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)

We previously reported that oxidized low-density lipoprotein (Ox-LDL)-induced expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) via PKC, leading to activation of phosphatidylinositol-3 kinase (PI-3K), was important for macrophage proliferation [J Biol Chem 275 (2000) 5810]. The aim of the present study was to elucidate the role of extracellular-signal regulated kinase 1/2 (ERK1/2) and of p38 MAPK in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneal macrophages assessed by [3H]thymidine incorporation and cell counting assays was significantly inhibited by MEK1/2 inhibitors, PD98059 or U0126, and p38 MAPK inhibitors, SB203580 or SB202190, respectively. Ox-LDL-induced GM-CSF production was inhibited by MEK1/2 inhibitors but not by p38 MAPK inhibitors in mRNA and protein levels, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by p38 MAPK inhibitors but enhanced by MEK1/2 inhibitors. Recombinant GM-CSF-induced PI-3K activation and Akt phosphorylation were significantly inhibited by SB203580 but enhanced by PD98059. Our results suggest that ERK1/2 is involved in Ox-LDL-induced macrophage proliferation in the signaling pathway before GM-CSF production, whereas p38 MAPK is involved after GM-CSF release. Thus, the importance of MAPKs in Ox-LDL-induced macrophage proliferation was confirmed and the control of MAPK cascade could be targeted as a potential treatment of atherosclerosis.
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PMID:Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase mediate macrophage proliferation induced by oxidized low-density lipoprotein. 1538 Apr 45

Increasing evidence suggests that CD45, a transmembrane protein tyrosine phosphatase, is an important modulator of macrophage activation. Microglia, resident brain macrophages, express CD45 and proliferate under pathologic conditions. In this study, we examined the role of CD45 in modulating GM-CSF-induced proliferation and signal transduction in primary human microglial cultures. Soluble, but not immobilized anti-CD45RO induced tyrosine phosphatase activity and inhibited GM-CSF-induced microglial proliferation. Microglial proliferation was also inhibited by PP2 (Src inhibitor), LY294002 (PI3K inhibitor), and U0126 (MEK inhibitor). GM-CSF induced phosphorylation of Jak2, Stat5, Hck (the myeloid-restricted Src kinase), Akt, Stat3, and Erk MAPKs in microglia. Of these, anti-CD45RO inhibited phosphorylation of Hck and Akt, and PP2 inhibited phosphorylation of Hck and Akt. In a macrophage cell line stably overexpressing wild-type or kinase-inactive Hck, GM-CSF increased proliferation of the control (empty vector) and wild-type but not kinase-inactive cells, and this was inhibited by anti-CD45RO. Together, these results demonstrate that, in macrophages, Hck tyrosine kinase is activated by GM-CSF, and that Hck plays a pivotal role in cell proliferation and survival by activating the PI3K/Akt pathway. Ab-mediated activation of macrophage and microglial CD45 tyrosine phosphatase may have therapeutic implications for CNS inflammatory diseases.
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PMID:Inhibition of granulocyte-macrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. 1572 79

This study was designed to investigate Bad phosphorylation at several of its key regulatory Ser residues in cytokine-dependent hemopoietic cells. These studies were initiated in light of numerous studies that have reported a key role for phosphorylated Bad in preventing apoptosis. One key question is whether the survival signaling effect of the PI 3-kinase pathway is mediated by PKB phosphorylation of Bad. We confirm previous reports that if Bad is overexpressed or if active PKB is overexpressed, then the increased phosphorylation of Bad at Ser136 is apparent. However, we were unable to detect phosphorylation of endogenous Bad at Ser136 in the MC/9 mast cell line or in murine bone marrow-derived macrophages. On the other hand, phosphorylation of Bad at Ser112 and Ser155 was observed in response to IL-3 or GM-CSF, which activate the MEK/erk pathway, but not with IL-4, which activates the PI 3-kinase, but not the MEK/erk pathway, and also promotes cell survival. In contrast to previous reports, we found that ceramide had no effect on the phosphorylation status of Bad. In summary, our results suggest that Bad phosphorylation at any of the three major sites is not a required event for cytokine-dependent cell survival, and in particular, the activation of PI 3-kinase/PKB pathway can be dissociated from phosphorylation of Bad at Ser136.
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PMID:Phosphorylation of Bad is not essential for PKB-mediated survival signaling in hemopoietic cells. 1584 95

