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)

Diabetic retinopathy induces an inflammatory response in the retina characterized by an increase in inflammatory cytokines and the activation of microglia. The degree of microglia activation may influence the extent of retina injury following retinal metabolic stress. We have previously shown that DR rats have elevated levels of advanced glycation end products (AGEs) in their blood. We have also suggested that AGEs might be involved in microglial activation and production of tumor necrosis factor alpha (TNF alpha). In this study, we attempted to confirm that AGEs induce the release of TNF alpha from rat retinal microglia using an in vitro microglia culture system, and concurrently to explore the mediating mechanisms. AGEs increased the protein secretion and mRNA expression of TNF alpha in cultured rat retinal microglia. These effects of AGEs were primarily mediated by reactive oxygen species (ROS). Furthermore, the inhibitors for mitogen-activated protein kinases (MAPK; p38, JNK and ERK 1/2) and nuclear factor-kB (NF-kB) could significantly decrease AGEs-induced TNF alpha release. AGEs-activated microglia showed an increase of NF-kB p65 nuclear translocation. These observations indicated that pathophysiological levels of AGEs may alter rat retinal microglia function by up-regulating TNF alpha expression and release via enhanced formation of intracellular ROS. AGEs-induced ROS subsequently activates MAPK (p38, JNK and ERK1/2) and NF-kB.
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PMID:AGEs mediated expression and secretion of TNF alpha in rat retinal microglia. 1770 71

In this report we characterize the mechanism of Rac-mediated cyclin D1 gene expression in mouse embryonic fibroblasts. Activated Rac strongly stimulated cyclin D1 gene transcription but did not alter the half-life of cyclin D1 mRNA. Inhibition of NFkappaB signaling with the IkappaB super-repressor blocked the Rac-dependent expression of cyclin D1 mRNA, and this effect was selective since ERK-dependent cyclin D1 mRNA induction was minimally affected by super-repressor expression. However, we found that p65 activity in this system was induced by serum and not by activated Rac. Moreover, mouse cyclin D1 promoter-luciferase assays showed that Rac stimulated cyclin D1 gene expression without activating NFkappaB and that an essential Rac-regulated promoter element is located far upstream or downstream of the cyclin D1 transcription start site. We conclude that, in MEFs, Rac-mediated induction of cyclin D1 mRNA requires activation of a parallel NFkappaB pathway whereas ERK induces cyclin D1 transcription independent of NFkappaB.
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PMID:NFkappaB-independent signaling to the cyclin D1 gene by Rac. 1742 54

Processes of human labour include increased oxidative stress, formation of inflammatory mediators (e.g. cytokines) and uterotonic phospholipid metabolites (e.g. prostaglandins). In non-gestational tissues, advanced glycation endproducts (AGE) induce the expression of pro-inflammatory molecules through mitogen-activated protein kinase and nuclear factor kappaB (NF-kappaB)-dependent pathways. Thus, the aim of this study was to investigate the effects of AGE on 8-isoprostane (a marker of oxidative stress), pro-inflammatory cytokine and prostaglandin release in human gestational tissues, and to define the signalling pathways involved. Human placenta and gestational membranes (amnion and choriodecidua combined; n=5) were incubated in the absence or presence of AGE-BSA (0.25, 0.5, 1 and 2 mg/ml) for 18 h. AGE significantly increased in vitro release of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, prostaglandin (PG)E(2), PGF(2alpha) and 8-isoprostane from human placenta and gestational membranes. This was associated with a concomitant increase in NF-kappaB p65 activation and ERK 1/2 phosphorylation. AGE-stimulated 8-isoprostane, cytokine and prostaglandin production was significantly suppressed by the ERK 1/2 inhibitor U0126 and the NF-kappaB inhibitor BAY 11-7082. In conclusion, AGE mediates inflammatory actions in human gestational tissues. Protein kinases and the NF-kappaB pathway play an essential role in AGE signalling in human gestational tissues.
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PMID:Advanced glycation endproducts mediate pro-inflammatory actions in human gestational tissues via nuclear factor-kappaB and extracellular signal-regulated kinase 1/2. 1747 May 18

