Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutral matrix metalloproteinases (MMPs) play an important role in bone matrix degradation accompanied by bone remodeling. We herein show for the first time that macrophage migration inhibitory factor (MIF) up-regulates MMP-13 (collagenase-3) mRNA of rat calvaria-derived osteoblasts. The mRNA up-regulation was seen at 3 h in response to MIF (10 microg/ml), reached the maximum level at 6-12 h, and returned to the basal level at 36 h. MMP-13 mRNA up-regulation was preceded by up-regulation of c-jun and c-fos mRNA. Tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-9 (92-kDa type IV collagenase) were also up-regulated, but to a lesser extent. The MMP-13 mRNA up-regulation was significantly suppressed by genistein, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Similarly, a selective mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 inhibitor (PD98059) and c-jun/activator protein (AP)-1 inhibitor (curcumin) suppressed MMP-13 mRNA up-regulation induced by MIF. The mRNA levels of c-jun and c-fos in response to MIF were also inhibited by PD98059. Consistent with these results, MIF stimulated phosphorylation of tyrosine, autophosphorylation of Src, activation of Ras, activation of extracellular signal-regulated kinases (ERK) 1/2, a MAPK, but not c-Jun N-terminal kinase or p38, and phosphorylation of c-Jun. Osteoblasts obtained from calvariae of newborn JunAA mice, defective in phosphorylation of c-Jun, or newborn c-Fos knockout (Fos -/- ) mice, showed much less induction of MMP-13 with the addition of MIF than osteoblasts obtained from wild-type or littermate control mice. Taken together, these results suggest that MIF increases the MMP-13 mRNA level of rat osteoblasts via the Src-related tyrosine kinase-, Ras-, ERK1/2-, and AP-1-dependent pathway.
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PMID:Macrophage migration inhibitory factor up-regulates matrix metalloproteinase-9 and -13 in rat osteoblasts. Relevance to intracellular signaling pathways. 1175 95

In response to oxidative stress, the pathogenesis of a number of cardiovascular events and several genes are stimulated by extracellular signal-regulated kinases (ERK1/2). Biphasic (early, 10 min; and delayed, 120 min) ERK1/2 activation by H(2)O(2), a reactive oxygen species, was observed in cultured neonatal rat cardiomyocytes. We investigated the hypothesis that the delayed activation of ERK1/2 depends on a factor secreted by oxidative stress (FSO). The delayed activation was inhibited by calphostin C, a protein kinase C inhibitor. Conditioned medium (CM) obtained from cells stimulated with H(2)O(2) induced rapid and monophasic ERK1/2 activation, which was not inhibited by calphostin C. In contrast, calphostin C-pretreated CM did not activate ERK1/2. Macrophage migration inhibitory factor (MIF) was one of the candidate FSOs activating ERK1/2. The existence of MIF in CM, the recombinant MIF-stimulated ERK1/2 rapid activation, and anti-MIF neutralizing antibody-induced inhibition of the delayed activation implied that MIF could be the FSO. Pretreatment of cardiomyocytes with a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor did not suppress the MIF secretion, although it prevented the ERK1/2 activation by H(2)O(2). These results indicate that MIF is secreted from cardiomyocytes as a result of oxidative stress and activates ERK1/2 through a MEK1/2-dependent mechanism, although the secretion is not regulated by ERK1/2 but by protein kinase C.
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PMID:Contribution of macrophage migration inhibitory factor to extracellular signal-regulated kinase activation by oxidative stress in cardiomyocytes. 1197 85

