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)

In our study, we examined the mechanism by which granulocyte-macrophage colony stimulating factor (GM-CSF) regulates angiogenesis using in vitro models. GM-CSF significantly increased precapillary sprout-like formation from endothelial cell spheroids seeded in type-I collagen gels and tubule formation on coculture of endothelial cells with fibroblasts. In both cases, sprout and tubule formation was highly dependent on metalloproteinase activity. Tissue Inhibitor of metalloproteinase (TIMP) profiling in the spheroid and coculture models showed inhibition by TIMP-2 but not by TIMP-1, indicative of activity of membrane-type matrix metalloproteinases (MT-MMPs). GM-CSF induced sprout formation in spheroids was found to be potently inhibited by siRNA specific for MT1-MMP. Subsequent analysis showed that GM-CSF transiently increased MT1-MMP mRNA in endothelial cells in a MEK-dependent mechanism, which led to increased surface levels of MT1-MMP. This was accompanied by an increase in MT1-MMP-dependent degradation of DQ-collagen by lysates of GM-CSF stimulated endothelial cells. GM-CSF did not increase MT1-MMP levels in fibroblasts. The effect of GM-CSF on endothelial cell sprout formation could be mimicked by adenoviral transduction of intact spheroids with virus expressing MT1-MMP, but not by transduction of endothelial cells before spheroid formation, suggesting that upregulation of MT1-MMP must only occur in cells directly involved in tubule formation.
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PMID:Granulocyte-macrophage colony stimulating factor induces endothelial capillary formation through induction of membrane-type 1 matrix metalloproteinase expression in vitro. 1802 71

Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors. PARs are activated by a serine-dependent cleavage generating a tethered activating ligand. PAR-2 was shown to be involved in inflammatory pathways. We investigated the in situ levels and modulation of PAR-2 in human normal and osteoarthritis (OA) cartilage/chondrocytes. Furthermore, we evaluated the role of PAR-2 on the synthesis of the major catabolic factors in OA cartilage, including metalloproteinase (MMP)-1 and MMP-13 and the inflammatory mediator cyclooxygenase 2 (COX-2), as well as the PAR-2-activated signalling pathways in OA chondrocytes. PAR-2 expression was determined using real-time reverse transcription-polymerase chain reaction and protein levels by immunohistochemistry in normal and OA cartilage. Protein modulation was investigated in OA cartilage explants treated with a specific PAR-2-activating peptide (PAR-2-AP), SLIGKV-NH2 (1 to 400 microM), interleukin 1 beta (IL-1beta) (100 pg/mL), tumor necrosis factor-alpha (TNF-alpha) (5 ng/mL), transforming growth factor-beta-1 (TGF-beta1) (10 ng/mL), or the signalling pathway inhibitors of p38 (SB202190), MEK1/2 (mitogen-activated protein kinase kinase) (PD98059), and nuclear factor-kappa B (NF-kappaB) (SN50), and PAR-2 levels were determined by immunohistochemistry. Signalling pathways were analyzed on OA chondrocytes by Western blot using specific phospho-antibodies against extracellular signal-regulated kinase 1/2 (Erk1/2), p38, JNK (c-jun N-terminal kinase), and NF-kappaB in the presence or absence of the PAR-2-AP and/or IL-1beta. PAR-2-induced MMP and COX-2 levels in cartilage were determined by immunohistochemistry. PAR-2 is produced by human chondrocytes and is significantly upregulated in OA compared with normal chondrocytes (p < 0.04 and p < 0.03, respectively). The receptor levels were significantly upregulated by IL-1beta (p < 0.006) and TNF-alpha (p < 0.002) as well as by the PAR-2-AP at 10, 100, and 400 microM (p < 0.02) and were downregulated by the inhibition of p38. After 48 hours of incubation, PAR-2 activation significantly induced MMP-1 and COX-2 starting at 10 microM (both p < 0.005) and MMP-13 at 100 microM (p < 0.02) as well as the phosphorylation of Erk1/2 and p38 within 5 minutes of incubation (p < 0.03). Though not statistically significant, IL-1beta produced an additional effect on the activation of Erk1/2 and p38. This study documents, for the first time, functional consequences of PAR-2 activation in human OA cartilage, identifies p38 as the major signalling pathway regulating its synthesis, and demonstrates that specific PAR-2 activation induces Erk1/2 and p38 in OA chondrocytes. These results suggest PAR-2 as a potential new therapeutic target for the treatment of OA.
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PMID:Activation of proteinase-activated receptor 2 in human osteoarthritic cartilage upregulates catabolic and proinflammatory pathways capable of inducing cartilage degradation: a basic science study. 1803 79

