197 85

Activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) requires dimerization that is induced by phosphorylation of Tyr705, but its activity can be further modulated by phosphorylation at Ser727 in a manner that is dependent on cell context and the stimulus used. The role of STAT3 Ser727 phosphorylation in leptin signalling is currently not known. While cells transfected with the signalling-competent long form of the leptin receptor (ObRb) have been used to study leptin signalling, these are likely to be of limited use in studying STAT3 Ser727 phosphorylation due to the importance of cell background in determining the nature of the response. However, we have recently found that J774.2 macrophages endogenously express high levels of ObRb, and using these cells we find that leptin stimulates STAT3 phosphorylation on both Tyr705 and Ser727. The phosphorylation of Ser727 was not affected by rapamycin or the protein kinase C inhibitor H7 [1-(5-isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride]. While the MEK-1 [mitogen-activated protein kinase (MAP kinase)/extracellular-signal-related kinase (ERK) kinase-1] inhibitor PD98059 [(2-amino-3'-methoxyphenyl)oxanaphthalen-4-one] had no effect on leptin-stimulated phosphorylation of STAT3 Tyr705, it greatly attenuated leptin's effects on STAT3 Ser727 phosphorylation. Further, Ob's effect on the DNA binding activity of STAT3 was also greatly reduced at all time points by PD98059. Leptin-induced ERK activation in J774.2 cells shows a biphasic pattern, with an initial reduction in ERK phosphorylation for up to 10 min following leptin stimulation, while at later time points phosphorylation of ERK was increased above basal levels. The increase in ERK activity corresponded with an increase in both phosphorylation of Ser727 and STAT3 DNA binding activity. These data provide the first evidence that ERK-mediated phosphorylation of Ser727 is required for full stimulation of STAT3 by leptin.
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PMID:Biphasic regulation of extracellular-signal-regulated protein kinase by leptin in macrophages: role in regulating STAT3 Ser727 phosphorylation and DNA binding. 1204 54

Glutamine is an essential nutrient for gut functions, but the regulation of its uptake by intestinal mucosal cells is poorly understood. Given the pivotal role of epidermal growth factor (EGF) in regulating gut metabolism, growth, and differentiation, this in vitro study was designed to investigate the intracellular signaling pathways involved in the regulation of EGF-mediated intestinal glutamine transport in intestinal epithelia. Continuous incubation with EGF (>30 hours, 100 ng/ml) stimulated glutamine transport activity across intestinal epithelial Caco-2 cell apical membrane. Exposure to EGF for 48 hours resulted in an increase in transport activity (50%) and glutamine transport system B gene ATB(0) mRNA levels (ninefold). EGF stimulated glutamine transport activity by increasing the glutamine transporter maximal velocity (V(max)) without altering the transporter apparent affinity (K(m)). Furthermore, EGF stimulated both intracellular protein kinase C and mitogen-activated protein kinase MEK1/2 activities. The EGF-stimulated glutamine transport activity was attenuated individually by the specific protein kinase C inhibitor chelerythrine chloride and the mitogen-activated protein kinase MEK1 inhibitor PD 98059. These data suggest that EGF activates glutamine transport activity across intestinal epithelial membrane via a signaling mechanism that involves activation of protein kinase C and the mitogen-activated protein kinase MEK1/2 cascade. EGF activates glutamine transport via alterations in transporter mRNA levels and the number of functional copies of transporter units.
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PMID:Epidermal growth factor activation of intestinal glutamine transport is mediated by mitogen-activated protein kinases. 1255 96

Growth hormone (GH) promotes signaling by causing activation of the non-receptor tyrosine kinase, JAK2, which associates with the GH receptor. GH causes phosphorylation of epidermal growth factor receptor (EGFR; ErbB-1) and its family member, ErbB-2. For EGFR, JAK2-mediated GH-induced tyrosine phosphorylation may allow EGFR to serve as a scaffold for GH signaling. For ErbB-2, GH induces serine/threonine phosphorylation that dampens basal and EGF-induced ErbB-2 kinase activation. We now further explore GH-induced EGFR phosphorylation in 3T3-F442A, a preadipocytic fibroblast cell line that expresses endogenous GH receptor, EGFR, and ErbB-2. Using a monoclonal antibody that recognizes ERK consensus site phosphorylation (PTP101), we found that GH caused PTP101-reactive phosphorylation of EGFR. This GH-induced EGFR phosphorylation was prevented by MEK1 inhibitors but not by a protein kinase C inhibitor. Although GH did not discernibly affect EGF-induced EGFR tyrosine phosphorylation, we observed by immunoblotting a substantial decrease of EGF-induced EGFR degradation in the presence of GH. Fluorescence microscopy studies indicated that EGF-induced intracellular redistribution of an EGFR-cyan fluorescent protein chimera was markedly reduced by GH cotreatment, in support of the immunoblotting results. Notably, protection from EGF-induced degradation and inhibition of EGF-induced intracellular redistribution afforded by GH were both prevented by a MEK1 inhibitor, suggesting a role for GH-induced ERK activation in regulating the trafficking itinerary of the EGF-stimulated EGFR. Finally, we observed augmentation of early aspects of EGF signaling (EGF-induced ERK2 activation and EGF-induced Cbl tyrosine phosphorylation) by GH cotreatment; the GH effect on EGF-induced Cbl tyrosine phosphorylation was also prevented by MEK1 inhibition. These data indicate that GH, by activating ERKs, can modulate EGF-induced EGFR trafficking and signaling and expand our understanding of mechanisms of cross-talk between the GH and EGF signaling systems.
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PMID:Growth hormone-induced phosphorylation of epidermal growth factor (EGF) receptor in 3T3-F442A cells. Modulation of EGF-induced trafficking and signaling. 1264 95


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