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 this study, we examined the role of mitogen-activated protein (MAP) kinases in the effects of verotoxins (VTs), from Escherichia coli O157:H7, upon both apoptosis and the release of tumour necrosis factor alpha (TNF-alpha) and granulocyte-macrophage colony-stimulated factor (GM-CSF) from human monocytes. 2. Both VT1 and VT2 stimulated a weak, transient increase in c-Jun-N-terminal kinase (JNK) activity and a strong activation of both p38 mitogen-activated protein kinase (MAP kinase) and extracellular-regulated kinase (ERK) activity in human monocytes, which was sustained in the case of p38 MAP kinase. 3. Stimulation of human monocytes with VT2 (100 ng ml-1) did not result in an increase in apoptosis; however, the toxin stimulated the release of both TNF-alpha and GM-CSF. 4. Pretreatment of human monocytes with the p38 MAP kinase inhibitor SB203580, at concentrations from 100 nM to 10 microM, significantly decreased the VT1- and VT2-induced TNF-alpha and GM-CSF release from monocytes. In contrast, inhibition of MEK1 with PD98059 only significantly decreased GM-CSF release. 5. Pretreatment of monocytes with SP600125 inhibited both GM-CSF and TNF-alpha production; however, significant effects upon p38 MAP kinase and ERK activation were observed. 6. Taken together, these results suggest a role for p38 MAP kinase and ERK in cytokine generation in response to the verotoxins. A role for JNK remains undetermined.
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PMID:Verotoxin activates mitogen-activated protein kinase in human peripheral blood monocytes: role in apoptosis and proinflammatory cytokine release. 1459 1

The role of transforming growth factor-beta (TGF-beta) in regulation of meningioma growth and intracellular events transducing its signals are not established. In this study, we evaluated the effects of TGF-beta1 on basal meningioma cell proliferation in 10 primary human meningioma cell cultures and whether TGF-beta's signals are transduced by the Smad 2/3, MAPK/Erk kinase-1 (MEK-1)-mitogen-activated protein kinase (MAPK), Akt-p70(S6K) or p38-JUNK pathways in 5. We also tested whether neutralizing antibodies to TGF-beta alter CSF stimulation of meningioma cell proliferation. On average, TGF-beta reduced meningioma cell [3H]-thymidine incorporation to 58% of controls at 24% and to 61% of controls at 36 h. TGF-beta inhibition of meningioma cell proliferation was associated with a suggestion increased phosphorylation of Smad 2/3 in 2 cases and high basal phosphorylation in 3 but no change in activation of the MEK-1-MAPK, Akt-p70(S6K) or p38-JUNK pathways. As shown previously, CSF stimulated meningioma cell proliferation in the 3 cultures tested. Neutralizing antibody against TGF-beta augmented this stimulation in 2 of 3 cultures. These findings suggest that TGF-beta exerts a largely inhibitory effect on basal meningioma proliferation, perhaps in part through Smad 2/3.
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PMID:Transforming growth factor-beta effects on meningioma cell proliferation and signal transduction pathways. 1501 65

Granulocyte/macrophage colony-stimulating factor (GM-CSF) inhibits Fas-induced apoptosis of neutrophils. However, the exact step in the apoptotic pathway blocked by GM-CSF remained unclear. Here, we found that pretreatment of neutrophils with GM-CSF inhibits the recruitment of Fas-associated protein with death domain (FADD) to Fas, abolishing the formation of the death-inducing signaling complex required for Fas-induced apoptosis. Two-dimensional electrophoresis revealed that GM-CSF modifies the ratio of FADD subspecies. These GM-CSF-triggered changes were abrogated, and Fas-induced apoptosis was restored by an inhibitor of classical protein kinase C (PKC), Go6976, and by the combination of a phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294002, and an inhibitor of mitogen-activated protein kinase kinase (MEK)1, PD98059. Go6976 blocked GM-CSF-elicited phosphorylation of Akt/PKB and extracellular signal-regulated kinase (ERK)1/2. These results indicated that GM-CSF suppresses Fas-induced neutrophil apoptosis by inhibiting FADD binding to Fas, through redundant actions of PI-3K and MEK1-ERK1/2 pathways downstream of classical PKC.
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PMID:Short-term delay of Fas-stimulated apoptosis by GM-CSF as a result of temporary suppression of FADD recruitment in neutrophils: evidence implicating phosphatidylinositol 3-kinase and MEK1-ERK1/2 pathways downstream of classical protein kinase C. 1532 34

