Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the signaling pathways responsible for the monocytic and/or megakaryocytic differentiation of K562 cells. The results demonstrated that although the mitogen-activated protein kinase (MAPK) was activated during the phorbol myristate acetate (PMA)-induced monocytic and/or megakaryocytic differentiation of K562 cells, the overexpression of Ha-ras which can activate the MAPK did not induce the monocytic and/or megakaryocytic differentiation of K562 cells. Instead PMA-induced megakaryocytic differentiation of K562 cells was inhibited by the pretreatment of pyrrolidine dithiocarbamate, a specific nuclear factor kappaB (NF-kappaB) inhibitor. Taken together, these results suggest that the activation of NF-kappaB rather than that of MAPK might be involved in the PMA-induced megakaryocytic differentiation of K562 cells.
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PMID:Signaling mechanism of PMA-induced differentiation of K562 cells. 866 Mar 51

AP-1 has been shown to behave as a redox-sensitive transcription factor that can be activated by both oxidant and antioxidant stimuli. However, the mechanisms involved in the activation of AP-1 by antioxidants are largely unknown. In this study we show that the structurally unrelated antioxidant agents pyrrolidine dithiocarbamate (PDTC), butylated hydroxyanisole, and Nacetylcysteine activated JNK (c-Jun NH2-terminal kinase) in Jurkat T cells. This activation differed substantially from that mediated by phorbol 12-myristate 13-acetate (PMA) and Ca2+ ionophore or produced by costimulation with antibodies against the T cell receptor-CD3 complex and to CD28. The activation of JNK by classical T cell stimuli was transient, whereas that mediated by PDTC and butylated hydroxyanisole (but not N-acetylcysteine) was sustained. The kinetics of JNK activation correlated with the expression of c-jun which was transient after stimulation with PMA plus ionophore and prolonged in response to PDTC, which also transiently induced c-fos. In addition, JNK activation by PMA plus ionophore was sensitive to inhibitors of signaling pathways involving Ca2+, protein kinase C, and tyrosine phosphorylation, which failed to inhibit the activation mediated by PDTC. Transfection of trans-dominant negative expression vectors of ras and raf, together with AP-1-dependent reporter constructs, as well as Western blot analysis using anti-ERK (extracellular signal-regulated kinase) antibodies, indicated that the Ras/Raf/ERK pathway did not appear to mediate the effect of the antioxidant. However, the combined treatment with PDTC and PMA, two agents that synergize on AP-1 activation, resulted in the persistent phosphorylation of ERK-2. In conclusion, our results identify JNK as a target of antioxidant agents which can be regulated differentially under oxidant and antioxidant conditions.
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PMID:JNK (c-Jun NH2-terminal kinase) is a target for antioxidants in T lymphocytes. 882 87

The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadium-based compounds. Sodium orthovanadate (Na3VO4), sodium oxodiperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato)-oxovanadium(IV) (BMOV) differentially induced oxidative stress in lymphocytes. Treatment with pV(phen), which caused intracellular oxidation, induced strong protein tyrosine phosphorylation compared with Na3VO4 and BMOV. Syk family kinases and the mitogen-activated protein kinase erk2 were rapidly activated by pV(phen) but not by BMOV or Na3VO4. In contrast, both BMOV and pV(phen) strongly activated NF-kappaB. The antioxidant pyrrolidine dithiocarbamate (PDTC) greatly diminished the intracellular oxidation and protein phosphotyrosine accumulation induced by pV(phen). Pretreatment of cells with PDTC reduced and delayed the activation of Syk kinases and erk2. However, NF-kappaB activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, and another antioxidant, N-acetylcysteine, did not prevent the activation of NF-kappaB by BMOV. These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-kappaB activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status.
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PMID:Role of oxidative stress in the action of vanadium phosphotyrosine phosphatase inhibitors. Redox independent activation of NF-kappaB. 911 Oct 69

Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.
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PMID:Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells. 918 53

