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)

In cultured rat vascular smooth muscle cells, sustained activation of ERK is required for interleukin-1beta to persistently activate NF-kappaB. Without ERK activation, interleukin-1beta induces only acute and transient NF-kappaB activation. The present study examined whether the temporal control of NF-kappaB activation by ERK could differentially regulate the expression of NF-kappaB-dependent genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1), and manganese-containing superoxide dismutase (Mn-SOD). Treatment of vascular smooth muscle cells with interleukin-1beta induced the expression of iNOS, COX-2, VCAM-1, and Mn-SOD in a time-dependent manner, but with different patterns. Either PD98059 or U0126, selective inhibitors of MEK, or overexpression of a dominant negative MEK-1 inhibited interleukin-1beta- induced ERK activation and the expression of iNOS and COX-2 but had essentially no effect on the expression of VCAM-1 and Mn-SOD. The expression of these genes was inhibited when NF-kappaB activation was down-regulated by MG132, a proteasome inhibitor, or by overexpression of an I-kappaBalpha mutant that prevented both the transient and the persistent activation of NF-kappaB. Inhibition of ERK did not affect interleukin-1beta-induced I-kappaBalpha phosphorylation and degradation but attenuated I-kappaBbeta degradation. Thus, although NF-kappaB activation was essential for interleukin-1beta induction of each of the proteins studied, gene expression was differentially regulated by ERK and by the duration of NF-kappaB activation. These results reveal a novel functional role for ERK as an important temporal regulator of NF-kappaB activation and NF-kappaB-dependent gene expression.
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PMID:Temporal control of NF-kappaB activation by ERK differentially regulates interleukin-1beta-induced gene expression. 1458 82

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Macrophages play a key role in directing the host immune response to infection. Interaction of Leishmania donovani with macrophages results in the antagonization of host defense mechanisms by interfering with a cascade of cell signaling processes in the macrophages. Macrophages secrete interferon (IFN), as well as other cytokines, following lipopolysaccharide (LPS) stimulation. The interferon regulatory factors (IRFs) comprise a family of DNA-binding proteins that have been implicated in the transcriptional regulation of IFN and certain IFN-inducible genes. IRF-1 is a transcription factor, which regulates induction of several macrophage effectors and is known to bind to IRF-E site in the inducible nitric oxide synthase (iNOS) promoter. We for the first time report that L. donovani and its surface molecule lipophosphoglycan (LPG) result in a dose- and time-dependent activation of IRF-DNA-binding activity in macrophages. The components of this novel LPG-stimulated IRF-like complex are unclear. The interaction of parasite with the macrophages and not the cellular uptake was important for IRF activation. The use of inhibitors selective for ERK (PD98059) and p38 (SB203580) mitogen-activated protein (MAP) kinase pathway showed that preincubation of cells with either SB203580 or PD98059 did not affect the binding activity of IRF-E, suggesting that both p38 and ERK MAP kinase activation are not necessary for IRF-E activation. It is likely that induction of IRF in response to infection by L. donovani represents a host defense mechanism.
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PMID:Leishmania donovani induces interferon regulatory factor in murine macrophages: a host defense response. 1506 6

We have investigated the possible effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on signal transduction pathways associated with inflammatory activation of BV-2 mouse microglia cells. Pretreatment of the cells with PACAP resulted in a significant decrease in LPS- or IFNgamma-induced NO production as well as iNOS and IL-1beta mRNA levels. The inhibitory effect of PACAP appeared to be mediated through an increase in intracellular cAMP. PACAP inhibition of LPS-induced NO production was accompanied by inhibition of p38 MAPK activation, but not ERK, JNK, or NF-kappaB. IFNgamma-induced STAT-1 activation or IRF-1 induction was not significantly influenced by PACAP. Therefore, PACAP appears to suppress inflammatory activation of BV-2 microglia via specific inhibition of LPS-induced p38 MAPK pathway.
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PMID:Selective modulation of microglial signal transduction by PACAP. 1519 76

1. We investigated the effects of serum albumin on inducible nitric oxide synthase (iNOS) expression in RAW 267.4 macrophages. Crude fraction-V type albumin as well as bovine serum albumin filtrated for endotoxin induced concentration-dependent iNOS expression in macrophages. Accordingly, NO production (estimated by supernatant nitrite) was markedly (up to 10-fold) increased in the presence of albumin. 2. Albumin-induced expression of iNOS protein was inhibited by cycloheximide and NO production was abolished after incubation of the cells with an iNOS inhibitor, N(G)-monomethyl-l-arginine (LNMMA). 3. An inhibitor of the NF-kappaB pathway, pyrrolidine dithiocarbamate (PDTC), as well as inhibitors of JAK2/STAT and ERK, AG490 and U0126, respectively, significantly reduced albumin-induced iNOS expression and NO production, while an inhibitor of the p38 pathway, SB203580, did not significantly affect NO production induced by albumin. 4. Both types of serum albumin were contaminated with traces of endotoxin. The endotoxin levels were found not to be sufficient for the observed induction of nitrite production in RAW 267.4 cells. In addition, the albumin-stimulated induction of iNOS was not reduced by preincubation of albumin-containing media with polymyxin B, a LPS inhibitor. 5. Polymerised albumin fractions were detected in the commercially available albumin tested in this study. A monomeric albumin-rich fraction, separated by ultrafiltration, showed a potent inducing effect on iNOS expression and NO production, while a polymer-rich fraction showed a smaller effect. 6. Advanced glycation endproducts (AGE) of albumin were not formed by interaction with glucose in incubation medium, as AGE was not increased even after long-time (4 weeks) incubation in albumin-containing media [3.2-4.4 microg ml(-1) (basal) vs 4.8-5.6 microg ml(-1) (in glucose-containing media)]. However, the duration of albumin exposure to glucose influenced the basal stimulatory properties of albumin. 7. Our results suggest that serum albumin fractions, as gained by cold alcoholic extraction, may include determinants that stimulate or further enhance stimulation of RAW 267.4 cells and are different from endotoxin, polymeric albumin and AGE.
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PMID:Serum albumin induces iNOS expression and NO production in RAW 267.4 macrophages. 1528 88

