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)

Human rhinovirus (HRV) infections can trigger exacerbations of lower airway diseases. Infection of airway epithelial cells induces production of a number of proinflammatory chemokines that may exacerbate airway inflammation, including CXCL10, a chemoattractant for type 1 lymphocytes and NK cells. Primary human bronchial epithelial cells and the BEAS-2B human bronchial epithelial cell line were used to examine the role of MAPK pathways in HRV-16-induced production of CXCL10. Surprisingly, PD98059 and U0126, two inhibitors of the MEK1/2-ERK MAPK pathway, significantly enhanced HRV-16-induced CXCL10 mRNA and protein. This enhancement was not seen with IFN-beta-induced production of CXCL10. Studies using small interfering RNA revealed that knockdown of MEK1, but not MEK2, was associated with enhanced HRV-induced CXCL10 production. Promoter construct studies revealed that PD98059 and U0126 enhanced HRV-16-induced transcriptional activation of CXCL10. HRV-16-induced promoter activation was regulated by two NF-kappaB binding sites, kappaB1 and kappaB2, and by an IFN-stimulated response element. Inhibitors of the MEK1/2-ERK pathway did not alter HRV-16-induced activation of tandem repeat kappaB1 or kappaB2 constructs, nor did they alter HRV-16-induced nuclear translocation/binding of NF-kappaB to either kappaB1 or kappaB2 recognition sequences. Furthermore, PD98059 and U0126 did not alter phosphorylation or degradation of IkappaBalpha. In contrast, inhibitors of the MEK1/2-ERK pathway, and small interfering RNA knockdown of MEK1, enhanced nuclear translocation/binding of IFN regulatory factor (IRF)-1 to the IFN-stimulated response element recognition sequence in HRV-16 infected cells. We conclude that activation of MEK1 selectively down-regulates HRV-16-induced expression of CXCL10 via modulation of IRF-1 interactions with the gene promoter in human airway epithelial cells.
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PMID:Selective transcriptional down-regulation of human rhinovirus-induced production of CXCL10 from airway epithelial cells via the MEK1 pathway. 1934 64

Psoriasis vulgaris is an autoimmune dermatosis with Th17 infiltration. Prolactin (PRL) may participate in the pathogenesis of psoriasis. The chemokine CCL20 recruits Th17 cells, and CCL20 production by epidermal keratinocytes is enhanced in psoriatic lesions. We examined the in vitro effects of PRL on CCL20 production in human keratinocytes. PRL increased basal and IL-17-induced CCL20 secretion, and mRNA expression in keratinocytes. CCL20 production by PRL was suppressed by antisense oligonucleotides against the AP-1 components c-Fos and c-Jun, whereas that by IL-17 was suppressed by antisense NF-kappaB p50 and p65. CCL20 production induced by PRL plus IL-17 was suppressed by antisense c-Fos, c-Jun, p50, and p65. PRL alone increased the transcriptional activity of AP-1, and c-Fos and c-Jun expression; moderately enhanced NF-kappaB activity and IkappaBalpha phosphorylation; and potently increased IL-17-induced NF-kappaB activity. MEK and JNK inhibitors suppressed PRL- or PRL-plus-IL-17-induced CCL20 production and AP-1 activities. MEK inhibitor suppressed PRL-induced c-Fos expression, whereas JNK inhibitor suppressed c-Jun expression. PRL induced ERK and JNK phosphorylation. These results suggest that PRL may enhance basal and IL-17-induced CCL20 production in keratinocytes by AP-1 and NF-kappaB activation, which is partially mediated via MEK/ERK and JNK. PRL may promote Th17 infiltration into psoriatic lesions via CCL20.
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PMID:Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes. 1935 May 75

Erbin is an ErbB2 binding protein, which belongs to the LAP (leucine-rich repeat (LRR) and PDZ domain) protein family. We previously reported that Tax1, a protein of the human T-cell leukemia virus type I (HTLV-I), associated with Erbin by using Erbin PDZ domain as a bait to screen a human T lymphocyte cDNA library by a yeast two hybrid strategy. In the present study, we demonstrated that Tax1 enhances cancer cell proliferation via Ras-Raf-MEK-ERK signaling pathway by using molecular section strategy. The pull-down assay showed that the four amino acid domain, that is, Tax1 350-353, might specifically interact with Erbin, but not any other Tax1 deletion mutants. The coimmunoprecipitation assay confirmed that Tax1 350-353 domain bound with Erbin in vivo. Functional study demonstrated that overexpression of Tax1 in cancer cell lines of liver cancer SMMC-7721, colon cancer HCT-116, and breast cancer MCF-7 facilitated the cell proliferation. And the transfection of Tax1 353 in MCF-7 cells with endogenous Erbin expression markedly increased phosphorylation of Ras, Raf, MEK1/2, ERK1/2, PI3K, and IkappaBalpha, suggesting that Tax1-enhanced cell proliferation tracks Ras-Raf-MEK-ERK signaling pathway.
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PMID:Tax1 enhances cancer cell proliferation via Ras-Raf-MEK-ERK signaling pathway. 1947 91

Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Osteopontin (OPN), which abundantly expressed in bone matrix, is involved in cell adhesion, migration, invasion and proliferation via interaction with its receptor, that is, alphavbeta3 integrin. However, the effect of OPN on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that OPN increased the migration and expression of matrix metalloproteinase (MMP)-9 in human chondrosarcoma cells (JJ012 cells). RGD peptide, alphavbeta3 monoclonal antibody and MAPK kinase (MEK) inhibitors (PD98059 and U0126) but not RAD peptide inhibited the OPN-induced increase of the migration and MMP-9 up-regulation of chondrosarcoma cells. OPN stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK and extracellular signal-regulated kinase (ERK). In addition, treatment of JJ012 cells with NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) inhibited OPN-induced cell migration and MMP-9 up-regulation. Stimulation of JJ012 cells with OPN also induced IkappaB kinase alpha/beta (IKK alpha/beta) phosphorylation, IkappaBalpha phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. The OPN-mediated increases in MMP-9 and kappaB-luciferase activities were inhibited by RGD peptide, PD98059 or FAK and ERK2 mutant. Taken together, our results indicated that OPN enhances the migration of chondrosarcoma cells by increasing MMP-9 expression through the alphavbeta3 integrin, FAK, MEK, ERK and NF-kappaB signal transduction pathway.
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PMID:Osteopontin increases migration and MMP-9 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. 1947 68

There is growing evidence that increased expression of cyclooxygenase-2 (COX-2) in the lungs of patients is a key event in the pathogenesis of lung diseases. In this study, we investigated the involvement of the extracellular signal-regulated kinase (ERK), IkappaB kinase alpha/beta (IKKalpha/beta), and nuclear factor-kappaB (NF-kappaB) signaling pathways in thrombin-induced COX-2 expression in human lung fibroblasts (WI-38). Treatment of WI-38 cells with thrombin caused increased COX-2 expression in a concentration- and time-dependent manner. Treatment of WI-38 cells with PD 98059 (2-[2-amino-3-methoxyphenyl]-4H-1-benzopyran-4-one, a MEK inhibitor) inhibited thrombin-induced COX-2 expression and COX-2-luciferase activity. Stimulation of cells with thrombin caused an increase in ERK phosphorylation in a time-dependent manner. In addition, treatment of WI-38 cells with Bay 117082, an IkappaB phosphorylation inhibitor, and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, inhibited thrombin-induced COX-2 expression. The thrombin-induced increase in COX-2-luciferase activity was also blocked by the dominant negative IkappaBalpha mutant (IkappaBalphaM). Treatment of WI-38 cells with thrombin induced IKKalpha/beta and IkappaBalpha phosphorylation, IkappaBalpha degradation, and kappaB-luciferase activity. The thrombin-mediated increases in IKKalpha/beta phosphorylation and kappaB-luciferase activity were inhibited by PD 98059. Taken together, these results suggest that the ERK-dependent IKKalpha/beta/NF-kappaB signaling pathway plays an important role in thrombin-induced COX-2 expression in human lung fibroblasts.
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PMID:Thrombin induces cyclooxygenase-2 expression via the ERK and NF-kappaB pathways in human lung fibroblasts. 1961 39

Inflammation and oxidative stress have been shown to play a critical role in the pathophysiology that leads to neurodegeneration. Omega-6 phospholipids, e.g. dilinoleoylphosphatidylcholine (DLPC), have been shown to have anti-inflammatory properties and therefore experiments were undertaken to determine whether DLPC can prevent inflammatory neurodegenerative events in the model neuronal cell line, SH-SY5Y. Tumor necrosis factor (TNF-alpha) and H(2)O(2) activate mitogen-activated protein kinase (MAPK) in SH-SY5Y cells within 5 min and this activation is completely blocked by DLPC (12 microM). DLPC blocks IkappaBalpha phosphorylation in the SH-SY5Y cells and prevents the phosphorylation and activation of nuclear factor-kappa B (NF-kappaB). The phospholipid inhibits induction of MAPK and NF-kappaB in similar fashion to the MEK1/2-inhibitor, U0126 (10 microM). DLPC completely abolishes TNF-alpha, H(2)O(2) and lipopolysaccaride (LPS)-induced neuronal tau phosphorylation. Cellular amyloid precursor protein levels are reduced by DLPC and LPS-induced amyloid-beta expression and secretion in SH-SY5Y cells are completely blocked by DLPC. Taken together, these data suggest that DLPC can act through MAPK to block neuronal inflammatory cascades and prevent potential pathological consequences in the neuronal metabolism of amyloid and tau proteins.
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PMID:Phospholipids block nuclear factor-kappa B and tau phosphorylation and inhibit amyloid-beta secretion in human neuroblastoma cells. 1978 16

