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)

Interleukin-6 is a pleiotropic cytokine that mediates cellular communication both in physiological and pathological states. In this work, we demonstrate that 50 ng/mL IL-6 increases the survival of retinal ganglion cells (RGCs) after 48 h in culture. This effect was blocked by an intracellular Ca(+2) chelator, by inhibition of ryanodinic receptors and by an inhibitor of L-type Ca(+2) channels. IL-6 effect is mediated by PKC, tyrosine kinase, PI3-kinase and MEK activity. The blockade of polypeptide release also abolished the effect of IL-6. These results suggest a role for this cytokine during the development of the central nervous system (CNS).
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PMID:Interleukin-6 increases the survival of retinal ganglion cells in vitro. 1143 Oct 3

Myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP) have been implicated in membrane-cytoskeletal events underlying cell adhesion, migration, secretion, and phagocytosis. In BV-2 microglial cells, lipopolysaccharide (LPS) elicited a dose-dependent increase in mRNA of both MRP (sixfold) and MARCKS (threefold) with corresponding increases in [3H]myristoylated and immunoreactive protein levels. LPS also produced significant increases in protein kinase C (PKC)-beta twofold and PKC-epsilon (1.5-fold). Pro-inflammatory cytokines produced by activated microglia (IL-1beta, IL-6, TNF-alpha) did not mimic LPS effects on MARCKS or MRP expression when added individually or in combination. LPS and IFN-gamma produced a synergistic induction of iNOS but not MARCKS or MRP. Induction of MARCKS and MRP by LPS was completely blocked by inhibitors of NF-kappaB (PDTC) and protein tyrosine kinases (herbimycin A), partially blocked by the p38 kinase inhibitor SB203580, and unaffected by the MEK inhibitor PD98059. LPS induction of iNOS was considerably more sensitive to all these inhibitors. The Src kinase inhibitor PP2 had no effect, while the closely related inhibitor PP1 actually increased LPS induction of MARCKS and MRP. Our results suggest that MARCKS and MRP may play an important role in LPS-activated microglia, but are not part of the neuroinflammatory response produced by cytokines.
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PMID:Regulation of MARCKS and MARCKS-related protein expression in BV-2 microglial cells in response to lipopolysaccharide. 1148 70

The mechanisms underlying the anti-apoptotic action of interleukin (IL)-6 on hematopoietic cells have been extensively studied, but those in the case of neuronal cells have been poorly reported. We investigated the effect of IL-6 on the survival of rat PC12 pheochromocytoma cells and analyzed the signaling pathways of the cytokine by means of some kinase inhibitors. IL-6 protects PC12 cells from the death induced by serum deprivation or anticancer agents, such as cisplatin, paclitaxel and 5-fluorouracil. Phosphatidylinositol (PI)3-kinase inhibitors (LY294002 and wortmannin) but not a mitogen-activated protein kinase kinase inhibitor (PD98059) completely suppressed the IL-6-promoted survival of the cells. A Janus tyrosine kinase 2 inhibitor (tyrphostin AG490) suppressed the phosphorylation of signal transducers and activators of transcription (STAT)3 and only partially inhibited the anti-apoptotic activity of IL-6. IL-6 stimulated phosphorylation of Akt, a downstream effector of PI3 kinase, and in the presence of LY294002, the phosphorylation of Akt was reduced to basal level. These results suggest that the signaling pathway for the anti-apoptotic effect of IL-6 in PC12 cells is mediated in major part by activation of the PI3-kinase/Akt pathway and thus is different from that in hematopoietic cells.
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PMID:Interleukin-6 protects rat PC12 cells from serum deprivation or chemotherapeutic agents through the phosphatidylinositol 3-kinase and STAT3 pathways. 1148 35

In this study we show that activation of p38MAPK by IL-6 acts as an inhibitory signal on IL-6-mediated activation of STAT and the alpha2-macroglobulin promoter. We analyzed the role of MKK6/p38MAPK for IL-6 signal transduction and transcriptional activation of the suppressor of cytokine signaling (SOCS) 3 promoter. Pretreatment of cells with the p38MAPK-specific inhibitor SB202190 downregulates the induction of SOCS3-mRNA expression by IL-6. Accordingly, overexpression of a constitutively active MKK6 in HepG2 cells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter reporter construct, whereas overexpression of a dominant negative mutant of MKK6 downregulated the IL-6-mediated activation of the SOCS3 promoter. These data indicate that p38MAPK-activation is crucial for IL-6-induced SOCS3 expression and downregulation of IL-6-mediated gene induction.
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PMID:The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. 1172 28

