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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common neurotrophin receptor (p75NGFR) can signal in vitro through activation of the c-Jun N-terminal kinase (JNK) pathway and nuclear translocation of NFKappaB. Activation of JNK and its substrate c-Jun can lead to apoptosis. We investigated these activities in vivo by comparing immunoreactivity for phosphorylated(p) SEK-1 (or MKK4, which activates JNK), c-Jun (ser63, ser73) and nuclear translocation of NFKappaB-p50 in tissue sections through the forebrain of control and p75NGFR-deficient mice. During postnatal development, SEK1p-immunoreactivity was detectable in p75NGFR-positive cholinergic neurons and p75NGFR-negative neurons throughout the forebrain in control mice. During development, few cells contained c-Junp, although many neurons contained c-Jun. No obvious c-Jun immunostaining was present in the adult forebrain. At any age, NFKappaB-p50 immunoreactivity was seen in nuclei of most cells throughout the forebrain. Following fimbria fornix transection in adult mice, few basal forebrain neurons contained SEK1p while many axotomized choline acetyltransferase (ChAT)-positive neurons contained c-Junp and nuclear NFKappaB-p50. The immunostaining patterns of SEK1p, c-Junp and NFKB during development and following injury were largely similar in p75NGFR-deficient mice. During development, cells throughout the forebrain had TdT-mediated dUTP-biotin nick end labelling (TUNEL)-labelling (a potential marker for apoptosis), however, their presence was not predicted by number of neurons stained for SEK1p or c-Junp. These results suggest that the expected activation of the JNK pathway by p75NGFR, as well as the expected relationship between SEK1 and downstream activation of c-Jun do not occur in the mammalian forebrain. Also, these results suggest that this activation does not necessarily lead to cell death.
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PMID:SEK1/MKK4, c-Jun and NFKappaB are differentially activated in forebrain neurons during postnatal development and injury in both control and p75NGFR-deficient mice. 1088 28

We investigated the role of stress-activated p38 MAP kinase (p38/SAPK-2) signaling in delayed preconditioning of the heart. Adult male out-bred ICR mice were treated with p38 activator, anisomycin (0.1 mg/kg IP), or vehicle (5% DMSO). Twenty-four hours later, hearts were perfused in Langendorff mode and subjected to 30 minutes of ischemia and 30 minutes of reperfusion. Improvement in postischemic recovery of end-diastolic pressure and reduction in infarct size was observed, which was abolished by SB203580, a specific p38 inhibitor, and pyrrolidinediethyldithiocarbamate (PDTC), the NF-kappaB inhibitor, but not by PD 98059, a specific inhibitor for MEK1 or 2. Transient increase in p38 phosphorylation was observed 15 minutes after anisomycin treatment which subsided by 30 minutes. Electrophoretic mobility shift assay demonstrated rapid activation of NF-kappaB DNA binding with anisomycin, peaking at 30 minutes. Western blot confirmed the accumulation of p50 and p65 in nuclear extracts after anisomycin treatment. Anisomycin-induced NF-kappaB DNA binding activity was inhibited by SB203580 and PDTC. Expression of inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) synthesis were enhanced in anisomycin-treated mice. SB203580 and PDTC blocked the increased expression of iNOS and increase in synthesis of NO. Selective iNOS inhibitor S-methylisothiourea abolished the protective effect of anisomycin. Furthermore, postischemic cardioprotective effect of anisomycin was absent in mice with targeted ablation of iNOS gene but not in the wild-type B6.129 mice. For the first time, these results suggest that direct pharmacological activation of p38 triggers delayed preconditioning by signaling mechanism involving NF-kappaB activation and synthesis of NO from iNOS.
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PMID:p38 Triggers late preconditioning elicited by anisomycin in heart: involvement of NF-kappaB and iNOS. 1170 19

We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC(4) synthase expression in mononuclear phagocytes. Conditioning of the monocyte-like cell line, THP-1, with LPS for 7 days resulted in significantly decreased ionophore-stimulated LTC(4) release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC(4) synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with down-regulation observed as early as 4 h. Conditioning of actinomycin D-treated cells with LPS resulted in no change in the rate of LTC(4) synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC(4) synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF-alpha and inhibition of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase did not inhibit the effect of LPS. Treatment of cells with a Toll-like receptor 4-blocking Ab and an inhibitor of NF-kappaB activation resulted in inhibition of the LPS effect, while activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism.
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PMID:Lipopolysaccharide down-regulates the leukotriene C4 synthase gene in the monocyte-like cell line, THP-1. 1257 84

Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was previously shown to have anti-oncogenic activity on ras-transformed cells. Since oncogenic Ras mediates transformation, in part, through the activation of the transcription factor nuclear factor-kappa B (NF-kappa B), we tested here the effects of LO on NF-kappa B activity. Expression of LO in ras-transformed NIH 3T3 cells led to decreased NF-kappa B binding and activity, as well as the expression of the NF-kappa B target gene c-myc. Importantly, ectopic expression of LO led to a dramatic decrease in colony formation by ras-transformed NIH 3T3 cells, a finding comparable to the expression of the I kappa B alpha dominant-negative mutant, which could be rescued by p65/p50 NF-kappa B subunit expression. LO was unable to directly inhibit the activity of ectopically expressed p65 and c-Rel NF-kappa B subunits, suggesting that LO affected an upstream signaling pathway(s) induced by Ras. Consistent with this hypothesis, LO expression decreased both the rate of I kappa B alpha turnover and the activities of IKK alpha and IKK beta. Moreover, the ectopic expression of a constitutively active version of either kinase reversed the negative effects of LO. Ras can induce NF-kappa B via both the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK pathways. LO potently downregulated the PI3K and Akt kinases, while partially inhibiting MEK kinase activity. Expression of a constitutively activated, myristylated Akt or PDK1 was able to counteract the effect of LO on NF-kappa B, whereas constitutively activated Raf was only partially effective. Importantly, LO blocked membrane localization of Akt and PDK1 in Ras-transformed cells. Overall, these results strongly argue that the anti-oncogenic effects of LO on ras-mediated transformation are due to its ability to inhibit signaling pathways that lead to activation of NF-kappa B.
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PMID:Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-kappa B. 1264 Jan 11

The roles of AP-1 and NFkappaB in the regulation of inducible nitric oxide synthase (iNOS) mRNA expression induced by the combination of lipopolysaccharide and tumor necrosis factor-alpha (LT) in C6 cells were examined in the present study. The iNOS mRNA level and NO release were increased by several cytokines alone or combination treatments at 24 hr. LT-induced iNOS mRNA level was maximally increased at 6 hr and maintained at higher level at least up to 24 hr. At 6 hr, iNOS protein level and NO release were also increased by LT. By western blot analysis, AP-1, such as Fra-1, Jun B, and phospho-CREB protein levels were increased by LT and translocation of NFkappaB p52 from the cytoplasm to the nucleus was increased. In addition, phosphorylations of MAPKs (ERK 1/2, p38, JNK 1/2) were increased by LT. LT-induced iNOS mRNA level was inhibited by PD98059 (MEK 1/2 inhibitor), SB203580 (p38 inhibitor), and cycloheximide (a protein synthesis blocker), indicating that the phosphorylation of ERK 1/2 and p38, and on-going protein synthesis are necessary for LT-induced iNOS expression. Electrophoretic mobility shift assay (EMSA) showed that AP-1 and NFkappaB DNA binding activities were increased at 6 hr and these AP-1 and NFkappaB DNA bands increased by LT were super-shifted when Fra-1, Jun B, or NFkappaB p50 antibody was coincubated. These findings strongly suggest that, in C6 cells, Fra-1, Jun B, NFkappaB p50, and NFkappaB p52 appear to be involved in the regulation of iNOS mRNA induced by LT.
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PMID:The regulation of inducible nitric oxide synthase gene expression induced by lipopolysaccharide and tumor necrosis factor-alpha in C6 cells: involvement of AP-1 and NFkappaB. 1277 Jun 14

