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)

Infection of epithelial-derived cells by adenovirus vectors has myriad effects on cellular behavior and function. Some are relevant to the desired effect of the encoded transgene and therapeutic goals of gene therapy approach. The current experiments describe the induction of COX-2 protein and PGE-2 production by non-small cell lung cancer (NSCLC) cells following infection with a first generation (DeltaE1, DeltaE3) Ad vector. COX-2 overexpression by malignant cells has been shown to enhance cellular invasion, induce angiogenesis, regulate anti-apoptotic cellular defenses and augment immunologic resistance through production of PGE-2. Data show DeltaE1, DeltaE3, Ad5 vector infection induces dose-dependent increases in PGE-2 production by NSCLC cell lines. Data with UV/psoralen inactivated vectors and control vectors show this effect is dependent on Ad vector gene expression, but independent of the transgene expressed. Selective blockade of ERK with PD98029 abrogated induction of PGE-2 by Ad vectors. Consistent with these data, detectable increases in COX-2 protein were seen at 48 h after infection by Western blot that were paralleled by increases in the phosphorylation of ERK-1/2. UV/psoralen-inactivated vector did not induce COX-2 protein or ERK phosphorylation at 48 h. Further, an inhibitor of NF-kappa B (NFkappaB) translocation to the nucleus, SN50, had no effect on PGE-2 levels. In contrast, Ad vector infection did induce NFkappaB activity measured by NFkappaB-luciferase reporter plasmid, transfected into a NSCLC cell line. Collectively the data indicate DeltaE1, DeltaE3, Ad5 vector infection leads to ERK phosphorylation with parallel increases in COX-2 protein and PGE-2 production. These effects appear unrelated to NFkappaB and are dependent on gene expression by the vector. This information may need to be considered when defining targets for cancer gene therapy and/or the choice of viral vector.
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PMID:Induction of cyclo-oxygenase-2 in non-small cell lung cancer cells by infection with DeltaE1, DeltaE3 recombinant adenovirus vectors. 1185 Jul 26

The RON receptor tyrosine kinase is activated by macrophage-stimulating protein, which regulates macrophage migration, phagocytosis, and nitric oxide production. We report here the inhibitory effect of RON on lipopolysaccharide (LPS)-induced cyclooxygenase (Cox)-2 expression in mouse macrophages. In RON-expressing macrophages treated with macrophage stimulating protein, LPS-induced prostaglandin E(2) (PGE(2)) production was significantly reduced. The inhibition was accompanied by reduction of Cox-2 protein and mRNA expression. Transcriptional studies indicated that RON activation inhibits LPS-induced luciferase activity driven by the Cox-2 gene promoter. To determine whether RON activation affects LPS-induced NF-kappa B pathway, which is important for Cox-2 expression. Western blot analyses were performed showing that RON activation inhibits LPS-induced I kappa B alpha degradation. The decreased I kappa B alpha degradation was due to reduced I kappa B alpha phosphorylation at Ser-32 as determined by I kappa B alpha (Ser-32) phosphor-antibody. Moreover, we found that LPS-induced IKK beta activity, an enzyme responsible for phosphorylation of I kappa B alpha, was inhibited upon RON activation. Interestingly, these inhibitory effects were not regulated by RON-mediated phosphatidylinositol-3 kinase. These results suggest that RON activation inhibits LPS-induced macrophage Cox-2 expression. The inhibitory effect is mediated by impairing LPS-activated cascade enzymes that activate NF-kappa B. The inhibition of Cox-2 expression might represent a novel mechanism for the inhibitory functions of RON in vivo against LPS-induced inflammation and septic shock.
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PMID:Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein inhibits inducible cyclooxygenase-2 expression in murine macrophages. 1217 64

