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)

Ischemia in the intact ventilated lung (oxygenated ischemia) leads to endothelial generation of reactive oxygen species (ROS) and nitric oxide (NO). This study investigated the signaling pathway for NO generation with oxygenated ischemia in bovine pulmonary artery endothelial cells (BPAEC) that were flow adapted in vitro. BPAECs were cultured in an artificial capillary system and subjected to abrupt cessation of flow (ischemia) under conditions where cellular oxygenation was maintained. Immunoblotting and dichlorofluorescein/triazolofluorescein fluorescence were used to assess extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation and ROS/NO generation, respectively. ERK1/2 phosphorylation significantly increased during ischemia, whereas total ERK1/2 did not change. ERK1/2 phosphorylation was suppressed by an inhibitor of tyrosine phosphorylation (genestein), cholesterol-binding reagents (filipin or cyclodextrin), or inhibitors of ROS (diphenyleneiodonium, N-acetylcysteine, or catalase), suggesting a role for both membrane cholesterol and ROS in ERK1/2 activation. Ischemia resulted in a 1.8-fold increase in NO generation that was suppressed by inhibitors of ERK1/2 activation (PD-98059 or U-0126). A calmodulin inhibitor (calmidizolium) or removal of Ca2+ from the medium also blocked NO generation, indicating that endothelial NO synthase (eNOS) is the activated isoform. These results indicate ischemia induces NO generation (possibly through a membrane cholesterol-sensitive flow sensor), the ERK1/2 cascade mediates signaling from the sensor to eNOS, and ROS are required for ERK activation.
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PMID:Signaling pathway for nitric oxide generation with simulated ischemia in flow-adapted endothelial cells. 1166 87

Recent evidence shows the involvement of reactive oxygen species (ROS) in the mitogenic cascade initiated by the tyrosine kinase receptors of several growth factor peptides. We have asked whether also the vascular endothelial growth factor (VEGF) utilizes ROS as messenger intermediates downstream of the VEGF receptor-2 (VEGFR-2)/KDR receptor given that the proliferation of endothelial cells during neoangiogenesis is physiologically regulated by oxygen and likely by its derivative species. In porcine aortic endothelial cells stably expressing human KDR, receptor activation by VEGF is followed by a rapid increase in the intracellular generation of hydrogen peroxide as revealed by the peroxide-sensitive probe dichlorofluorescein diacetate. Genetic and pharmacological studies suggest that such oxidant burst requires as upstream events the activation of phosphatidylinositol 3-kinase and the small GTPase Rac-1 and is likely initiated by lipoxygenases. Interestingly, ROS generation in response to VEGF is not blocked but rather potentiated by endothelial nitric-oxide synthase inhibitors diphenyleneiodonium and N(G)methyl-l-arginine, ruling out the possibility of nitric oxide being the oxidant species here detected in VEGF-stimulated cells. Inhibition of KDR-dependent generation of ROS attenuates early signaling events including receptor autophosphorylation and binding to a phospholipase C-gamma-glutathione S-transferase fusion protein. Moreover, catalase, the lipoxygenase inhibitor nordihydroguaiaretic acid, the synthetic ROS scavenger EUK-134, and phosphatidylinositol 3-kinase inhibitor wortmannin all reduce ERK phosphorylation in response to VEGF, and antioxidants prevent VEGF-dependent mitogenesis. Finally, cell culture and stimulation in a nearly anoxic environment mimic the effect of ROS scavenger on receptor and ERK phosphorylation, reinforcing the idea that ROS are necessary components of the mitogenic signaling cascade initiated by KDR. These data identify ROS as a new class of intracellular angiogenic mediators and may represent a potential premise for new antioxidant-based antiangiogenic therapies.
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PMID:Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR. 1171 8

Oral administration of rats to L-2-chloropropionate (L-CPA) causes selective necrosis to the granule cell layer of the cerebellum in vivo and to cultured rat cerebellar granule cells in vitro. The present study was conducted to characterize the involvement of reactive oxygen species (ROS) in cell death of L-CPA to rat cerebellar granule cells in vitro. Exposure to L-CPA (0.625-10 mM) produced a concentration dependent increase in formation of 2,7-dichlorofluorescein (DCF) as a measure of formation of ROS. The elevation of ROS was inhibited after incubation of the cells with the ERK-type of MAP kinases inhibitor U0126, the mitochondrial permeability transition pore inhibitor cyclosporin A (CSA), the antioxidant vitamin E, and the spin trap N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN). Measurements of nitrite (NO(2)) in the cell culture supernatant using the Griess reagent indicate generation of nitric oxide (NO) after exposure to L-CPA. Incubation with L-CPA (10 mM) for 48 hr lead to cell death (90%). When the granule cells were incubated with L-CPA in combination with the inhibitors of free radical production, the cell death was ameliorated. The results show that L-CPA is toxic to granular cells by production of ROS.
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PMID:Toxic effect of L-2-chloropropionate on cultured rat cerebellar granule cells is ameliorated after inhibition of reactive oxygen species formation. 1174 28