In a previously published report (Kurland, J. F., Kodym, R., Story, M. D., Spurgers, K. B., McDonnell, T. J., and Meyn, R. E. (2001) J. Biol. Chem. 276, 45380-45386), we described the NF kappa B status for two murine B-cell lymphoma cell lines, LY-as (apoptosis-sensitive) and LY-ar (apoptosis-refractory) and provided evidence that NF kappa B1 (p50) homodimers contribute to the expression of Bcl-2 in the LY-ar line. In the present study, we investigated the upstream signals leading to p50 homodimer activation and Bcl-2 expression. We found that in LY-ar cells, ERK1 and ERK2 were constitutively phosphorylated, whereas LY-as cells had no detectable ERK1 or ERK2 phosphorylation. Treatment of LY-ar cells with the MEK inhibitors PD 98059, U0126, and PD 184352 led to a loss of phosphorylated ERK1 and ERK2, a reversal of nuclear p50 homodimer DNA binding, and a decrease in Bcl-2 protein expression. Similarly, activation of the MEK/ERK pathway in LY-as cells by phorbol ester led to Bcl-2 expression that could be blocked by PD 98059. Furthermore, treatment of LY-ar cells with tumor necrosis factor-alpha, an I kappa B kinase activator, did not alter the suppressive effect of PD 98059 on p50 homodimer activity, suggesting an I kappa B kinase-independent pathway for p50 homodimer activation. Lastly, all three MEK inhibitors sensitized LY-ar cells to radiation-induced apoptosis. We conclude that the MEK/ERK pathway acts upstream of p50 homodimer activity and Bcl-2 expression in this B-cell lymphoma cell system and suggest that the use of MEK inhibitors could be useful clinically in combination with ionizing radiation to treat lymphoid malignancies.
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PMID:The MEK/ERK pathway acts upstream of NF kappa B1 (p50) homodimer activity and Bcl-2 expression in a murine B-cell lymphoma cell line. MEK inhibition restores radiation-induced apoptosis. 1280 33

Granulocyte macrophage-colony-stimulating factor (GM-CSF), released from alveolar macrophages (AM), is an important regulator of eosinophil, T cell, and macrophage function and survival. We determined the mechanisms of GM-CSF regulation in AM from normal volunteers activated by lipopolysaccharide (LPS) by examining the role of nuclear factor-kappaB (NF-kappaB), and of p38 mitogen-activated protein (MAP) kinase and MAP kinase kinase (MKK-1). PD 098059 (10 microM), an inhibitor of upstream activator of MKK-1, inhibited GM-CSF expression, but the expression of GM-CSF was not inhibited by SB 203580 (10 microM), an inhibitor of p38-MAP kinase. Phosphorylation of extracellular signal-regulated kinase-1 (ERK-1), ERK-2, and p38 MAP kinase by LPS were demonstrated on Western blot analysis. LPS increased NF-kappaB:DNA binding as examined by electrophoretic mobility shift assay, but this was not suppressed by PD 098059 or by SB 203580. LPS induced an increase in NF-kappaB activation as examined by p50 translocation assay without suppression by PD 098059 or by SB 203580. SN50 (100 microM), an inhibitor of NF-kappaB translocation and the specific IKK-2-Inhibitor (AS602868; 10 microM), also prevented GM-CSF expression and release induced by LPS, indicating that GM-CSF release is NF-kappaB-dependent. PD 098059, but not SB 203580, inhibited LPS-induced histone acetyltransferase (HAT) activity, indicating chromatin modification. Furthermore, AS602868 and SN 50 suppressed LPS-induced HAT activity. TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), reversed the inhibitory effect of PD 098059, SB 203580, SN 50 and AS602868 on GM-CSF release. GM-CSF expression and release in AM is controlled by NF-kappaB activation, and this is modulated by phosphorylation of MKK-1 and p38 MAP kinase acting on histone acetylation.
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PMID:Mitogen-activated protein kinase modulation of nuclear factor-kappaB-induced granulocyte macrophage-colony-stimulating factor release from human alveolar macrophages. 1287 51

MMP-9 (92 kDa) is the major gelatinase able to degrade collagen IV, secreted by keratinocytes that are actively involved in wound-healing or tumorigenesis. Since the invasive phenotype of cancers is dependent on MMP-9 expression, it appeared of interest to precisely characterize which signal transduction pathways activated by TNF-alpha are involved in MMP-9 up-regulation induced by TNF-alpha. In HaCaT cells, activation of MMP-9 occurs at the transcriptional level. Inhibition of the MAPK pathway using specific inhibitors of the Ras, Raf, MEK1/2, and Erk1/2 cascade was correlated with a marked inhibition of MMP-9 activity, as determined by gene and protein expression. MAPK pathway activation via TNF-alpha was confirmed by marked AP-1 activation detected in EMSA. Under our experimental conditions, p38 MAPK and SAPK/JNK pathways were not activated. Gene and protein expression of other MMPs that regulate MMP-9, such as MMP-1 and MMP-13, were also up-regulated by TNF-alpha and inhibited by UO126, providing evidence that the MAPK pathway plays a fundamental role in the regulation of MMP-9 secretion by keratinocytes. As TNF-alpha is known to be a main activator of NF-kappaB pathway, the effects of campthothecin and caffeic acid were investigated, such as, TNF-alpha campthothecin up-regulated MMP-9 activity but caffeic acid only weakly inhibited MMP-9 activation induced by TNF-alpha. However, NF-kappaB is activated as shown from immunostaining data, a nuclear staining and higher Western blotting expression of p50 and p65 NF-kappaB subunits were detected after TNF-alpha treatment. A higher specific signal was also detected in EMSA for TNF-alpha-treated cells.
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PMID:The inhibition of MAPK pathway is correlated with down-regulation of MMP-9 secretion induced by TNF-alpha in human keratinocytes. 1451 92