Autoimmune regulator (AIRE) gene is a responsible gene for the rare autosomal recessive autoimmune disease: autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). Although it has been reported that AIRE is expressed in the thymic epithelial cells and monocyte-dendritic cell lineage, the regulatory mechanisms of AIRE gene expression have as yet been poorly understood. Here we show that the expression of AIRE gene was induced in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells. In GM-CSF-stimulated OTC-4 cells, stat5 was not phosphorylated, while mitogen-activated protein kinases (MAPKs), including MAPK kinase (MEK) 1/2 and p38 MAPK, were phosphorylated, indicating activation of MAPK pathway. In addition, the expression of AIRE gene was inhibited by specific p38 MAPK inhibitor (SB203580), whereas the expression was rather enhanced by the MEK1/2 inhibitor (U0126), suggesting that AIRE gene expression is regulated by mitogen-activated protein kinase pathway.
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PMID:Mitogen-activated protein kinase pathway controls autoimmune regulator (AIRE) gene expression in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells. 1589 21

Lipopolysaccharide (LPS) induces a marked delay in human neutrophil apoptosis that is reversed by the anti-inflammatory cytokine IL-10. The effect of IL-10 is specific since other agents that delay neutrophil apoptosis are not affected. To investigate mechanisms underlying the actions of IL-10, we examined signaling pathways activated by LPS per se and in response to IL-10. The MAPK kinase (MEK) 1 inhibitor PD098059, the protein kinase C (PKC) inhibitor Ro31,8220, and the phosphatidylinositol-3 kinase (PI3-K) inhibitor LY294002 all partially reversed LPS-mediated retardation of neutrophil apoptosis, but the p38 MAPK inhibitor SB203850 did not. LPS activates the transcription factor NF-kappaB, however, IL-10 did not affect the ability of LPS to activate NF-kappaB as assessed by IkappaB-alpha proteolysis. Although IL-10 did not alter activation of ERK by GM-CSF or TNF-alpha, it did inhibit activation induced by LPS. Thus our data illustrate that LPS-induced neutrophil survival is regulated by the MAPK, PKC and PI3-K pathways as well as NF-kappaB, and can be reversed by IL-10, through a mechanism involving inhibition of ERK activation. Because of the specific nature of this inhibition, we conclude that IL-10 interferes with an ERK activation pathway, which is not involved in GM-CSF or TNF-alpha signaling.
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PMID:Interleukin-10 inhibits lipopolysaccharide-induced survival and extracellular signal-regulated kinase activation in human neutrophils. 1610 68

Macrophage colony-stimulating factor (M-CSF) is a physiological regulator of monocyte-macrophage lineage. Ectopic expression of the M-CSF receptor (M-CSFR, or Fms) in murine myeloid cell line FDC-P1 (FD/Fms cells) results in M-CSF-dependent macrophage differentiation. Previously, we observed that M-CSF induces two temporally distinct phases of mitogen-activated protein kinase (MAPK) phosphorylation. Here we show that levels of phosphorylated MAPK kinase MEK1 follow the same kinetics as MAPK phosphorylation, characterized by an early and transient phase (the first 30 min of M-CSF stimulation) and a late and persistent phase from 4 h of stimulation. The MEK inhibitor U0126 strongly inhibited both phases of MAPK phosphorylation as well as FD/Fms cell differentiation, indicating that MAPK may relay M-CSF differentiation signaling downstream of M-CSFR. Treatment of FD/Fms cells with U0126 during the first hour of M-CSF stimulation reversibly blocked the early phase of MAPK phosphorylation but did not affect differentiation. In contrast, U0126 still inhibited FD/Fms cell differentiation when its addition was delayed by 24 h. This demonstrated that late and persistent MEK activity is specifically required for macrophage differentiation to occur. Furthermore, disrupting Grb2-Sos complexes with a specific blocking peptide did not prevent FD/Fms cells differentiation in response to M-CSF, nor did it abolish MAPK phosphorylation. The role of phosphatidylinositol 3-kinase (PI 3-kinase), another potential regulator of the MAPK pathway, was examined using the specific inhibitor LY294002. This compound could not impede FD/Fms cell commitment to macrophage differentiation and did not significantly affect MAPK phosphorylation in response to M-CSF. Therefore, M-CSF differentiation signaling in myeloid progenitor cells is mediated through persistent MEK activity but it is not strictly dependent upon Grb2-Sos interaction or PI 3-kinase activity.
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PMID:M-CSF stimulated differentiation requires persistent MEK activity and MAPK phosphorylation independent of Grb2-Sos association and phosphatidylinositol 3-kinase activity. 1612 55