The cytokine receptor common beta subunit (beta(c)) transmits intracellular signals upon binding ligand such as granulocyte-macrophage colony-stimulating factor or interleukin-3 (IL-3); however, transcriptional regulation under the control of signaling events downstream of the beta(c) is not fully understood. Using murine Ba/F3 cells, here we demonstrate that the beta(c)-mediated signals stimulate NF-kappa B-driven gene expression of not only the reporter construct but also endogenous target genes such as IL-6. Analyzing the effects of several inhibitors or mutant receptors revealed that this NF-kappa B activation is mediated neither by MEK/ERK/MAPK nor by the phosphatidylinositol 3-kinase pathway but by STAT5. Overexpression experiments of the wild-type or constitutive active form of STAT5 further confirmed this notion. In addition, STAT5-dependent NF-kappa B activation is mediated not through an inducible nuclear translocation but via up-regulation of both DNA binding activity and transactivation potential of NF-kappa B. Furthermore, we also show that as yet undefined humoral factor(s) may be involved in this NF-kappa B activation process. Taken together, we may propose that cytokine receptor-mediated STAT5 activation and expression of its target genes culminates in a unique mode of NF-kappa B activation and gene expression.
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PMID:Cytokine receptor common beta subunit-mediated STAT5 activation confers NF-kappa B activation in murine proB cell line Ba/F3 cells. 1174 13

A novel cytokine, ML-1, was recently discovered, which shares a similar sequence homology with, but is functionally distinct from, IL-17 (Kawaguchi, M., Onuchic, L., Li, X. D., Essayan, D. M., Schroeder, J., Xiao, H. Q., Liu, M. C., Krishnaswamy, G., Germino, G., and Huang, S. K. (2001) J. Immunol. 167, 4430-4435). To determine the signaling mechanisms of ML-1, we investigated activation of mitogen-activated protein (MAP) kinases induced by ML-1. Results show that ML-1 induces in a time-dependent fashion the expression of IL-6 and IL-8 in both primary bronchial epithelial cells (PBECs) and human umbilical vein endothelial cells (HUVECs). ML-1 activated a MAP kinase and an extracellular signal-regulated kinase (ERK)1/2 but not p38 or the c-Jun N-terminal kinase (JNK) in both cell types. Selective MAP kinase kinase (MEK)1/2 inhibitors, PD98059 and U0126, inhibited, in a dose-dependent manner, ML-1-induced expression of IL-6 and IL-8. These findings suggest that ML-1-induced IL-6 and IL-8 production is mediated through the activation of ERK1/2 in both cell types.
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PMID:Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1. 1189 Dec 14

Although Fas (APO-1/CD95) is expressed ubiquitously and induces cell death, it is also known to mediate other responses such as inflammation and angiogenesis in vivo. Previously, we have reported that Fas ligation induces selective expression of chemokines (IL-8 and MCP-1) in human astroglioma cells in vitro. In this study, we investigated whether Fas ligation can induce expression of other cytokines. Expression of IL-1alpha, IL-1beta, IL-6, IL-10, IL-12, IFN-beta, IFN-gamma, LT-beta, TGF-beta, TNF-a and TNF-beta mRNA levels in CRT-MG human astroglioma cells upon Fas ligation was investigated using RNase protection assay (RPA). We found that IL-6 mRNA is selectively induced upon Fas ligation, and IL-6 mRNA and protein expression was further investigated using single probe RPA and ELISA. To investigate the in vivo expression of IL-6, human brain specimens were homogenized and ELISA was performed for IL-6 expression. Herein, we demonstrate that: (1) Among these cytokines, only IL-6 was induced upon Fas ligation in a dose- and time-dependent manner; (2) A selective p38 MAP kinase inhibitor, SB202190, and a MEK inhibitor, U0126, suppressed induction of IL-6 mRNA and protein expression by Fas ligation; and (3) Glioblastoma multiforme samples (n = 11) contain significantly higher levels of IL-6 compared to those of control brains (n = 5), which correlate with increased levels of Fas. These results suggest that the Fas-FasL system may play a role in the regulation of tumor growth and survival by inducing the pleiotropic cytokine IL-6.
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PMID:Fas engagement increases expression of interleukin-6 in human glioma cells. 1194 22