The role of nitric oxide (NO) produced by adherent spleen cells in the systemic immunosuppression developing in tumor-bearing hosts was investigated. After therapeutic immunization of rats carrying an intrahepatic colon carcinoma, H1D2, the spleen cell antitumor immune responsiveness was analyzed. Compared to parallel immunized tumor-free rats, tumor-bearing rats (TB rats) had a greatly reduced proliferative T-cell response to wild-type tumor stimulator cells. The TB rats had a depressed proliferative response to anti-CD3 and to the superantigen SEA. TB rats with small tumors had a stronger response to IL-18-producing H1D2 stimulator cells than to wild type H1D2 cells. This was not the case with TB rats carrying larger tumors. Also the IFN-gamma production and cytotoxicity against the wild-type tumor cells and the NK sensitive YAC cells were depressed in spleen cells of TB rats after 5-day restimulation with wild-type tumor cells. A part of this immunosuppression was mediated by adherent spleen cells, mostly consisting of macrophages. An important mode of action appears to involve their production of an enhanced level of nitric oxide, since the competitive nitric oxide synthase (NOS) inhibitor L-NAME could partially counteract the suppression in vitro. We conclude that NOS inhibitors in combination with immunostimulatory cytokines, such as IL-18, could be useful tools to enhance anti-tumor immune responses in TB rats and therefore to increase the efficiency of immunotherapies.
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PMID:Nitric oxide synthase inhibitor and IL-18 enhance the anti-tumor immune response of rats carrying an intrahepatic colon carcinoma. 1176 44

Extracorporeal shock wave (ESW) is an alternative non-invasive method for the promotion of bone growth and tendon repair. In an animal model, we have reported that ESW promoted bone marrow osteoprogenitor growth through transforming growth factor-beta1 induction. We have further explored the mechanism for the ESW promotion of osteogenesis. Results showed that an optimal ESW treatment at 0.16 mJ/mm(2) for 500 impulses rapidly induced a higher O(2)(-) and ONOO(-) production associated with a decrease of nitric oxide level in 1 h, and induced a higher transforming growth factor-beta1 production in 24 h, and a higher colony-forming units-osteoprogenitor formation in 12 days. The colony-forming units-osteoprogenitor colonies revealed positive staining of bone alkaline phosphatase and turned into bone nodules in 21 days. Early scavenging of O(2)(-) but not Ca(2+), H(2)O(2), or prostaglandin E(2) suppressed osteoprogenitor cell growth and maturation. Scavenging of O(2)(-) by superoxide dismutase raised the nitric oxide level back to the basal level and suppressed ESW-promoted osteoprogenitor cell growth, whereas inhibition of ONOO(-) by urate or NO by N-nitro-l-arginine methyl ester did not affect ESW promotion of osteogenesis, indicating that O(2)(-) acted as an early signal for ESW-induced cell growth. Further studies demonstrated that ESW induced ERK activation, and blockage of O(2)(-) production or inhibition of tyrosine kinase, but not protein kinase A and C inhibitors, suppressed ESW-induced ERK activation. In support that O(2)(-) mediated the ESW-induced ERK activation and osteogenic differentiation, we further demonstrated that scavenging of O(2)(-) by superoxide dismutase and inhibition of ERK activation by PD98059 decreased specific osteogenic transcription factor, core binding factor A1 activation, and decreased osteocalcin expression. Taken together, we showed that ESW-induced O(2)(-) production followed by tyrosine kinase-mediated ERK activation and core binding factor A1 activation resulted in osteogenic cell growth and maturation. Thus, an appropriate modulation of redox reaction by ESW may have some positive effect on the bone regeneration.
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PMID:Superoxide mediates shock wave induction of ERK-dependent osteogenic transcription factor (CBFA1) and mesenchymal cell differentiation toward osteoprogenitors. 1178 11

Endotoxin (lipopolysaccharide, LPS) is a component of the outer membrane of Gram-negative bacteria and promotes the activation of macrophages and microglia. Although these cells are highly LPS-responsive, they serve unique tissue-specific functions and exhibit different LPS sensitivities. Accordingly, it was of interest to evaluate whether these biological differences reside in variations within LPS signaling pathways between these two cell types. Because the mitogen-activated protein kinases ERK-1 and ERK-2 have been implicated in the control of many immune responses, we tested the concept that they are a key indicator for differences in cellular LPS sensitivity. We observed that murine RAW 264.7 macrophages and murine BV-2 microglial cells both respond to LPS by exhibiting increased IkappaBalpha degradation, enhanced NF-kappaB DNA binding activity, and elevated nitric oxide and interleukin-1beta production. Although LPS potently stimulates ERK activation in RAW 264.7 macrophages, it does not activate ERK-1/-2 in BV-2 microglia. Moreover, antagonism of the MEK/ERK pathway potentiates LPS-stimulated nitric oxide production, suggesting that LPS-stimulated ERK activation can exert inhibitory effects in macrophage-like cells. These data support the idea that ERK activation is not a required function of LPS-mediated signaling events and illustrate that alternative/additional pathways for LPS action exist in these cell types.
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PMID:A differential role for the mitogen-activated protein kinases in lipopolysaccharide signaling: the MEK/ERK pathway is not essential for nitric oxide and interleukin 1beta production. 1178 32