The intracellular signaling pathways that mediate cytokine-induced granulocytic and monocytic differentiation are incompletely understood. In this study, we examined the importance of the MEK/ERK signal transduction pathway in granulocyte-colony stimulating factor (G-CSF)-induced granulocytic differentiation of murine 32 Dc l3 cells, and in interleukin-6 (IL-6)-induced monocytic differentiation of murine M1 cells. Induction of granulocytic differentiation with G-CSF, or monocytic differentiation with IL-6, led to rapid and sustained activation of the MEK-1/-2 and ERK-1/-2 enzymes. Inhibition of the MEK/ERK pathway by pretreatment with the MEK inhibitor U 0126 dramatically attenuated G-CSF-induced granulocytic differentiation and IL-6-induced monocytic differentiation. Inhibition of MEK/ERK signaling also significantly reduced cytokine-induced DNA binding activities of STAT 3 and PU.1, transcription factors that have been implicated in myeloid differentiation. Additionally, interleukin-3, which inhibits G-CSF-induced differentiation of 32 Dc l3 cells, also inhibited the ability of G-CSF to stimulate prolonged MEK/ERK activation. Thus, the opposing actions of different hematopoietic cytokines on myeloid progenitors may be mediated at the level of MEK/ERK activation. Taken together, these studies demonstrate an important requirement for MEK/ERK activation during cytokine-induced granulocytic and monocytic differentiation.
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PMID:Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway. 1609 86

The present work focused on the study of the secretory activity of pre-B acute lymphoblastic leukaemia (ALL) cells harvested from bone marrow (BM) and peripheral blood (PB) in 16 children. The basal and cytokine (SDF-1, GM-CSF, bFGF, VEGF)-stimulated secretions of gelatinases 2 and 9 (MMPs-2 and -9) and expression of their genes were monitored by zymography and RT-PCR, respectively. A wide heterogeneity was found in the secretory capacities of these cells. The basal secretion of MMP-9 was more frequently observed than that of MMP-2 in both cell types. The cytokines VEGF and bFGF were found to induce predominant stimulatory effects on the MMP-2 secretion. In contrast, GM-CSF was shown to exert a more pronounced activation of the MMP-9 production. Experiments using inhibitors of metabolic pathways (U0126, LY294002 and SN50) revealed that the secretion of MMP-9 was mediated through PI3/MEK1 kinases. The MMP-2 secretion appeared to be however, stimulated through a different metabolic pathway. The microfluorimetric approach showed that the basal and stimulated secretions of MMPs-2 and -9 depended on the extracellular calcium pool. The cytokines VEGF and bFGF represent potent factors increasing the intracellular calcium concentration with similar kinetics. In contrast, GM-CSF was found to activate a verapamil-sensitive efflux of indo-1 from cytosol suggesting that this cytokine could be responsible for the activation of xenobiotic membrane transporters. Experiments using the trypan blue exclusion test demonstrated that bFGF, in contrast to VEGF and GM-CSF, markedly augmented pre-B ALL cell survival. Further investigations into a possible correlation between the plasma concentrations of MMP-2 and -9, VEGF, bFGF and GM-CSF, and the poor evolution of pre-B ALL in children could have valuable diagnostic implications.
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PMID:Spontaneous and cytokine-evoked production of matrix metalloproteinases by bone marrow and peripheral blood pre-B cells in childhood acute lymphoblastic leukaemia. 1626 64