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

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

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

Mos and the mitogen-activated protein kinase (MAPK) cascade have been established as crucial regulators of second meiotic metaphase arrest, the so-called CSF arrest, in mammalian oocytes. They are also thought to play a role in regulating mitotic metaphase arrest of early mammalian embryos. In the present study, we examined whether mitotic arrest is induced in early mouse embryos by activation of extracellular signal-regulated kinases (ERKs), which are major MAPKs in mouse eggs, and their substrate, p90Ribosomal S6 kinase (RSK), as reported in Xenopus embryos. Wild-type Mos (wt-Mos), degradation-resistant Mos mutant (P2G-Mos) or constitutive active mutant of MAPK/ERK kinase, MEK (SDSE-MEK), was expressed in early mouse embryos by injecting the respective expression vectors into the pronucleus of fertilized eggs, and the developmental rates were then examined up to 72 h after insemination. Expression of P2G-Mos and SDSE-MEK succeeded in activating ERKs and RSK in developing mouse embryos, while wt-Mos failed to activate them in spite of expression of mos mRNA, indicating that the wt-Mos protein is unstable in early mouse embryos. Although the activated levels of ERKs and RSK in the vector-injected embryos were comparable to those of meiotically arrested mouse oocytes, their developmental rates were identical to those of the control embryos. These results suggest that activation of MAPK and RSK does not induce mitotic arrest in early mouse embryos. The present study indicates that there are large physiological differences between early mouse embryos and mouse oocytes and that CSF arrest of mouse eggs in mitosis should be discussed separately from that in meiosis.
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PMID:Mos and the mitogen-activated protein kinase do not show cytostatic factor activity in early mouse embryos. 1782 76

Aberrant growth factor production is a prevalent mechanism in tumourigenesis. If T-cells responded positively to a cancer-derived cytokine, this might result in selective enhancement of function within the tumour microenvironment. Here, we have chosen colony-stimulating factor-1 (CSF-1) as a candidate to test this concept. CSF-1 is greatly overproduced in many cancers but has no direct effects upon T-lymphocytes, which do not express the c-fms-encoded CSF-1 receptor. To confer CSF-1-responsiveness, we have expressed the human c-fms gene in immortalized and primary T-cells. Addition of soluble CSF-1 resulted in synergistic enhancement of IL-2-driven T-cell proliferation. CSF-1 also co-stimulated the production of interferon (IFN)-gamma by activated T-cells. These effects required Y809 of the CSF-1R and activation of the Ras-MEK-MAP kinase cascade, but were independent of PI3K signalling. T-cells that express c-fms are also responsive to membrane-anchored CSF-1 (mCSF-1) which, unlike its soluble counterpart, could co-stimulate IL-2 production. CSF-1 promoted chemotaxis of c-fms-expressing primary human T-cells and greatly augmented proliferation mediated by a tumour-targeted chimeric antigen receptor, with preservation of tumour cytolytic activity. Taken together, these data establish that T-cells may be genetically modified to acquire responsiveness to CSF-1 and provide proof-of-principle for a novel strategy to enhance the effectiveness of adoptive T-cell immunotherapy.
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PMID:Harnessing the tumour-derived cytokine, CSF-1, to co-stimulate T-cell growth and activation. 1795 Aug 77

Macrophage colony-stimulating factor (M-CSF) has been found to be involved in multiple developmental processes, especially production of cells belonging to the mononuclear phagocyte system. The decision of myeloid progenitor cells to commit to differentiation depends on activation levels of the mitogen-activated protein kinases (MAPK), ERK1 and ERK2. Using the murine myeloid progenitor cell line FD-Fms, we show here that persistent activity of Src-family kinases (SFK) is necessary for FD-Fms cell differentiation to macrophages in response to M-CSF. Chemical inhibition of SFK blocked FD-Fms cell differentiation while it caused strong inhibition of the late phosphorylation of phospholipase C (PLC)-gamma2 and MAPK. The PLC inhibitor U73122, previously shown to block M-CSF-induced differentiation, strongly decreased long-term MAPK phosphorylation. Interestingly, inhibiting SFK with SU6656 or the MAPK kinases MEK with U0126 significantly impaired development of mononuclear phagocytes in cultures of mouse bone marrow cells stimulated with M-CSF. Collectively, results support a model in which SFK are required for sustained PLC activity and MAPK activation above threshold required for commitment of myeloid progenitors to macrophage differentiation.
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PMID:Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-gamma2 and MAP kinases ERK1 and ERK2. 1797 59


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