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)

Phosphoinositide 3-kinase (PI3-kinase)-dependent phosphorylation of the proapoptotic Bcl-2 family member Bad has been proposed as an important regulator of apoptotic cell death. To understand the importance of this pathway in nontransformed hematopoietic cells, we have examined the effect of survival cytokines on PI3-kinase activity and Bad expression and phosphorylation status in human neutrophils. Granulocyte macrophage-colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) both reduced the rate of apoptosis in neutrophils cultured in vitro for 20 hours. Coincubation with the PI3-kinase inhibitor LY294002, which in parallel experiments abolished GM-CSF-primed, fMLP-stimulated superoxide anion production and GM-CSF-stimulated PtdIns(3,4,5)P(3) accumulation, inhibited the GM-CSF and TNF-alpha survival effect. In contrast, the MAP kinase kinase (MEK1/2) inhibitor PD98059 and the protein kinase A inhibitor H-89 had only a marginal effect on GM-CSF-mediated neutrophil survival. GM-CSF substantially increased Bad phosphorylation at Ser112 and Ser136 and increased the cytosolic accumulation of Bad. GM-CSF also regulated Bad at a transcription level with a marked decrease in mRNA levels at 4 hours. TNF-alpha caused a biphasic effect on the rate of morphologic apoptosis, which corresponded to an early increase, and a late inhibition, of Bad mRNA levels. LY294002 inhibited GM-CSF- and TNF-alpha-mediated changes in Bad phosphorylation and mRNA levels. These data suggest that the survival effect of GM-CSF and TNF-alpha in neutrophils is caused by a PI3-kinase-dependent phosphorylation and cytosolic translocation of Bad, together with an inhibition of Bad mRNA levels. This has important implications for the regulation of neutrophil apoptosis in vivo.
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PMID:Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. 1223 75

IL-1beta inhibits isoproterenol (ISO)-induced relaxation of cultured human airway smooth muscle (HASM) cells. The purpose of this study was to determine whether IL-1beta can also suppress ISO-induced cAMP response element (CRE)-dependent gene expression. ISO (10 microM) caused a marked increase in CRE-binding protein (CREB) phosphorylation, which was attenuated by IL-1beta (2 ng/ml). This effect of IL-1beta was abolished by the cyclooxygenase (COX) inhibitor indomethacin. To examine CRE-driven gene expression, we transiently transfected HASM cells with a construct containing CRE upstream of a luciferase reporter gene. ISO (6 h) caused a sixfold increase in luciferase activity. IL-1beta (24 h) alone also increased luciferase activity, although to a lesser extent (2-fold). However, the ability of ISO to elicit luciferase expression was markedly reduced in cells treated with IL-1beta. Indomethacin, the MEK and p38 inhibitors U-0126 and SB-203580, the protein kinase A inhibitor H-89, and dexamethasone each completely abolished the ability of IL-1beta to induce CRE-driven gene expression but only slightly increased the ability of ISO to induce CRE-driven gene expression in IL-1beta-treated cells. IL-1beta also attenuated dibutyryl cAMP-induced CRE-driven gene expression, but not dibutyryl cAMP-induced CREB phosphorylation. Tumor necrosis factor-alpha (10 ng/ml) also attenuated ISO-induced CRE-driven gene expression, even though it was without effect on ISO-induced cAMP formation or ISO-induced CREB phosphorylation. The results suggest that IL-1beta and tumor necrosis factor-alpha may attenuate the ability of beta-agonists to induce expression of genes with CRE in their regulatory regions at least in part through events downstream of CREB phosphorylation.
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PMID:Effect of IL-1beta on CRE-dependent gene expression in human airway smooth muscle cells. 1238 41

We have focused our attention on the molecular events underlying the antagonistic activities of pro-inflammatory cytokines against transforming growth factor-beta (TGF-beta)/SMAD signaling. Using jnk1/2-knockout (jnk(-/-)) and I kappa B kinase-gamma/nemo(-/-) fibroblasts, we have determined the specific roles played by the JNK/AP-1 and NF-kappa B/Rel pathways in this phenomenon. We demonstrate that, in a cellular context devoid of JNK activity (i.e. jnk(-/-) fibroblasts), interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) did not inhibit the formation of SMAD-DNA complexes and the resulting SMAD-driven transcription in response to TGF-beta. On the other hand, lack of NF-kappa B activity in nemo(-/-) fibroblasts did not affect the antagonistic effect of pro-inflammatory cytokines against TGF-beta. In the latter cell type, overexpression of antisense c-jun mRNA or of a dominant-negative form of MKK4 blocked the inhibitory activity of TNF-alpha, similar to what was observed in normal human dermal fibroblasts. Among JNK substrates, c-Jun and JunB (but not activating transcription factor-2) antagonized TGF-beta/SMAD signaling in a JNK-dependent manner. Overexpression of JNK1 in jnk(-/-) fibroblasts restored the ability of cytokines and Jun proteins to interfere with SMAD signaling. In junAA mouse embryo fibroblasts, in which c-Jun can no longer be phosphorylated by JNK, JunB substituted for c-Jun in mediating the cytokine effect against SMAD-driven transcription in a JNK-dependent manner. These results suggest a critical role for JNK-mediated c-Jun and JunB phosphorylation in transmitting the inhibitory effect of pro-inflammatory cytokines against TGF-beta-induced SMAD signaling. In addition, we demonstrate that such a JNK-dependent regulatory mechanism underlies the antagonistic activity of TNF-alpha against TGF-beta-induced up-regulation of type I and III collagens in fibroblasts.
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PMID:A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression. 1242 18