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.
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PMID:Suppression of protein kinase C and nuclear oncogene expression as possible action mechanisms of cancer chemoprevention by Curcumin. 1535 94

Little is known about the interaction of tumor cells with host vascular smooth muscle cells. In reconstitution experiments, tumorigenic cell lines (including the rat hepatocarcinoma Morris 7777 and human melanoma M-21) were cultured for 17 hr in the presence of rat aortic rings, subsequently evaluated in contractility assays (response to phenylephrine and KCl). An agonist-independent loss of contractility was observed in rings pre-incubated with either tumorigenic cell lines or their conditioned medium (CM). The depressing effect of Morris cells depends largely on the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and was reversed by an inhibitor of this enzyme; iNOS immunoreactivity was verified in some muscular vessels at the periphery of tumors formed by the Morris cell line in rats. The M-21 melanoma produces cytotoxicity in rat aortic rings (presence of single stranded DNA, cleavage of PARP, in differentiated smooth muscle only), accounting for the irreversible loss of contractility. The cytotoxicity produced by M-21 CM is not dependent on NO. Gel filtration of CM suggests that both the iNOS- and cytotoxicity-inducing substances from Morris hepatoma cells or M-21 cells, respectively, are mainly of low molecular weight (1 kDa or less). Other cell lines derived from rat or human tumors produce minimal effects on the rat aorta smooth muscle (H4-II-E-C3) or an irreversible anergy (RBL, MDA-MB-231, HEP-3B, HEP G2). The results emphasize that inhibition of vascular smooth muscle is relevant to tumor biology both by modulation of tumoral hemodynamics and by influencing the state of vessel maturation.
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PMID:Loss of function of vascular smooth muscle cells by nitric oxide-dependent and -independent interactions with tumorigenic cells. 1538 69

Mutations in beta-globin, glucose-6-phosphate dehydrogenase, and promoters for tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) were examined for associations with the incidence of symptomatic malaria in a cohort of 307 Ugandan children. After adjustment of incidence rates for age, water source, use of preventative measures, and proximity to mosquito breeding sites, glucose-6-phosphate dehydrogenase A- heterozygous females had a significantly higher incidence of malaria (incidence rate ratio [IRR] = 1.63, P = 0.03) and a trend towards higher parasite densities (37,100 versus 26,200 parasites/microL; P = 0.18) compared with wild-type children. Male hemizygotes had trends in the same direction. Heterozygotes for sickle hemoglobin had trends toward a lower incidence of malaria and lower parasite density at presentation. Heterozygotes for the iNOS promoter G954C polymorphism, but not other promoter polymorphisms, had a significantly lower incidence of malaria compared with wild-type children (IRR = 0.69, P = 0.05). Host polymorphisms appear to impact upon the incidence of uncomplicated malaria in Ugandan children.
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PMID:Host polymorphisms and the incidence of malaria in Ugandan children. 1564 65

The role of reactive oxygen species (ROS) in regulating the expression of the inducible nitric oxide synthase (iNOS) was studied in rat aortic vascular smooth muscle cells (VSMC). We hypothesized that ROS regulate iNOS expression through the mitogen-activated protein kinases ERK and p38(MAPK). We found that interleukin-1beta (IL-1beta) stimulated the production of hydrogen peroxide (H2O2) which could be inhibited by loading the cells with the H2O2-scavenging enzyme catalase. Inhibition of the upstream ERK1,2 activator MEK1,2 with U0126 prevented IL-1beta-stimulated iNOS expression, while the p38MAPK inhibitor SB03580 potentiated iNOS expression. Loading the cells with catalase enhanced ERK activation and iNOS expression but had no effect on p38MAPK activation or PDGF-induced ERK activation. These data indicated that H2O2 negatively regulates iNOS expression through ERK inhibition independently of p38MAPK. The present results outline a novel role for H2O2 in suppressing signaling pathways leading to gene expression such as iNOS in VSMC in response to cytokines.
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PMID:Catalase potentiates interleukin-1beta-induced expression of nitric oxide synthase in rat vascular smooth muscle cells. 1568 16

Recently we have reported that glucose deprivation induces the potentiated death and loss of ATP in immunostimulated astroglia via the production of NO and eventually peroxynitrite. This study examined the role of the ERK1/2 signaling pathways in the glucose deprivation-induced death of immunostimulated astroglia. Immunostimulation with LPS+IFN-gamma induced the sustained activation of ERK1/2 for up to 48 h. Glucose deprivation caused the loss of ATP and consequently cell death in immunostimulated astroglia, which was significantly blocked by the treatment with the ERK kinase (MEK1) inhibitor, PD98059 (10-40 microM), to inhibit the ERK1/2 pathways. The systems for generating NO (iNOS) or superoxide (NADPH oxidase) were regulated by the ERK1/2 signaling pathways because the addition of PD98059 reduced the level of both. Interestingly, glucose deprivation caused an approximately two-fold increase in the level of peroxynitrite formation in immunostimulated astroglia, which was significantly reduced by the PD98059 treatment. This demonstrates that the ERK1/2 signaling pathways play an important role in glucose deprivation-induced death in immunostimulated astroglia by regulating the generation of NO, superoxide and their reaction product, peroxynitrite.
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PMID:Role of MAPK/ERK1/2 in the glucose deprivation-induced death in immunostimulated astroglia. 1572 Dec 16


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