Vomitoxin (VT) and other trichothecene mycotoxins mediate a broad range of immunotoxic effects via the induction of inflammation-associated genes in leukocytes. The purpose of this study was to test the hypothesis that VT induces cyclooxygenase-2 (COX-2) gene expression in macrophages and that this is regulated at the level of mitogen-activated protein kinases (MAPKs). Exposure of the murine macrophage cell line RAW 264.7 to 50-250 ng/ml VT for 24 h markedly enhanced the production of prostaglandin E(2) (PGE(2)), a major COX-2 metabolite. PGE(2) elevation was preceded by increases in COX-2 mRNA (2 h) and COX-2 protein (15 h) in VT-treated cells. VT induced rapid (15 min) and persistent (up to 240 min) phosphorylation of extracellular, signal regulated protein kinases 1 and 2 (ERK1/2) and p38 MAPK as well as a rapid (15 min) but transient (up to 60 min) phosphorylation of c-Jun N-terminal kinases 1 and 2 (JNK1/2). The ERK inhibitor PD98059 and p38 inhibitor SB203580 suppressed VT-induced PGE(2) and COX-2 protein expression, whereas impairment of JNK function by transient transfection with a dominant negative (dn) JNK vector had no effect on COX-2 protein expression. Relatedly, in cells transfected with a COX-2 promoter-luciferase construct, PD98059- and SB203580-, but not dnJNK-treatment, suppressed VT-induced luciferase transcription. VT also increased COX-2 mRNA stability, and this was inhibited by PD98059 but not by SB203580. Taken together, these results indicate that VT-induced PGE(2) production and COX-2 expression by elevating transcriptional activity and mRNA stability. Enhanced transcriptional activity was modulated by ERK and p38 signaling pathways, whereas mRNA stability was promoted exclusively by VT-activated p38 phosphorylation. These data provide insight into possible general mechanisms by which VT and other trichlothecenes upregulate proinflammatory genes and impart immunotoxicity.
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PMID:Vomitoxin-induced cyclooxygenase-2 gene expression in macrophages mediated by activation of ERK and p38 but not JNK mitogen-activated protein kinases. 1237 76

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the progressive enlargement of cysts derived from tubules. Tubule cell proliferation and chloride-dependent fluid accumulation, mechanisms underlying cyst expansion, are accelerated by adenosine 3':5'-cyclic monophosphate (cAMP). This study examined the extent to which caffeine may stimulate the production of cAMP by cyst epithelial cells, thereby adversely increasing proliferation and fluid secretion. Mural epithelial cells from ADPKD cysts and normal human kidney cortex cells (HKC) were cultured, and cAMP levels were determined in response to caffeine and receptor-mediated agonists linked to adenylyl cyclase. Caffeine, a methylxanthine, slightly increased basal levels of cAMP, as did other nonselective phosphodiesterase (PDE) inhibitors, 1-methyl-3- isobutyl xanthine and theophylline and rolipram, a specific PDE IV inhibitor. More importantly, clinically relevant concentrations of caffeine (10 to 50 micro M) potentiated the effects of desmopressin (DDAVP), prostaglandin E(2) (PGE(2)), and isoproterenol to increase cAMP levels in both ADPKD and HKC cells. By contrast, at concentrations that augmented the DDAVP response, caffeine attenuated cAMP accumulation by adenosine, implicating an action apart from the inhibition of PDE. Caffeine enhanced the effect of DDAVP to stimulate transepithelial short-circuit current of polarized ADPKD monolayers, reflecting an increase in chloride secretion. Caffeine potentiated the effect of DDAVP and PGE(2) to increase the levels of phosphorylated extracellular signal-regulated kinase (P-ERK). By contrast, P-ERK levels in HKC cells were not raised by increased intracellular concentrations of cAMP. It is concluded that PDE inhibition by caffeine increases the accumulation of cAMP, and through this mechanism activates the ERK pathway to cellular proliferation and increases transepithelial fluid secretion in ADPKD cystic epithelium. Caffeine is, therefore, a risk factor for the promotion of cyst enlargement in patients with ADPKD.
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PMID:The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease. 1239 42

Although large amounts of epidermal growth factor (EGF) are found in the synovial fluids of arthritic cartilage, the role of EGF in arthritis is not clearly understood. This study investigated the effect of EGF on differentiation and on inflammatory responses such as cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) production in articular chondrocytes. EGF caused a loss of differentiated chondrocyte phenotype as demonstrated by inhibition of type II collagen expression and proteoglycan synthesis. EGF also induced COX-2 expression and PGE(2) production. EGF-induced dedifferentiation was caused by EGF receptor-mediated activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) but not p38 kinase, whereas the activation of both ERK1/2 and p38 kinase was necessary for COX-2 expression and PGE(2) production. Neither the inhibition of COX-2 expression and PGE(2) production nor the addition of exogenous PGE(2) affected EGF-induced dedifferentiation. However, COX-2 expression and PGE(2) production were significantly enhanced in chondrocytes that were dedifferentiated by serial subculture, and EGF also potentiated COX-2 expression and PGE(2) production, although these cells were less sensitive to EGF. Dedifferentiation-induced COX-2 expression and PGE(2) production were mediated by ERK1/2 and p38 kinase signaling. Our results indicate that EGF in articular chondrocytes stimulates COX-2 expression and PGE(2) production via ERK and p38 kinase signaling in association with differentiation status.
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PMID:Differentiation status-dependent regulation of cyclooxygenase-2 expression and prostaglandin E2 production by epidermal growth factor via mitogen-activated protein kinase in articular chondrocytes. 1249 46