Family studies of asthma suggest that the genes ESE-2 and ESE-3 contain polymorphisms that contribute to disease susceptibility. Each gene codes for an ETS transcription factor that is characterized by epithelium-restricted constitutive expression and may function as a context-dependent activator or repressor of transcription; however, nothing is known about the role of these genes in lung homeostasis or the pathogenesis of airway disease. In this study, we show that ESE-3 mRNA and protein are constitutively expressed in bronchial and mucous gland epithelial cells. Consistent with these findings, ESE-3 mRNA is constitutively expressed in human bronchial epithelial cells grown in tissue culture. In contrast, ESE-2 mRNA could not be detected in the lung or cultured human bronchial epithelial cells. Human bronchial smooth muscle cells and fibroblasts do not constitutively express ESE-3; however, after stimulation with interleukin-1beta or tumor necrosis factor-alpha, levels of ESE-3 mRNA and protein increase dramatically by 24 h. This cytokine induction is dose-dependent and abrogated by specific inhibitors of the MEK1/2 (U0126) and p38 (SB03580) signal transduction pathways. Overexpression of ESE-3 protein in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity, suggesting that ESE-3 may function as a transcriptional repressor.
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PMID:Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. 1244 29

Expression of inducible nitric oxide synthase (iNOS), which leads to the production of nitric oxide (NO), is stimulated by proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Here we report on the roles of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases in IL-1beta/TNF-alpha-induced iNOS expression in adult rat astroglia. Cytokine-induced increases in nitrite accumulation (an index of NO production) and iNOS expression were attenuated by inhibition of NF-kappaB with pyrrolidine dithiocarbamate (PDTC). Similar attenuation of these cytokine-induced responses was produced by inhibition of MAP kinase (MEK), the immediate upstream activator of Erk, using PD098,059. Combined treatment of astroglia with PDTC and PD098,059 completely abolished the cytokine-induced increases in iNOS expression and nitrite accumulation. By contrast, the selective p38 kinase inhibitor SB203,580 amplified the effects of IL-1beta/TNF-alpha on nitrite accumulation. In accordance with these findings, IL-1beta- and TNF-alpha-induced a time-dependent increase in Erk1/Erk2 activation. This cytokine action was completely abolished by PD098,059 but was not altered by PDTC. Finally, IL-1beta and TNF-alpha induced degradation of NF-kappaB's bound inhibitory protein, IkappaB-alpha, leading to translocation of NF-kappaB into the nucleus. IkappaB-alpha expression was not restored to control levels by inhibition of MEK. Furthermore, inhibition of MEK with PD098,059 did not alter IL-1beta- and TNF-alpha-induced expression of active NF-kappaB. The results demonstrate that autonomous Erk and NF-kappaB pathways mediate cytokine-induced increases in iNOS expression in astroglia.
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PMID:Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. 1250 5

Double-stranded RNA (dsRNA) is produced during replicative viral infection or genotoxic stress. Thus knowledge of the cellular response to dsRNA is necessary to understand the effects of DNA damage or viral infection in biliary epithelia. We assessed the effect of dsRNA on biliary epithelial cell proliferation and apoptosis and the role of the stress-activated p38 MAPK signaling pathway in these responses. dsRNA did not induce apoptosis or proliferation in Mz-ChA-1 human malignant cholangiocytes, but decreased cytotoxicity induced by camptothecin or tumor necrosis factor-related apoptosis inducing ligand and decreased activity of caspases 3, 8, and 9. Furthermore, dsRNA increased p38 MAPK and JNK kinase active site phosphorylation but had no effect on either MAPK kinase (MEK)1/2 or protein kinase R phosphorylation. Inhibition of p38 MAPK with SB-203580 increased basal caspase activity. Thus dsRNA stimulates a p38 MAPK-dependent cell-survival pathway in biliary epithelial cells that may modulate the response of the biliary epithelia to dsRNA produced during genotoxic injury or virus infection.
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PMID:Double-stranded RNA activates a p38 MAPK-dependent cell survival program in biliary epithelia. 1254 Mar 69