The obligate intracellular human pathogenic bacterium Chlamydia trachomatis has evolved multiple mechanisms to circumvent the host immune system. Infected cells exhibit a profound resistance to the induction of apoptosis and down-regulate the expression of major histocompatibility complex class I and class II molecules to evade the cytotoxic effect of effector immune cells. Here we demonstrate the down-regulation of tumor necrosis factor receptor 1 (TNFR1) on the surface of infected cells. Interestingly, other members of the TNFR family such as TNFR2 and CD95 (Fas/Apo-1) were not modulated during infection, suggesting a selective mechanism underlying surface reduction of TNFR1. The observed effect was not due to reduced expression since the overall amount of TNFR1 protein was increased in infected cells. TNFR1 accumulated at the chlamydial inclusion and was shed by the infected cell into the culture supernatant. Receptor shedding depended on the infection-induced activation of the MEK-ERK pathway and the metalloproteinase TACE (TNFalpha converting enzyme). Our results point to a new function of TNFR1 modulation by C. trachomatis in controlling inflammatory signals during infection.
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PMID:Reduced display of tumor necrosis factor receptor I at the host cell surface supports infection with Chlamydia trachomatis. 1816 50

Adenosine triphosphate (ATP) is coreleased with catecholamines from adrenal medullary chromaffin cells in response to sympathetic nervous system stimulation and may regulate these cells in an autocrine or paracrine manner. Increases in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation were observed in response to ATP stimulation of bovine chromaffin cells. The signaling pathway involved in ATP-mediated ERK1/2 phosphorylation was investigated via Western blot analysis. ATP and uridine 5'-triphosphate (UTP) increased ERK1/2 phosphorylation potently, peaking between 5 and 15 min. The mitogen-activated protein kinase (MAPK/ERK)-activating kinase (MEK) inhibitor PD98059 blocked this response. UTP, which is selective for G-protein-coupled P2Y receptors, was the most potent agonist among several nucleotides tested. Adenosine 5'-O-(3-thio) triphosphate (ATPgammaS) and ATP were also potent agonists, characteristic of the P2Y(2) or P2Y(4) receptor subtypes, whereas agonists selective for P2X receptors or other P2Y receptor subtypes were weakly effective. The receptor involved was further characterized by the nonspecific P2 antagonists suramin and reactive blue 2, which each partially inhibited ATP-mediated ERK1/2 phosphorylation. Inhibitors of protein kinase C (PKC), protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), and phosphoinositide-3 kinase (PI3K) had no effect on ATP-mediated ERK1/2 phosphorylation. The Src inhibitor PP2, epidermal growth factor receptor (EGFR) inhibitor AG1478, and metalloproteinase inhibitor GM6001 decreased ATP-mediated ERK1/2 phosphorylation. These results suggest nucleotide-mediated ERK1/2 phosphorylation is mediated by a P2Y(2) or P2Y(4) receptor, which stimulates metalloproteinase-dependent transactivation of the EGFR.
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PMID:UTP and ATP increase extracellular signal-regulated kinase 1/2 phosphorylation in bovine chromaffin cells through epidermal growth factor receptor transactivation. 1877 8

Leptin plays a role in both energy homeostasis and reproduction, and it is required in early pregnancy. It stimulates metalloproteinase activity in cultured human trophoblasts and invasiveness of cultured mouse trophoblasts. Our goal has been to examine mechanisms that underpin the ability of leptin to promote trophoblast invasiveness in primary cultures of mouse trophoblasts. Leptin stimulated the phosphorylation of MEK (MAP2K1) but not signal transducer and activator of transcription 3 (STAT3) in the cultures, increased the concentration of the suppressor of cytokine signaling 3 (SOCS3) protein, and upregulated metalloproteinase activity. Microarray analysis revealed that leptin stimulated select genes with roles in cell motility, including Stmn, a gene linked to invasiveness in other cell types. There was also an increase in activity of several genes associated with MAPK and RhoGTPase signaling. In addition, leptin muted expression of genes correlated with terminal differentiation of trophoblast giant cells, including ones associated with the TGFbeta signaling pathway and endoreduplication of DNA, and upregulated selected prolactin-related family members. Feulgen staining of leptin-treated cells revealed a loss of cells with low ploidy. The data suggest that leptin accelerates disappearance of non-giant cells while inhibiting terminal differentiation of committed giant cells, possibly by maintaining cells in an intermediate stage of differentiation.
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PMID:Effect of leptin on mouse trophoblast giant cells. 1903 58