The heart is a resistin target tissue and can function as an autocrine organ. We sought to investigate whether cyclic mechanical stretch could induce resistin expression in cardiomyocytes and to test whether there is a link between the stretch-induced TNF-alpha and resistin. Neonatal Wistar rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation at 60 cycles/min. Cyclic stretch significantly increased resistin protein and mRNA expression after 2-18 h of stretch. Addition of PD-98059, TNF-alpha antibody, TNF-alpha receptor antibody, and ERK MAP kinase small interfering RNA 30 min before stretch inhibited the induction of resistin protein. Cyclic stretch increased, whereas PD-98059 abolished, the phosphorylated ERK protein. Gel-shift assay showed a significant increase in DNA-protein binding activity of NF-kappaB after stretch, and PD-98059 abolished the DNA-protein binding activity induced by cyclic stretch. DNA binding complexes induced by cyclic stretch could be supershifted by p65 monoclonal antibody. Cyclic stretch increased resistin promoter activity, whereas PD-98059 and p65 antibody decreased resistin promoter activity. Cyclic stretch significantly increased TNF-alpha secretion from myocytes. Recombinant resistin protein and conditioned medium from stretched cardiomyocytes reduced glucose uptake in cardiomyocytes, and recombinant small interfering RNA of resistin or TNF-alpha antibody reversed glucose uptake. In conclusion, cyclic mechanical stretch enhances resistin expression in cultured rat neonatal cardiomyocytes. The stretch-induced resistin is mediated by TNF-alpha, at least in part, through ERK MAP kinase and NF-kappaB pathways. Glucose uptake in cardiomyocytes was reduced by resistin upregulation.
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PMID:Mechanical stretch enhances the expression of resistin gene in cultured cardiomyocytes via tumor necrosis factor-alpha. 1757 61

Inflammatory processes are implicated in gastric cancer development. In contrast, the role of inflammation and proinflammatory cytokines in established cancer remains to be clarified. We investigated the contribution of IL-17A versus IL-17F-mediated intracellular signalling pathways in human gastric adenocarcinoma AGS cells. IL-8 secretion was evaluated by ELISA, mitogen-activated protein kinase (MAPK)(4) by Western blotting, and activator protein 1(AP-1) and nuclear factor kappa B (NFkappaB) by TransAM transcription factor assay or qRT-PCR. IL-17RA and IL-17RC inhibition were achieved by small interfering RNA (siRNA). IL-17A significantly induced activation of all three MAPK (ERK, p38 and JNK) and downstream transcription factors AP-1 and p65 NFkappaB. IL-17F was less potent but induced a significant activation of p65 NFkappaB. Consistently, IL-17A was more potent to induce IL-8 secretion than IL-17F. Inhibition of either IL-17RA or IL-17RC expression via siRNA led to near complete abrogation of IL-17A-mediated c-Jun and p65 activation. These data suggest that in gastric cancer, absence of either IL-17RA or IL-17RC can inhibit IL-17 responsiveness. Conversely, downstream of IL-17R binding, IL-17A and IL-17F induce key signal transduction pathways implicated in inflammation and carcinogenesis. IL-17A, and possibly IL-17F, may contribute to amplification and persistence of inflammatory processes implicated in inflammation-associated cancer.
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PMID:IL-17A versus IL-17F induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in AGS gastric adenocarcinoma cells. 1764 50

Progastrin (PG) exerts proliferative and antiapoptotic effects on intestinal epithelial and colon cancer cells via Annexin II (ANX-II). In here, we show that ANX-II similarly mediates proliferative and antiapoptotic effects of PG on a pancreatic cancer cell line, AR42J. The role of several signaling molecules was examined in delineating the biological activity of PG. PG (0.1-1.0 nmol/L) caused a significant increase (2- to 5-fold) in the phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt (Thr(308)), p38 mitogen-activated protein kinase (MAPK; Thr(180)/Tyr(182)), extracellular signal-regulated kinases (ERK; Thr(202)/Tyr(204)), IkappaB kinase alpha/beta (IKKalpha/beta; Ser(176)/(180)), IkappaBalpha (Ser(32)), and p65 nuclear factor-kappaB (NF-kappaB; Ser(536)). Inhibition of p44/42 ERKs (PD98059), p38 MAPK (SB203580), Akt, and PI3K (LY294002), individually or combined, partially reversed antiapoptotic effects of PG. The kinetics of phosphorylation of IKKalpha/beta in response to PG matched the kinetics of phosphorylation and degradation of IkappaBalpha and correlated with phosphorylation, nuclear translocation, and activation of p65 NF-kappaB. NF-kappaB essential modulator-binding domain peptide (an inhibitor of IKKalpha/beta) effectively blocked the activity of p65 NF-kappaB in response to PG. Activation of p65 NF-kappaB, in response to PG, was 70% to 80% dependent on phosphorylation of MAPK/ERK and PI3K/Akt molecules. Down-regulation of p65 NF-kappaB by specific small interfering RNA resulted in the loss of antiapoptotic effects of PG on AR42J cells. These studies show for the first time that the canonical pathway of activation of p65 NF-kappaB mediates antiapoptotic effects of PG. Therefore, targeting PG and/or p65 NF-kappaB may be useful for treating cancers, which are dependent on autocrine or circulating PGs for their growth.
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PMID:Antiapoptotic effects of progastrin on pancreatic cancer cells are mediated by sustained activation of nuclear factor-{kappa}B. 1767 Nov 95

Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth.
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PMID:Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways. 1789 81