Inflammation is accompanied by activation of the coagulation cascade, manifested by thrombosis and fibrin generation. Whereas endothelial cells normally provide a nonthrombogenic surface, inflammatory mediators may induce the expression of tissue factor, rendering their surface thrombogenic. In order to define the mechanisms regulating the expression of tissue factor in the skin microvasculature, we examined tissue factor expression in human dermal microvascular endothelial cells. Quiescent human dermal microvascular endothelial cells did not constitutively express tissue factor protein, but were induced to express tissue factor by treatment with tumor necrosis factor-alpha in a time- and concentration-dependent fashion. Increased expression of tissue factor protein was accompanied by increases in steady-state mRNA levels. Tumor necrosis factor-alpha treatment resulted in increased expression of tissue factor heterogeneous nuclear RNA without changes in mRNA stability, suggesting that increased mRNA was mediated primarily via increased tissue factor gene transcription. In order to define the pathways regulating tissue factor induction, we examined the effects of MG-132, an inhibitor of nuclear factor-kappaB activation, PD98059, an inhibitor of MEK1 action, and SB203580, an inhibitor of activated p38 activity. MG132 only partially blocked tumor necrosis factor-alpha-induced tissue factor protein expression, despite an almost complete inhibition of tumor necrosis factor-alpha-induced E-selectin expression. In contrast, SB203580, almost completely inhibited tumor necrosis factor-alpha-induced tissue factor expression but inhibition of MEK1 by PD98059 had a minimal effect on tumor necrosis factor-alpha-mediated tissue factor induction in human dermal microvascular endothelial cells. Both SB203580 and MG132 treatment inhibited tumor necrosis factor-alpha-mediated increases in tissue factor mRNA and tissue factor gene transcription as measured by expression of tissue factor heterogeneous nuclear RNA. These data support a transcriptional role for both nuclear factor-kappaB and p38 mitogen-activated protein kinase, but not MEK1 in tissue factor gene expression in human dermal microvascular endothelial cells.
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PMID:Regulation of tissue factor in microvascular dermal endothelial cells. 1260 64

In insulin-secreting cells, cytokines activate the c-Jun N-terminal kinase (JNK), which contributes to a cell signaling towards apoptosis. The JNK activation requires the presence of the murine scaffold protein JNK-interacting protein 1 (JIP-1) or human Islet-brain 1(IB1), which organizes MLK3, MKK7 and JNK for proper signaling specificity. Here, we used adenovirus-mediated gene transfer to modulate IB1/JIP-1 cellular content in order to investigate the contribution of IB1/JIP-1 to beta-cell survival. Exposure of the insulin-producing cell line INS-1 or isolated rat pancreatic islets to cytokines (interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta) induced a marked reduction of IB1/JIP-1 content and a concomitant increase in JNK activity and apoptosis rate. This JNK-induced pro-apoptotic program was prevented in INS-1 cells by overproducing IB1/JIP-1 and this effect was associated with inhibition of caspase-3 cleavage. Conversely, reducing IB1/JIP-1 content in INS-1 cells and isolated pancreatic islets induced a robust increase in basal and cytokine-stimulated apoptosis. In heterozygous mice carrying a selective disruption of the IB1/JIP-1 gene, the reduction in IB1/JIP-1 content in happloinsufficient isolated pancreatic islets was associated with an increased JNK activity and basal apoptosis. These data demonstrate that modulation of the IB1-JIP-1 content in beta cells is a crucial regulator of JNK signaling pathway and of cytokine-induced apoptosis.
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PMID:The scaffold protein IB1/JIP-1 is a critical mediator of cytokine-induced apoptosis in pancreatic beta cells. 1264 31

We reported previously that bone marrow granulocytes respond to small amounts of enterobacterial lipopolysaccharide (LPS) via a CD14-independent and TLR4-mediated mechanism by de novo expression of an inducible receptor (CD14) and by down-modulation of a constitutive receptor (L-selectin). In this report we address another effect of LPS: the down-regulation of receptors for tumor necrosis factor-alpha. In mouse bone marrow cells (BMC), this down-regulation is detectable soon (20 min) after exposure of the cells to low levels (0.5 ng/ml) of LPS. This temperature-dependent effect is rather selective for LPS and requires the presence of a conventional lipid A structure in the LPS molecule and a functional TLR4 molecule in the cells. The down-modulation, due to a shedding of the receptors, is blocked by p38 MAPK inhibitors, by a furin inhibitor, and by three metalloproteinase inhibitors (BB-3103, TIMP-2, and TIMP-3). In contrast, inhibitors of MEK, protein kinase C, cAMP-dependent protein kinase, and kinases of the Src family do not block the shedding. Analysis of BMC from mice lacking tumor necrosis factor receptor-1 (CD120a-/-) or tumor necrosis factor receptor-2 (CD120b-/-) indicates that the LPS-induced shedding is specific for CD120b. Thus, exposure of BMC to LPS triggers a rapid shedding of CD120b via a protein kinase C- and Src-independent pathway mediated by p38 MAPK, furin, and metalloproteinase. The additive effects of furin and metalloproteinase inhibitors suggest that these enzymes are involved in parallel shedding pathways.
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PMID:TLR4-dependent lipopolysaccharide-induced shedding of tumor necrosis factor receptors in mouse bone marrow granulocytes. 1266 67

The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
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PMID:MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. 1268 28


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