Phenotypic remodeling of Schwann cells is required to ensure successful regeneration of damaged peripheral axons. After nerve damage, Schwann cells produce an over 100-fold increase in metalloproteinase-9 (MMP-9), and therapy with an MMP inhibitor increases the number of resident (but not infiltrating) cells in injured nerve. Here, we demonstrate that MMP-9 regulates proliferation and trophic signaling of Schwann cells. Using in vivo BrdU incorporation studies of axotomized sciatic nerves of MMP-9-/- mice, we found increased Schwann cell mitosis in regenerating (proximal) stump relative to wild-type mice. Treatment of cultured primary Schwann cells with recombinant MMP-9 suppressed their growth, mitogenic activity, and produced a dose-dependent, biphasic, and selective activation of ERK1/2, but not JNK and p38 MAPK. MMP-9 induced ERK1/2 signaling in both undifferentiated and differentiated (using dbcAMP) Schwann cells. Using inhibitors to MEK and trophic tyrosine kinase receptors, we established that MMP-9 regulates Ras/Raf/MEK-ERK pathways through IGF-1, ErbB, and PDGF receptors. We also report on the early changes of MMP-9 mRNA expression (within 24 h) after axotomy. These studies establish that MMP-9 controls critical trophic signal transduction pathways and phenotypic remodeling of Schwann cells.
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PMID:MMP-9 controls Schwann cell proliferation and phenotypic remodeling via IGF-1 and ErbB receptor-mediated activation of MEK/ERK pathway. 1922 95

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.
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PMID:Anthrax toxin: pathologic effects on the cardiovascular system. 1927 4

Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)-beta, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)-1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI-1 induced by TGF-beta in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf-1, MEK-1/2, and ERK-1/2. PAI-1 transcription also is suppressed by treatment with kinase inhibitors for MEK-1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI-1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR-dependent signal transduction pathway activated by metalloproteinases.
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PMID:Suppression of PAI-1 expression through inhibition of the EGFR-mediated signaling cascade in rat kidney fibroblast by ascofuranone. 1930 96

Matrix metalloproteinase-1 (MMP-1) is an inflammation-inducible neutral protease that mediates extracellular matrix remodeling and promotes tumor invasion. In this study, we examined the activation of MMP-1 gene expression in A549 lung carcinoma cells stimulated with the inflammatory cytokine interleukin-1beta (IL-1beta). We found that MMP-1 mRNA levels were maximal following 16 hours of IL-1beta stimulation and that this correlated with the expression of the transcription factor CCAAT enhancer-binding protein-beta (CEBPB). Knockdown of CEBPB expression with short hairpin RNA abrogated the expression of MMP-1, MMP-3, and MMP-10 in IL-1beta-stimulated A549 cells. An established CEBP element in the MMP-1 promoter was found to be required for basal and IL-1beta-induced transcription. Electrophoresis mobility shift assays showed that CEBPB binds to this promoter element maximally 16 hours after IL-1beta stimulation. DNA affinity chromatography studies showed that the LAP1, LAP2, and LIP isoforms of CEBPB bind to the IL-1beta-responsive CEBPB site in the MMP-1 promoter. Exogenous expression of the LAP1 and LAP2 isoforms stimulated the MMP-1 promoter, whereas LIP had no effect. Phosphorylation of CEBPB at Thr(235) peaked at 16 hours in IL-1beta-stimulated cells. The MEK inhibitor U0126 inhibited this phosphorylation and reduced MMP-1 gene induction. These studies establish CEBPB as an important mediator of metalloproteinase gene activation during inflammatory responses in lung cancer cells and highlight the different regulatory roles of CEBPB isoforms.
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PMID:CCAAT enhancer binding protein-beta regulates matrix metalloproteinase-1 expression in interleukin-1beta-stimulated A549 lung carcinoma cells. 1972 73

Transforming growth factor-beta1 (TGF-beta1) activates Rac1 GTPase in mouse transformed keratinocytes. Expression of a constitutively active Q61LRac1 mutant induced an epithelial to mesenchymal transition (EMT) linked to stimulation of cell migration and invasion. On the contrary, expression of a dominant-negative N17TRac1 abolished TGF-beta1-induced cell scattering, migration and invasion. Moreover, Q61LRac1 enhanced metalloproteinase-9 (MMP9) production to levels comparable to those induced by TGF-beta1, while N17TRac1 was inhibitory. TGF-beta1-mediated EMT involves the expression of the E-cadherin repressor Snail1, regulated by the Rac1 and mitogen-activated protein kinase (MAPK) pathways. Furthermore, MMP9 production was MAPK-dependent, as the MEK inhibitor PD98059 decreased TGF-beta1-induced MMP9 expression and secretion in Q61LRac1 expressing cells. We propose that regulation of TGF-beta1-mediated plasticity of transformed keratinocytes requires the cooperation between the Rac1 and MAPK signalling pathways.
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PMID:Rac1 modulates TGF-beta1-mediated epithelial cell plasticity and MMP9 production in transformed keratinocytes. 2035 88


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