The sphingomyelin signal transduction pathway is known to play a role in mediating the action of various cytokines. Here we examined the possible role of the sphingomyelin signaling pathway on lipopolysaccharide (LPS)- and cytokine-mediated production of NO and the expression of inducible nitric-oxide synthase (iNOS). Sphingomyelinase (SMase) treatment of astrocytes increased the cellular levels of ceramide without the induction of NO production. However, incubation of LPS or cytokine-stimulated astrocytes with SMase or by increasing intracellular ceramide by cell-permeable ceramide analogs (C2- or C6-ceramide) or inhibitor of ceramidase (N-oleoyl ethanolamine) led to a time- and dose-dependent increase in the production of NO. This increase in NO production was accompanied by an increase in iNOS activity, iNOS protein, and iNOS mRNA. Similar to astrocytes, SMase or ceramide analogs also stimulated the LPS- and cytokine-mediated expression of iNOS in the C6 glial cell line. Since activation of NF-kappaB is necessary for the induction of iNOS, we examined the effect of SMase and C2-ceramide on the activation of NF-kappaB. Although SMase or C2-ceramide alone was ineffective in activating NF-kappaB, both stimulated the LPS-mediated activation of NF-kappaB in LPS-activated astrocytes. Inhibition of ceramide and LPS-mediated induction of iNOS by antioxidant inhibitors of NF-kappaB (N-acetylcysteine and pyrrolidine dithiocarbamate) suggest that the stimulatory effect of ceramide on the induction of iNOS is due to the stimulation of NF-kappaB activation and that cellular redox plays a role in the activation of NF-kappaB and induction of iNOS. Inhibition of LPS-mediated as well as LPS and ceramide-mediated induction of iNOS and activation of NF-kappaB by PD98059, a specific inhibitor of activation of mitogen-activated protein (MAP) kinase kinase (MEK), and FPT inhibitor II, a selective inhibitor of Ras farnesyl protein transferase, indicate that the Ras-MAP kinase pathway is involved in LPS-ceramide induced activation of NF-kappaB and induction of iNOS, and that ceramide-mediated signaling events probably converge into the LPS-modulated MAP kinase signaling pathway resulting in greater activation of NF-kappaB and iNOS induction. This study illustrates a novel role of the sphingomyelin-ceramide signaling pathway in stimulating the expression of iNOS via LPS- or cytokine-mediated activation of NF-kappaB in astrocytes.
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PMID:Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. 944 61

Induction of the alpha-platelet-derived growth factor receptor (PDGF-Ralpha) by IL-1beta in lung myofibroblasts enhances mitogenic and chemotactic responses to PDGF, and this could be a mechanism of myofibroblast hyperplasia during lung fibrogenesis. Since the regulation of many genes by IL-1beta involves activation of NF-kappaB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Ralpha expression by IL-1beta in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-kappaB activation, completely blocked PDGF-Ralpha up-regulation by IL-1beta as assayed by [125I]PDGF-AA binding and PDGF-Ralpha mRNA expression, suggesting a role for NF-kappaB. However, while IL-1beta and TNF-alpha both induced nuclear binding of the Rel proteins p50 and p65 to an NF-kappaB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-kappaB-alpha (IkappaB-alpha) in the cytoplasm of myofibroblasts, only IL-1beta upregulated PDGF-Ralpha. These results suggest that NF-kappaB activation alone is not sufficient for up-regulation of PDGF-Ralpha. An investigation of MAP kinase signaling pathways revealed that IL-1beta or PDTC activated extracellular signal-regulated kinase-2 (ERK-2) and c-jun NH2 terminal kinase-1 (JNK-1) phosphorylation of PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked IL-1beta-induced activation of ERK-2 by more than 90% but enhanced IL-1beta-stimulated induction of PDGF-Ralpha expression fourfold. Taken together, these data suggest that IL-1beta activates both positive and negative signaling pathways that control the expression of PDGF-Ralpha. IL-1beta appears to mediate its negative effects on PDGF-Ralpha expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Ralpha remain to be elucidated.
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PMID:Role of nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways in IL-1 beta-mediated induction of alpha-PDGF receptor expression in rat pulmonary myofibroblasts. 975 65

We have observed that acute medial cell loss is an initial event in the response to vascular injury induced by balloon-catheter distention of the rabbit carotid artery. Numerous apoptotic medial cells were observed as early as 30 minutes after balloon inflation, and a 70% loss of cellularity was evident by 90 minutes. Balloon injury was associated with oxidative stress as reflected by a fall in glutathione levels by 63% within 30 minutes after injury. We hypothesized that balloon injury activated a redox-sensitive signaling pathway coupled to the regulation of apoptosis. Indeed, the activity of the proapoptotic signal mediator, stress-activated protein kinase, was increased severalfold within 10 minutes after injury. Moreover, modifying the vascular redox state by the administration of 1 of 2 structurally dissimilar antioxidants, N-acetyl cysteine or pyrrolidine dithiocarbamate, markedly attenuated both stress-activated protein kinase activation and the induction of apoptosis at 30 minutes. We hypothesized further that the induction of vascular smooth muscle cell apoptosis is modulated by phenotype. In contrast to medial cells, we observed that neointimal cells were relatively resistant to apoptotic death induced by angioplasty injury. This resistance to balloon injury-induced death was associated with an upregulation of the antiapoptotic mediator bcl-xL. This study suggests that acute apoptotic cell death after vascular injury is a highly regulated process governed by cellular redox state and the relative expression of antiapoptotic genes. Angioplasty-induced vascular cell apoptosis may be an important determinant of vascular remodeling and restenosis.
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PMID:Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury. Influence of redox state and cell phenotype. 991 80