The enterovirus 71 (EV71) causes severe neurological diseases that were mediated through cyclooxygenase-2 (COX-2) expression in brain. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown in neurons. Here we report that exposure of SK-N-SH cells to EV71 increased COX-2 expression and PGE(2) generation in a time- and virus titer-dependent manner, revealed by Western blot, real-time PCR, and PGE(2) analyses. These EV71-induced responses were mediated through activation of p42/p44 MAPK, p38 MAPK, JNK, NF-kappaB, and AP-1, revealed by using selective pharmacological inhibitors or transfection with respective siRNAs. Consistently, EV71-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaBalpha in the cytosol was blocked by pretreatment with the selective inhibitors of MEK1/2 (U0126) and NF-kappaB (Bay11-7085), respectively, suggesting that MEK1/2-p42/p44 MAPK cascade linking to NF-kappaB was involved in COX-2 expression. In addition, EV71-induced AP-1 subunits (c-jun and c-fos mRNA) expression was also attenuated by pretreatment with a selective JNK inhibitor SP600125, suggesting that JNK cascade linking to AP-1 was involved in COX-2 expression induced by EV71. These findings suggested that up-regulation of COX-2 associated with the release of PGE(2) from EV71-infected SK-N-SH cells which was mediated through activation of p38 MAPK, JNK, p42/p44 MAPK, NF-kappaB, and AP-1 pathways.
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PMID:Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication. 1980 Apr 3

Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IkappaBalpha, which all negatively interact with components of the pro-survival NFkappaB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFkappaB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IkappaBalpha) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFkappaB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFkappaB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted.
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PMID:NFkappaB modulators in a model of glucocorticoid resistant, childhood acute lymphoblastic leukemia. 2010 24

Enterovirus 71 (EV71) induces the expression of cyclooxgenase (COX)-2 served as a major neurotoxic factor in CNS injury. However, the mechanisms underlying EV71-initiated intracellular signaling pathways leading to COX-2 expression remain unknown. Therefore, we investigated the mechanisms underlying EV71-induced COX-2 expression and prostaglandin E(2) (PGE(2)) production in rat brain astrocytes (RBA)-1, determined by Western blotting, RT-PCR, and promoter assay. Here, we reported that EV71-induced COX-2 expression and PGE(2) production were attenuated by pretreatment with the inhibitors of c-Src (PP1), PDGFR (AG1296), PI3K (Wortmannin), MEK1/2 (PD98059), NF-kappaB (helenalin), and AP-1 (Tanshinone) and transfection with shRNA or siRNA of c-Src, PDGFR, p85, c-Jun, c-Fos, ERK1, or ERK2. We further observed that EV71-induced activation of Akt and p42/p44 MAPK were mediated via c-Src and PDGFR. Pretreatment with PP1 attenuated EV71-stimulated phosphorylation of Src, PDGFR, Akt, and p42/p44 MAPK. Inhibition of PI3K by Wortmannin attenuated EV71-induced Akt and p42/p44 MAPK phosphorylation, but had no effect on PDGFR phosphorylation, suggesting that PDGFR is an upstream and p42/p44 MAPK is a downstream component of PI3K/Akt in these responses. EV71-stimulated NF-kappaB translocation from the cytoplasm to the nucleus, IkappaBalpha degradation and NF-kappaB promoter activity were attenuated by pretreatment with helenalin, but not AG1296, Wortmannin, and PD98059. EV71-induced c-Jun mRNA expression was attenuated by pretreatment with PD98059, AG1296, or Wortmannin. These results demonstrate that in RBA-1 cells, EV71-induced COX-2 expression associated with PGE(2) production is mediated through activation of c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK to initiate the expression of AP-1.
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PMID:EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. 2033 48

The ribosomal S6 kinase 2 (RSK2) is a well-known serine/threonine kinase and a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins. It is activated downstream of the MEK/ERKs cascade by mitogenic stimuli such as EGF or TPA. Here, we show that RSK2 is activated by treatment with tumor necrosis factor-alpha (TNF-alpha) and directly phosphorylates IkappaBalpha at Ser-32, leading to IkappaBalpha degradation. The phosphorylation of IkappaBalpha promotes the activation and translocation of the nuclear factor-kappaB (NF-kappaB) subunits p65 and p50 to the nucleus. The net result is an increased NF-kappaB activity, which serves as a mechanism for RSK2 blockade of TNF-alpha-induced apoptosis and enhanced cell survival.
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PMID:RSK2 mediates NF-{kappa}B activity through the phosphorylation of IkappaBalpha in the TNF-R1 pathway. 2038 20


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