Angiogenesis, the formation of new blood vessels from preexisting ones, is a central process during normal development and during pathological repair. Vascular endothelial growth factor-A (VEGF-A) can stimulate both physiological and pathological angiogensis. VEGF-A is a ligand for the two receptor tyrosine kinases VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). Most biological functions of VEGF-A are mediated via VEGFR-2, whereas the role of VEGFR-1 is largely unknown. Activation of mitogen-activated kinase, stress-activated kinase, protein kinase C, and the Akt pathway are implicated in VEGF-A-dependent endothelial function, including cell survival, proliferation, generation of nitric oxide, and the induction of angiogenesis. Induction of metalloproteinases, activation of focal adhesion kinase and of PI3-kinase are implicated in VEGF-A-induced endothelial cell migration. The important role of nitric oxide as a mediator of endothelial function in vivo links the receptor signaling network to other biological effects.
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PMID:VEGF receptor signaling and endothelial function. 1179 95

The present study examined the effect of ambroxol on free radical production, granule enzyme release, and cell death in silica-activated rat alveolar macrophages. The action of ambroxol was assayed by measuring changes in the activities of protein kinase C (PKC) and tyrosine kinase (PTK) and in the intracellular calcium level. Ambroxol attenuated the production of superoxide, hydrogen peroxide, and nitric oxide and the release of acid phosphatase and lysozyme in macrophages activated by silica. Staurosporine, genistein, EGTA, and trifluoperazine inhibited the silica-induced free radical production and granule enzyme release. Silica induced the increase in PKC and PTK activities and the elevation of intracellular calcium level in macrophages, which was decreased by ambroxol. Silica induced a cell death and increased the caspase-3 activity in macrophages in a concentration-dependent manner. Ambroxol decreased the silica-induced cell viability loss in macrophages. The results show that ambroxol decreases the stimulated responses and cell death in rat alveolar macrophages exposed to silica, which may be accomplished by inhibition of activation processes, protein kinases, and calcium transport. The inhibitory effect of ambroxol on silica-induced cell death appears to provide the protective effect on pulmonary tissues against the toxic action of silica.
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PMID:Depressant effect of ambroxol on stimulated functional responses and cell death in rat alveolar macrophages exposed to silica in vitro. 1180 26

RON is a receptor tyrosine kinase activated by macrophage-stimulating protein. We demonstrate here that RON activation inhibits LPS-induced apoptosis of mouse peritoneal macrophages and Raw264.7 cells expressing RON or a constitutively active RON mutant. The antiapoptotic effect of RON was accompanied with the inhibition of LPS-induced production of nitric oxide (NO), a molecule responsible for LPS-induced cell apoptosis. This conclusion is supported by experiments using a chemical NO donor GSNO, in which RON activation directly blocked GSNO-induced apoptotic death of Raw264.7 cells and inhibited LPS-induced p53 accumulation. Furthermore, we showed that treatment of cells with wortmannin, which inhibits phosphatidylinositol (PI)-3 kinase, prevents the inhibitory effect of RON on LPS-induced macrophage apoptosis. These results were confirmed further by expression of a dominant inhibitory PI-3 kinase p85 subunit. These data suggest that by activating PI-3 kinase and inhibiting p53 accumulation, RON protects macrophage from apoptosis induced by LPS and NO. The antiapoptotic effect of RON might represent a novel mechanism for the survival of activated macrophages during inflammation.
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PMID:Activation of the RON receptor tyrosine kinase protects murine macrophages from apoptotic death induced by bacterial lipopolysaccharide. 1181 58

The functional role of p53 in nitric oxide (NO)-mediated vascular smooth muscle cell (VSMC) apoptosis remains unknown. In this study, VSMC from p53-/- and p53+/+ murine aortas were exposed to exogenous or endogenous sources of NO. Unexpectedly, p53-/- VSMC were much more sensitive to the proapoptotic effects of NO than were p53+/+ VSMC. Furthermore, this paradox appeared to be specific to NO, because other proapoptotic agents did not demonstrate this differential effect on p53-/- cells. NO-induced apoptosis in p53-/- VSMC occurred independently of cGMP generation. However, mitogen-activated protein kinase (MAPK) pathways appeared to play a significant role. Treatment of the p53-/- VSMC with S-nitroso-N-acetylpenicillamine resulted in a marked activation of p38 MAPK and, to a lesser extent, of c-Jun NH(2)-terminal kinase, mitogen-activated protein kinase kinase (MEK) 1/2, and p42/44 (extracellular signal-regulated kinase, ERK). Furthermore, basal activity of the MEK-p42/44 (ERK) pathway was increased in the p53+/+ VSMC. Inhibition of p38 MAPK with SB-203580 or of MEK1/2 with PD-98059 blocked NO-induced apoptosis. Therefore, p53 may protect VSMC against NO-mediated apoptosis, in part, through differential regulation of MAPK pathways.
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PMID:Potentiation of nitric oxide-induced apoptosis in p53-/- vascular smooth muscle cells. 1183 48


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