Matrix metalloproteinases (MMPs) degrade collagen and mediate tissue remodeling. The novel cytokine IL-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP-1 expression in primary human cardiac fibroblasts (HCF) and delineated the signaling pathways involved. HCF were treated with recombinant human IL-17. MMP-1 expression was analyzed by Northern blotting, RT-quantitative PCR, Western blotting, and ELISA; transcriptional induction and transcription factor binding by EMSA, ELISA, and reporter assay; and p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, small interfering RNA (siRNA), and adenoviral dominant-negative expression vectors. IL-17 stimulated MMP-1 gene transcription, net mRNA levels, protein, and promoter-reporter activity in HCF. This response was blocked by IL-17 receptor-Fc chimera and IL-17 receptor antibodies, but not by IL-6, TNF-alpha, or IL-1beta antibodies. IL-17-stimulated type I collagenase activity was inhibited by the MMP inhibitor GM-6001 and by siRNA-mediated MMP-1 knockdown. IL-17 stimulated activator protein-1 [AP-1 (c-Fos, c-Jun, and Fra-1)], NF-kappaB (p50 and p65), and CCAAT enhancer-binding protein (C/EBP)-beta DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominant-negative signaling proteins. Inhibition of AP-1, NF-kappaB, or C/EBP activation attenuated IL-17-stimulated MMP-1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB-203580 and PD-98059 blunted IL-17-mediated transcription factor activation and MMP-1 expression. Our data indicate that IL-17 induces MMP-1 in human cardiac fibroblasts directly via p38 MAPK- and ERK-dependent AP-1, NF-kappaB, and C/EBP-beta activation and suggest that IL-17 may play a critical role in myocardial remodeling.
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PMID:IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-beta , NF-kappaB, and AP-1 activation. 1792 24

Smooth muscle cell (SMC) migration plays an important role in normal angiogenesis and is relevant to disease-related vascular remodeling in conditions such as brain arteriovenous malformations, pulmonary hypertension, arteriosclerosis, and restenosis after angioplasty. In this present study, we showed that tanshinone IIA, the major lipid-soluble pharmacological constituent of Salvia miltiorrhiza BUNGE, inhibits human aortic smooth muscle cell (HASMC) migration and MMP-9 activity. Tanshinone IIA significantly inhibited IkappaBalpha phosphorylation and p65 nuclear translocation through inhibition of AKT phosphorylation. Tanshinone IIA inhibited TNF-alpha-induced ERK and c-jun phosphorylation, but not other MAPKs such as JNK and p38. Tanshinone IIA also inhibited NF-kappaB and AP-1 DNA-binding. Moreover, tanshinone IIA inhibited the migration of TNF-alpha-induced HASMCs. Our results provide evidence that tanshinone IIA has multiple effects in the inhibition of HASMC migration and may offer a therapeutic approach to block HASMC migration.
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PMID:Tanshinone IIA from Salvia miltiorrhiza BUNGE inhibits human aortic smooth muscle cell migration and MMP-9 activity through AKT signaling pathway. 1797 38

Efficient clearance of apoptotic cells is essential for tissue homeostasis, allowing for cellular turnover without inflammatory consequences. The Mer (Nyk and c-Eyk) receptor tyrosine kinase (Mertk) is involved in two aspects of apoptotic cell clearance by acting as a receptor for Gas6, a gamma-carboxylated phosphatidylserine-binding protein that bridges apoptotic and viable cells. First, Mertk acts in a bona fide engulfment pathway in concert with alphavbeta5 integrin by regulating cytoskeletal assemblages, and second, it acts as a negative regulator for inflammation by down-modulating pro-inflammatory signals mediated from bacterial lipopolysaccharide-Toll-like receptor 4 (TLR4) signaling, and hence recapitulating anti-inflammatory immune modulation by apoptotic cells. Here we describe Mertk post-receptor events that govern phagocytosis and cytoskeletal signaling are principally mediated by autophosphorylation site Tyr-867. Using the Mertk Y867F mutant and pharmacological inhibitors, we show that Tyr-867 is required for phosphatidylinositol 3-kinase and phospholipase Cgamma2 activation; their activation in turn elicits protein kinase C-dependent signals that act on the actin cytoskeleton. Although Mertk(Y867F) blocked the tyrosine phosphorylation of FAK on Tyr-861 and p130(cas) and also abrogated the phagocytosis of apoptotic cells, this mutant did not suppress lipopolysaccharide-inducible NF-kappaB transcription, nor was NF-kappaB activation dependent on the protein kinase C inhibitor, calphostin C. Finally, unlike the cytoskeletal events associated with Tyr-867 autophosphorylation, the trans-inhibition of NF-kappaB occurred in a postnuclear-dependent fashion independent of cytosolic IkappaB phosphorylation and p65/RelA sequestration. Taken together, these data suggest that Mertk has distinct and separable effects for phagocytosis and for resolving inflammation, providing a molecular rationale for how immune licensing and inflammation can be dissociated from phagocytosis in a single phagocytic receptor.
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PMID:Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation. 1803 60


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