Matrix metalloproteinases (MMPs) are thought to be responsible for dermal photoaging in human skin. In the present study, we evaluated the involvement of macrophage migration inhibitory factor (MIF) in MMP-1 expression under ultraviolet A (UVA) irradiation in cultured human dermal fibroblasts. UVA (20 J/cm(2)) up-regulates MIF production, and UVA-induced MMP-1 mRNA production is inhibited by an anti-MIF antibody. MIF (100 ng/ml) was shown to induce MMP-1 in cultured human dermal fibroblasts. We found that MIF (100 ng/ml) enhanced MMP-1 activity in cultured fibroblasts assessed by zymography. Moreover, we observed that fibroblasts obtained from MIF-deficient mice were much less sensitive to UVA regarding MMP-13 expression than those from wild-type BALB/c mice. Furthermore, after UVA irradiation (10 J/cm(2)), dermal fibroblasts of MIF-deficient mice produced significantly decreased levels of MMP-13 compared with fibroblasts of wild-type mice. Next we investigated the signal transduction pathway of MIF. The up-regulation of MMP-1 mRNA by MIF stimulation was found to be inhibited by a PKC inhibitor (GF109203X), a Src-family tyrosine kinase inhibitor (herbimycin A), a tyrosine kinase inhibitor (genistein), a PKA inhibitor (H89), a MEK inhibitor (PD98089), and a JNK inhibitor (SP600125). In contrast, the p38 inhibitor (SB203580) was found to have little effect on expression of MMP-1 mRNA. We found that PKC-pan, PKC alpha/beta II, PKC delta (Thr505), PKC delta (Ser(643)), Raf, and MAPK were phosphorylated by MIF. Moreover, we demonstrated that phosphorylation of PKC alpha/beta II and MAPK in response to MIF was suppressed by genistein, and herbimycin A as well as by transfection of the plasmid of C-terminal Src kinase. The DNA binding activity of AP-1 was significantly up-regulated 2 h after MIF stimulation. Taken together, these results suggest that MIF is involved in the up-regulation of UVA-induced MMP-1 in dermal fibroblasts through PKC-, PKA-, Src family tyrosine kinase-, MAPK-, c-Jun-, and AP-1-dependent pathways.
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PMID:Ultraviolet A-induced production of matrix metalloproteinase-1 is mediated by macrophage migration inhibitory factor (MIF) in human dermal fibroblasts. 1458 88

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been shown to play a role in wound-healing processes. In this study, we investigated whether protease-activated receptor (PAR)-1 and PAR-2 mediated MIF expression in human endothelial cells. Thrombin, factor Xa (FXa), and trypsin induced MIF expression in human dermal microvascular endothelial cells and human umbilical vein endothelial cells, but other proteases, including kallikrein and urokinase, failed to do so. Thrombin-induced MIF mRNA expression was significantly reduced by the thrombin-specific inhibitor hirudin. Thrombin receptor activation peptide-6, a synthetic PAR-1 peptide, induced MIF mRNA expression, suggesting that PAR-1 mediates MIF expression in response to thrombin. The effects of FXa were blocked by antithrombin III, but not by hirudin, indicating that FXa might enhance MIF production directly rather than via thrombin stimulation. The synthetic PAR-2 peptide SLIGRL-NH(2) induced MIF mRNA expression, showing that PAR-2 mediated MIF expression in response to FXa. Concerning the signal transduction, a mitogen-activated protein kinase kinase inhibitor (PD98089) and a nuclear factor (NF)-kappaB inhibitor (SN50) suppressed the up-regulation of MIF mRNA in response to thrombin, FXa, and PAR-2 agonist stimulation, whereas a p38 inhibitor (SB203580) had little effect. These facts indicate that up-regulation of MIF by thrombin or FXa is regulated by p44/p42 mitogen-activated protein kinase-dependent pathways and NF-kappaB-dependent pathways. Moreover, we found that PAR-1 and PAR-2 mRNA expression in endothelial cells was enhanced by MIF. Furthermore, we examined the inflammatory response induced by PAR-1 and PAR-2 agonists injected into the mouse footpad. As shown by footpad thickness, an indicator of inflammation, MIF-deficient mice (C57BL/6) were much less sensitive to either PAR-1 or PAR-2 agonists than wild-type mice. Taken together, these results suggest that MIF contributes to the inflammatory phase of the wound healing process in concert with thrombin and FXa via PAR-1 and PAR-2.
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PMID:Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. 1473 78