We have previously demonstrated that shear stress increases transcription of the endothelial nitric-oxide synthase (eNOS) by a pathway involving activation of the tyrosine kinase c-Src and extracellular signal-related kinase 1/2 (ERK1/2). In the present study sought to determine the events downstream of this pathway. Shear stress activated a human eNOS promoter chloramphenicol acetyl-CoA transferase chimeric construct in a time-dependent fashion, and this could be prevented by inhibition of the c-Src and MEK1/2. Studies using electromobility shift assays, promoter deletions, and promoter mutations revealed that shear activation of the eNOS promoter was due to binding of nuclear factor kappaB subunits p50 and p65 to a GAGACC sequence -990 to -984 base pairs upstream of the eNOS transcription start site. Shear induced nuclear translocation of p50 and p65, and activation of the eNOS promoter by shear could be prevented by co-transfection with a dominant negative I kappa Balpha. Exposure of endothelial cells to shear resulted in Ikappa kinase phosphorylation, and this was blocked by the MEK1/2 inhibitor PD98059 and the cSrc inhibitor PP1, suggesting these signaling molecules are upstream of NFkappaB activation. These experiments indicate that shear stress increases eNOS transcription by NFkappaB activation and p50/p65 binding to a GAGACC sequence present of the human eNOS promoter. While NFkappaB activation is generally viewed as a proinflammatory stimulus, the current data indicate that its transient activation by shear may increase expression of eNOS, which via production of nitric oxide could convey anti-inflammatory and anti-atherosclerotic properties.
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PMID:Shear stress regulates endothelial nitric-oxide synthase promoter activity through nuclear factor kappaB binding. 1457 Sep 28

In this study, we investigated the signaling pathways involved in bradykinin (BK)-induced NF-kappaB activation and cyclooxygenase-2 (COX-2) expression in human airway epithelial cells (A549). BK caused concentration- and time-dependent increase in COX-2 expression, which was attenuated by a selective B2 BK receptor antagonist (HOE140), a Ras inhibitor (manumycin A), a Raf-1 inhibitor (GW 5074), a MEK inhibitor (PD 098059), an NF-kappaB inhibitor (pyrrolidine dithiocarbate), and an IkappaB protease inhibitor (L-1-tosylamido-2-phenylethyl chloromethyl ketone). The B1 BK receptor antagonist (Lys-(Leu8)des-Arg9-BK) had no effect on COX-2 induction by BK. BK-induced increase in COX-2-luciferase activity was inhibited by cells transfected with the kappaB site deletion of COX-2 construct. BK-induced Ras activation was inhibited by manumycin A. Raf-1 phosphorylation at Ser338 by BK was inhibited by manumycin A and GW 5074. BK-induced ERK activation was inhibited by HOE140, manumycin A, GW 5074, and PD 098059. Stimulation of cells with BK activated IkappaB kinase alphabeta (IKKalphabeta), IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 and p50 translocation from the cytosol to the nucleus, the formation of an NF-kappaB-specific DNA-protein complex, and kappaB-luciferase activity. BK-mediated increase in IKKalphabeta activity and formation of the NF-kappaB-specific DNA-protein complex were inhibited by HOE140, a Ras dominant-negative mutant (RasN17), manumycin A, GW 5074, and PD 098059. Our results demonstrated for the first time that BK, acting through B2 BK receptor, induces activation of the Ras/Raf-1/ERK pathway, which in turn initiates IKKalphabeta and NF-kappaB activation, and ultimately induces COX-2 expression in human airway epithelial cell line (A549).
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PMID:Bradykinin B2 receptor mediates NF-kappaB activation and cyclooxygenase-2 expression via the Ras/Raf-1/ERK pathway in human airway epithelial cells. 1547 67


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