The shear-induced intracellular signal transduction pathway in vascular endothelial cells involves tyrosine phosphorylation and activation of mitogen-activated protein (MAP) kinase, which may be responsible for the sustained release of nitric oxide. MAP kinase is known to be activated by reactive oxygen species (ROS), such as H2O2, in several cell types. ROS production in ligand-stimulated nonphagocytic cells appears to require the participation of a Ras-related small GTP-binding protein, Rac1. We hypothesized that Rac1 might serve as a mediator for the effect of shear stress on MAP kinase activation. Exposure of bovine aortic endothelial cells to laminar shear stress of 20 dyn/cm2 for 5-30 min stimulated total cellular and cytosolic tyrosine phosphorylation as well as tyrosine phosphorylation of MAP kinase. Treating endothelial cells with the antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate inhibited in a dose-dependent manner the shear-stimulated increase in total cytosolic and, specifically, MAP kinase tyrosine phosphorylation. Hence, the onset of shear stress caused an enhanced generation of intracellular ROS, as evidenced by an oxidized protein detection kit, which were required for the shear-induced total cellular and MAP kinase tyrosine phosphorylation. Total cellular and MAP kinase tyrosine phosphorylation was completely blocked in sheared bovine aortic endothelial cells expressing a dominant negative Rac1 gene product (N17rac1). We concluded that the GTPase Rac1 mediates the shear-induced tyrosine phosphorylation of MAP kinase via regulation of the flow-dependent redox changes in endothelial cells in physiological and pathological circumstances.
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PMID:Shear-induced tyrosine phosphorylation in endothelial cells requires Rac1-dependent production of ROS. 1019 14

We have previously shown that hydrogen peroxide is an important mediator of ultraviolet B induced phosphorylation of the epidermal growth factor receptor in human keratinocytes. Here we demonstrate that physiologic doses of ultraviolet B and hydrogen peroxide stimulate activation of two related but distinct mitogen-activated protein kinase pathways: extracellular regulated kinase 1 and 2 (ERK1/2), as well as p38, the mammalian homolog of HOG1 in yeast which is a major kinase for a recently identified stress-induced signaling pathway. The time-dependent activation of ERK1/2 and p38 are distinct, and ultraviolet B-induced ERK1/2 activation is downregulated more rapidly than p38. Using dihydrorhodamine or Amplex as specific fluorescent dye probes, we show that ultraviolet B-induced peroxides can be inhibited by ascorbic acid. Ascorbic acid strongly blocks ERK1/2 and p38 activation by ultraviolet B and hydrogen peroxide whereas pyrrolidine dithiocarbamate and butyl hydroxyanisole are less effective. Pyrrolidine dithiocarbamate was unable to inhibit ultraviolet B-induced p38 activation. Cell death was increased after ultraviolet B when ERK1/2 activation was attenuated by the specific inhibitor PD098059. The distinct time courses and extents of activation and inhibition of ERK1/2 and p38 indicate that these pathways are separate and regulated independently in keratinocytes. Specific types of reactive oxygen species induced by ultraviolet B as well as selective activation or inhibition of specific phosphatases may mediate these responses in keratinocytes. These findings demonstrate that reactive oxygen species are important multifunctional mediators of ultraviolet B-induced ERK1/2 and p38 signaling transduction pathways and suggest that ERK1/2 may play an important part in protecting keratinocytes from cell death following oxidative stress.
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PMID:UVB activates ERK1/2 and p38 signaling pathways via reactive oxygen species in cultured keratinocytes. 1023 67

1. The intracellular transport of leukotriene C4 (LTC4) in hematopoietic cells such as human monocytes is controlled by an ATP dependent carrier encoded by the multidrug resistance protein1 (MRPI) gene whose function can be blocked by the compound MK-571. Since LTs play a major role in control of cytokine expression in monocytes, we questioned whether blocking of the MRPI mediated function by MK-571 might affect cytokine production. 2. MK-571 strongly enhanced IL-6 expression at mRNA and protein level in lipopolysaccharide (LPS) and interleukin-1 (IL-1) stimulated human monocytes giving rise to 2.0+/-0.4 (x+/-s.d.) and 5.7+/-3.5 fold induction of IL-6 protein secretion. The increase in IL-6 secretion was accompanied by an enhanced phosphorylation of p38 but not of c-Jun-N terminal kinase. 3. The involvement of the kinase signalling pathways was further analysed by using SB203580 and PD98059, specific inhibitors of the p38 and ERK1/2 signalling route. MK-571 mediated upregulation of IL-6 in the presence of IL-1 was partially attenuated by SB203580 and PD98059. Electrophoretic mobility shift assays demonstrated that MK-571 did not affect the IL-1 induced DNA binding activity of Activator Protein-1 and Nuclear Factor-kappaB but rather enhanced the transactivational activity of an IL-6 promoter construct. Finally it was shown that the MK-571 mediated effects on IL-6 secretion could not be inhibited by the LT synthesis inhibitor SB203347 or by the anti-oxidant pyrrolidine dithiocarbamate (PDTC). 4. These results indicate that the membrane transporter MRP1 is involved in the regulation of IL-6 expression in activated human peripheral blood monocytes.
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PMID:Interleukin-6 production by activated human monocytic cells is enhanced by MK-571, a specific inhibitor of the multi-drug resistance protein-1. 1038 44


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