Macrophage migration inhibitory factor (MIF) is a 12.5 kD polypeptide that serves as a critical regulator of cell functions such as gene expression, proliferation or apoptosis. However, the signal transduction pathways through which MIF takes part in cellular regulation are only incompletely understood. MIF leads to CD74-dependent "sustained" activation of ERK1/2 MAPK, but MIF's role in "transient" ERK activation and the involved upstream pathways are unknown. Here we report that the transient ERK pathway was markedly activated by MIF. This effect involved the phosphorylation and activation of Raf-1, MEK, ERK, and Elk-1. Of note, rapid and transient ERK phosphorylation by MIF was measurable in MIF-deficient cells, suggesting that MIF acted in a non-autocrine fashion. Applying the inhibitor genistein, a tyrosine kinase (TPK) activity was identified as a critical upstream signalling event in MIF-induced transient ERK signalling. Experiments using the Src kinase inhibitor PP2 indicated that the involved TPK was a Src-type tyrosine kinase. A role for an upstream Src kinase was proven by applying Src-deficient cells which did not exhibit transient ERK activation upon treatment with MIF, but in which MIF-induced ERK signalling could be restored by re-expressing Src. Intriguingly, JAB1/CSN5, a signalosome component, cellular binding protein of MIF and regulator of cell proliferation and survival, had a marked, yet dual, effect on MIF-induced ERK signalling. JAB1 overexpression inhibited sustained, but not transient, ERK phosphorylation. By contrast, JAB1-knock-down by siRNA revealed that minimum JAB1 levels were necessary for transient activation of ERK by MIF. In conclusion, MIF rapidly and transiently activates the ERK pathway, an effect that has not been recognized previously. This signalling pathway involves the upstream activation of a Src-type kinase and is co-regulated by the cellular MIF binding protein JAB1/CSN5. Our study thus has unravelled a novel MIF-driven signalling pathway and an intricate regulatory system involving extra- and possibly intracellular MIF, and which likely critically participates in controlling cell proliferation and survival.
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PMID:Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. 1612 7

Macrophage migration inhibitory factor (MIF) plays some pivotal roles in innate immunity and inflammation. Ursolic acid (UA), an anti-inflammatory triterpene carboxylic acid, was recently reported to induce the release of pro-inflammatory mediators in resting macrophages (Mvarphi). We investigated the effects of UA on MIF protein release in resting RAW264.7 mouse Mvarphi, and found that it decreased intracellular MIF protein levels and promoted the release of MIF into the culture media in dose- and time-dependent manners, without affecting mRNA levels. Further, the triterpene strikingly induced activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2) within 30min, whereas no phosphorylation of p38 MAPK or JNK protein was observed. In addition, UA-promoted MIF release was significantly inhibited by PD98059, a MEK1/2 inhibitor, while siRNA for ERK2, but not ERK1, significantly decreased the amount of MIF protein released. These results suggest that UA triggers the release of intracellular MIF protein through the ERK2 activation.
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PMID:Ursolic acid promotes the release of macrophage migration inhibitory factor via ERK2 activation in resting mouse macrophages. 1618 40

We have shown previously that macrophage migration inhibitory factor (MIF) may play a role in the destabilization of atherosclerotic plaques by activating matrix metalloproteinase protein-9 (MMP-9). The aim of this study is to investigate the signaling mechanism by which MIF induces MMP-9 expression and activation in a murine macrophage line (RAW264.7). MIF was able to activate extracellular signal-regulated kinase 1/2 (ERK1/2), to a less extent JNK, but not p38 mitogen-activated protein (MAP), MAP kinase to induce MMP9 mRNA and protein expression in RAW264.7 murine macrophages. This was confirmed by the findings that addition of an ERK MAP kinase inhibitor (PD98059) but not a p38 inhibitor (SB203589) abolished MIF-induced MMP-9 expression and activation, whereas addition of a JNK inhibitor (SP600125) produced a partially inhibitory effect. The functional role of mitogen-activated protein kinase kinase (MEK)-ERK MAP kinase in MIF-induced MMP-9 expression was further confirmed by overexpressing dominant negative MEK (DN-MEK) and DN-ERK MAP kinases. Interestingly, constitutive expression of a wild-type (WT)-MEK alone was also capable of inducing a low, but significant MMP-9 mRNA and protein expression but did not cause a further increase in MMP-9 in response to MIF. MIF activates the MEK-ERK MAP kinase pathway to induce MMP-9 expression by murine macrophages. Activation of this pathway is necessary for MMP-9 expression and activation in response to MIF stimulation.
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PMID:Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. 1731 37