Lipoproteins derived from Mycoplasma salivarium and a synthetic lipopeptide (FSL-1) activate human gingival fibroblasts to induce IL-6 production and ICAM-1 expression. Human gingival fibroblasts were treated with lipoproteins or FSL-1 and then examined for the activation of mitogen-activated protein kinases (MAPKs), ERK1/2, p38, and SAPK/JNK, and transcription factors, AP-1 and NF-kappaB. Western blotting indicated that p38 and SAPK/JNK were activated in response to the stimulators, but the activation of ERK1/2 could not be discriminated because ERK1/2 was activated in the absence of stimulators. The p38 inhibitor SB 203580 also suppressed their IL-6 production-inducing activities, whereas the ERK1/2-activating MAPK kinase (MEK1) inhibitor PD 98059 did not suppress their activities. Moreover, they were capable of inducing the activation of AP-1 and NF-KB. NF-kappaB activation was also confirmed by the phosphorylation of IkappaB-alpha. On the basis of these results, it was concluded that lipoproteins of M. salivarium and FSL-1 are capable of activating the MAPKs p38 and SAPK/JNK and the transcriptional factors AP-1 and NF-kappaB in human gingival fibroblasts.
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PMID:Signaling pathways induced by lipoproteins derived from Mycoplasma salivarium and a synthetic lipopeptide (FSL-1) in normal human gingival fibroblasts. 1200 23

Negative regulation of cytokine signaling is important for limiting the intensity and duration of cytokine action and for maintaining homeostasis. Several constitutive mechanisms for suppressing cytokine Jak-STAT signaling have been described. Inducible or regulated inhibition of cytokine signaling is equally important, and much attention has been focused on inhibition mediated through the induction of expression of suppressors of cytokine signaling (SOCS proteins). We have previously reported IL-1-induced inhibition of IL-6 signaling in monocytes, and herein we use inhibitors of protein synthesis to demonstrate that inhibition of IL-6 signaling can occur in the absence of new protein synthesis. Surprisingly, some protein synthesis inhibitors themselves inhibited IL-6 signaling rapidly, strengthening the conclusion that IL-6 signaling can be inhibited in the absence of protein synthesis. Inhibition of IL-6 signaling by IL-1 and protein synthesis inhibitors was dependent on the p38 stress kinase, and activation of p38 secondary to inducible expression of MKK6 was sufficient to inhibit IL-6 signaling. Inhibition was specific for IL-6, as induction of STAT activation by IFN-gamma, IFN-alpha, and vanadate was not inhibited. IL-1-induced inhibition of IL-6 signaling was not mediated by the activation of tyrosine phosphatases or by p38-dependent activation of phospholipase A(2) or cyclooxygenases, which could lead to indirect inhibition via production of prostaglandins. These results identify an inducible mechanism of inhibition of IL-6 signaling that is direct and independent of induction of negative regulators such as SOCS proteins. A role for p38 in mediating inhibition suggests that multiple cytokines and stress agents that activate p38 pathways in monocytes, such as IL-1, TNF, Toll-like receptors, and Fc receptors, can modulate Jak-STAT signaling by pleiotropic cytokines such as IL-6.
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PMID:Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis. 1210 Dec 75

The evolutionarily conserved Ras/Raf/MEK/ERK pathway is thought to be essential for proliferation of eukaryotic cells. The human multiple myeloma (MM) cell line 8226 encodes an activated K-ras allele and proliferates without requirement for the main MM growth and survival factor IL-6. Surprisingly, the addition of the MEK1/2 inhibitors PD98059 or U0126 to 8226 cultures at doses that block virtually all ERK1/2 activity had minimal effects on the rapid proliferation of this cell line. In contrast, proliferation of the IL-6-dependent MM cell line, ANBL-6 was blocked by PD98059. Levels of activated forms of the other classical MAP kinases (JNK and p38) were very low during MM cell proliferation and, therefore, do not substitute for the mitogenic activities normally regulated by ERK kinases. These data demonstrate that proliferation of 8226 cells does not require ERK1/2 activity, and suggest that IL-6-independent growth of MM may correlate with independence from a requirement for ERK activity. Other signal transduction pathways that appear to regulate cell cycle progression in these cells were examined.
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PMID:Proliferation of IL-6-independent multiple myeloma does not require the activity of extracellular signal-regulated kinases (ERK1/2). 1220 79


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