Successful implantation requires synergism between the developing embryo and the receptive endometrium. In the baboon, infusion of chorionic gonadotropin (CG) modulates both morphology and physiology of the epithelial and stromal cells of the receptive endometrium. This study explored the signal transduction pathways activated by CG in endometrial epithelial cells from baboon (BE) and human (HES). Incubations of BE and HES cells with CG did not significantly alter adenylyl cyclase activity or increase intracellular cAMP when compared with Chinese hamster ovarian cells stably transfected with the full-length human CG/luteinizing hormone (LH) receptor (CHO-LH cells). However, in BE and HES cells, CG induced the phosphorylation of several proteins, among them, extracellular signal-regulated protein kinases 1 and 2 (ERK 1/2). Phosphorylation of ERK 1/2 in uterine epithelial cells was protein kinase A (PKA) independent. This novel signaling pathway is functional because, in response to CG stimulation, prostaglandin E(2) (PGE(2)) was released into the media and increased significantly 2 h following CG stimulation. CG-stimulated PGE(2) synthesis in epithelial cells was inhibited by a specific mitogen-activated protein kinase (MEK 1/2) inhibitor, PD 98059. In conclusion, immediate signal transduction pathways induced by CG in endometrial epithelial cells are cAMP independent and stimulate phosphorylation of ERK 1/2 via a MEK 1/2 pathway, leading to an increase in PGE(2) release as the possible result of cyclooxygenase-2 activation.
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PMID:Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. 1253 8

Interleukin (IL)-9 is a pleiotropic cytokine that has been proposed as a candidate gene for asthma. As IL-9 expression is correlated with airway hyperresponsiveness in animals, we examined the effects of IL-9 on cultured human airway smooth muscle (HASM) cells. IL-9 alone had no effect on IL-8 release, but at concentrations of > or =30 ng/ml, IL-9 significantly increased IL-8 release induced by TNF-alpha. IL-9 increased phosphorylation of extracellular signal-regulated protein kinase (ERK, p42 and p44) in a concentration- and time-dependent fashion, and U-0126 (10 micro M), which inhibits ERK phosphorylation, abolished the synergism between TNF-alpha and IL-9 on IL-8 release. IL-9 alone had no effect on eotaxin release into HASM cell supernatants but at concentrations of > or =10 ng/ml caused an approximately 50% increase in release of eotaxin evoked by IL-13 (10 ng/ml). U-0126 blocked the synergism between IL-9 and IL-13 on eotaxin release. IL-9 had no effect on cyclooxygenase-2 (COX-2) expression or PGE(2) release and did not augment the COX-2 expression that was induced by IL-1beta. Our results indicate that airway smooth muscle is a target for IL-9 and that IL-9 amplifies the potential for these cells to recruit eosinophils and neutrophils into the airways by a mechanism involving ERK.
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PMID:Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. 1258 3

Extracellular ATP is a pro-inflammatory mediator involved in the release of prostaglandin from articular chondrocytes, but little is known about its effects on intracellular signaling. ATP triggered the rapid release of prostaglandin E(2) (PGE(2)) by acting on P2Y(2) receptors in rabbit articular chondrocytes. We have explored the signaling events involved in this synthesis. ATP significantly increased arachidonic acid production, which involved the activation of the 85-kDa cytosolic phospholipase A(2) (cPLA(2)) but not a secreted form of PLA(2), as demonstrated by various PLA(2) inhibitors and translocation experiments. We also showed that ATP induced the phosphorylation of p38 and ERK1/2 mitogen-activated-protein kinases (MAPKs). Both PD98059, an inhibitor of the ERK pathway, and SB203580, an inhibitor of p38 MAPK, completely inhibited the ATP-induced release of PGE(2). Finally, dominant-negative plasmids encoding p38 and ERK transfected alone into the cells impaired the ATP-induced release of PGE(2) to about the same extent as both plasmids transfected together. These results suggest that PGE(2) production induced by ATP requires the activation of both ERK1/2 and p38 MAPKs. Thus, ATP acts via P2Y(2)-purine receptors to recruit cPLA(2) by activating both ERK1/2 and p38 MAPKs and stimulates the release of PGE(2) from articular chondrocytes.
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PMID:Concomitant recruitment of ERK1/2 and p38 MAPK signalling pathway is required for activation of cytoplasmic phospholipase A2 via ATP in articular chondrocytes. 1259 27