The cytokine macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity, inflammation and oncogenesis. However, four decades after its identification, the molecular mechanism(s) regulating the expression of the MIF gene remain largely unknown. Analyses of human monocytic (THP-1), epithelial (HeLa and A549) and keratinocytic (HaCat) cells transfected with wild-type, truncated and mutated MIF promoter reporter constructs, and electrophoretic mobility shift assay, chromatin immunoprecipitation, and siRNA inhibition indicated that the transcription factors specificity protein (Sp)1 and cAMP response element-binding protein (CREB) are critical positive regulators of constitutive human MIF gene expression. Albeit located in a cytosine guanine dinucleotide island, the MIF gene was found to be hypomethylated, an observation consistent with high baseline transcriptional activity. Moreover, stimulation of THP-1 cells and of peripheral blood mononuclear cells with microbial products up-regulated phosphorylated Sp1 nuclear content, Sp1 DNA-binding activity, MIF promoter activity and MIF mRNA levels in a MEK1/2-, Sp1-dependent manner. Taken together with previous observations of an important role for MIF in pro-inflammatory macrophage responses, these present findings suggest a key role for Sp1 and CREB in transcriptional regulation of MIF gene expression and MIF-dependent host antimicrobial innate immune defense.
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PMID:Regulation of constitutive and microbial pathogen-induced human macrophage migration inhibitory factor (MIF) gene expression. 1803 23

Dengue virus (DENV) infection can cause mild dengue fever or severe dengue hemorrhage fever (DHF) and dengue shock syndrome (DSS). Serum levels of the macrophage migration inhibitory factor (MIF) have been shown to be correlated with severity and mortality in DENV patients, but the pathogenic roles of MIF in DHF/DSS are still unclear. Increase in vascular permeability is an important hallmark of DHF/DSS. In this study, we found that DENV infection of the human hepatoma cell line (Huh 7) induced MIF production. Conditioned medium collected from DENV-infected Huh 7 cells enhanced the permeability of the human endothelial cell line (HMEC-1) which was reduced in the presence of a MIF inhibitor, ISO-1 or medium from DENV-infected MIF knockdown Huh 7 cells. To further identify whether MIF can alter vascular permeability, we cloned and expressed both human and murine recombinant MIF (rMIF) and tested their effects on vascular permeability both in vitro and in vivo. Indirect immunofluorescent staining showed that the tight junction protein ZO-1 of HMEC-1 was disarrayed in the presence of rMIF and partially recovered when cells were treated with ISO-1 or PI3K/MEK-ERK/JNK signaling pathway inhibitors such as Ly294002, U0126, and SP600215. In addition, ZO-1 disarray induced by MIF was also recovered when CD74 or CXCR2/4 expression of HMEC-1 were inhibited. Last but not least, the vascular permeabilities of the peritoneal cavity and dorsal cutaneous capillary were also increased in mice treated with rMIF. Taken together; these results suggest that MIF induced by DENV infection may contribute to the increase of vascular permeability during DHF/DSS. Therapeutic intervention of MIF by its inhibitor or neutralizing antibodies may prevent DENV-induced lethality.
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PMID:Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. 2132 Jul 86

Pulmonary hypertension (PH) contributes to the mortality of patients with lung and heart diseases. However, the underlying mechanism has not been completely elucidated. Accumulating evidence suggests that inflammatory response may be involved in the pathogenesis of PH. Macrophage migration inhibitory factor (MIF) is a critical upstream inflammatory mediator which promotes a broad range of pathophysiological processes. The aim of the study was to investigate the role of MIF in the pulmonary vascular remodeling of hypoxia-induced PH. We found that MIF mRNA and protein expression was increased in the lung tissues from hypoxic pulmonary hypertensive rats. Intensive immunoreactivity for MIF was observed in smooth muscle cells of large pulmonary arteries (PAs), endothelial cells of small PAs, and inflammatory cells of hypoxic lungs. MIF participated in the hypoxia-induced PASMCs proliferation, and it could directly stimulate proliferation of these cells. MIF-induced enhanced growth of PASMCs was attenuated by MEK and JNK inhibitor. Besides, MIF antagonist ISO-1 suppressed the ERK1/2 and JNK phosphorylation induced by MIF. In conclusion, the current finding suggested that MIF may act on the proliferation of PASMCs through the activation of the ERK1/2 and JNK pathways, which contributes to hypoxic pulmonary hypertension.
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PMID:Role of macrophage migration inhibitory factor in the proliferation of smooth muscle cell in pulmonary hypertension. 2236 4


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