CCL20, like human beta-defensin (hBD)-2, is a potent chemoattractant for CCR6-positive immature dendritic cells and T cells in addition to recently found antimicrobial activities. We previously demonstrated that IL-17 is the most potent cytokine to induce an apical secretion and expression of hBD-2 by human airway epithelial cells, and the induction is JAK/NF-kappaB-dependent. Similar to hBD-2, IL-17 also induced CCL20 expression, but the nature of the induction has not been elucidated. Compared with a panel of cytokines (IL-1alpha, 1beta, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, IFN-gamma, GM-CSF, and TNF-alpha), IL-17 was as potent as IL-1alpha, 1beta, and TNF-alpha, with a time- and dose-dependent phenomenon in stimulating CCL20 expression in both well-differentiated primary human and mouse airway epithelial cell culture systems. The stimulation was largely dependent on the treatment of polarized epithelial cultures from the basolateral side with IL-17, achieving an estimated 4- to 10-fold stimulation at both message and protein levels. More than 90% of induced CCL20 secretion was toward the basolateral compartment (23.02 +/- 1.11 ng/chamber/day/basolateral vs 1.82 +/- 0.82 ng/chamber/day/apical). Actinomycin D experiments revealed that enhanced expression did not occur at mRNA stability. Inhibitor studies showed that enhanced expression was insensitive to inhibitors of JAK/STAT, p38, JNK, and PI3K signaling pathways, but sensitive to inhibitors of MEK1/2 and NF-kappaB activation, suggesting a MEK/NF-kappaB-based mechanism. These results suggest that IL-17 can coordinately up-regulate both hBD-2 and CCL20 expressions in airways through differentially JAK-dependent and -independent activations of NF-kappaB-based transcriptional mechanisms, respectively.
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PMID:Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway. 1627 23

We used cytokine protein array to analyze the expression of cytokines from human cord blood-derived mesenchymal stem cells (CB-MSCs). Several cytokines, interleukins (IL), and growth factors, including ENA-78, GM-CSF, GRO, IL-1beta, IL-6, IL-8, MCP-1, OSM, VEGF, FGF-4, FGF-7, FGF-9, GCP-2, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IP-10, LIF, MIF, MIP-3alpha, osteoprotegerin, PARC, PIGF, TGF-beta2, TGF-beta3, TIMP-1, as well as TIMP-2, were secreted by CB-MSCs, while IL-4, IL-5, IL-7, IL-13, TGF-beta1, TNF-alpha, and TNF-beta were not expressed under normal growth conditions. IL-6, IL-8, TIMP-1, and TIMP-2 were the most abundant interleukins expressed by CB-MSCs. A set of growth factors were selected to evaluate their stimulatory effects on the IL6 secretion for CB-MSCs. IL-1beta was the most important factor inducing CB-MSC to secret IL-6. The mechanism by which IL-1beta promoted IL-6 expression in CB-MSCs was studied. By using various inhibitors of signal transduction, we found that activation of p38 mitogen-activated protein kinases (MAPK) and MAPK kinase (MEK) is essential in the IL-1beta stimulated signaling cascade which leads to the increase in IL-6 synthesis. Additionally, continuous supplement of IL-1beta in the CB-MSCs culture will facilitate adipogenic maturation of CB-MSCs as evidenced by the presence of oil drops in the CB-MSCs and secretion of leptin, a molecule marker of adipocytes. These results strongly suggest that cytokine induction and signal transduction are important for the differentiation of CB-MSCs.
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PMID:Cytokine interactions in mesenchymal stem cells from cord blood. 1637 3


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