Signal transduction events in monocyte matrix metalloproteinase (MMP) production have been shown to include a PGE(2)-cAMP-dependent step. To determine earlier pathway components, we examined the role of mitogen-activated protein kinases (MAPKs) in the regulation of monocyte MMP-1 and MMP-9, two major MMPs induced by LPS. Stimulation with LPS resulted in the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen-activated kinase p38. The p38-specific inhibitor SB203580 suppressed p38 activity and MMP-1 mRNA and protein, but increased ERK activity and MMP-9 mRNA and protein. In contrast, the MAPK kinase 1/2-specific inhibitor PD98059 inhibited MMP-1 and MMP-9. However, both MAPK inhibitors decreased the production of cyclooxygenase-2 and PGE(2), but only the inhibition of MMP-1 by SB203580 was reversed by PGE(2) or dibutyryl cAMP. Examination of the effect of these MAPK inhibitors on the promoters of MMP-1 and MMP-9 revealed that PD98059 inhibited the binding of transcription factors to all of the MMP promoter-specific complementary oligonucleotides tested. However, SB203580 only inhibited the binding of MMP-1-specific CREB and SP 1 oligonucleotides, which was reversed by PGE(2). Additionally, SB203580 enhanced transcription factor binding to the oligonucleotides complementary to a NF-kappaB site in the promoter of MMP-9. Thus, LPS induction of MMP-1 production by monocytes is regulated by both ERK1/2 and p38, whereas MMP-9 stimulation occurred mainly through the ERK1/2 pathway. Moreover, p38 regulates MMP-1 mainly through a PGE(2)-dependent pathway, whereas ERK1/2-mediated MMP-1 and MMP-9 production involves the activation of additional MMP promoter sites through a PGE(2)-independent mechanism.
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PMID:Differential regulation of lipopolysaccharide-induced monocyte matrix metalloproteinase (MMP)-1 and MMP-9 by p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. 1279 56

Steroidogenic acute regulatory protein (StAR) regulates the first committed step in the biosynthesis of steroids, and thus aberrant expression of StAR in endometriotic implants plays a critical role in the etiology of endometriosis. However, the mechanism responsible for abnormal expression of StAR in ectopic endometriotic tissues remains unknown. In the present study, we demonstrate that prostaglandin (PG) E(2) stimulates StAR protein expression at the cellular and molecular levels. PGE(2) caused a rapid increase in StAR expression that involves activation of the EP2 receptor-coupled protein kinase A pathway. Activation of EP2 receptor-induced phosphorylation of ERK and cAMP response element binding protein (CREB). However, activation of ERK did not involve in CREB phosphorylation or concomitantly StAR expression. Phosphorylation of CREB induced by PGE(2) increased the recruitment of CREB binding protein and thus histone H3 acetylation. Chromatin immunoprecipitation experiments showed that acetylated histone H3 bound to the proximal region of the StAR promoter was increased after 30 min treatment with PGE(2), and this was mirrored by an increase in nascent StAR RNA transcription. Treatment with the histone deacetylase inhibitor, tricostatin A, enhanced PGE(2)-induced nascent StAR RNA transcription. We conclude that increased histone H3 acetylation involving the EP2 receptor, protein kinase A, CREB, and CREB binding protein is responsible for PGE(2)-induced StAR gene activation in endometriotic stromal cells. Our current report may provide new insights in understanding mechanism of abnormally local production of estrogen and the etiology of endometriosis.
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PMID:Transactivation of steroidogenic acute regulatory protein in human endometriotic stromalcells is mediated by the prostaglandin EP2 receptor. 1293 67


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