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)

The Raf kinases play a key role in relaying signals elicited by mitogens or oncogenes. Here, we report that c-raf-1(-/-) embryos are growth retarded and die at midgestation with anomalies in the placenta and in the fetal liver. Although hepatoblast proliferation does not appear to be impaired, c-raf-1(-/-) fetal livers are hypocellular and contain numerous apoptotic cells. Similarly, the poor proliferation of Raf-1(-/-) fibroblasts and hematopoietic cells cultivated in vitro is due to an increase in the apoptotic index of these cultures rather than to a cell cycle defect. Furthermore, Raf-1- deficient fibroblasts are more sensitive than wild- type cells to specific apoptotic stimuli, such as actinomycin D or Fas activation, but not to tumor necrosis factor-alpha. MEK/ERK activation is normal in Raf-1-deficient cells and embryos, and is probably mediated by B-RAF. These results indicate that the essential function of Raf-1 is to counteract apoptosis rather than to promote proliferation, and that effectors distinct from the MEK/ERK cascade must mediate the anti-apoptotic function of Raf-1.
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PMID:Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. 1129 28

Oncogenic Ras (H-Ras G12V) inhibits skeletal myogenesis through multiple signaling pathways. Previously, we demonstrated that the major downstream effectors of Ras (i.e., MEK/MAPK, RalGDS and Rac/Rho) play a minor, if any, role in the differentiation-defective phenotype of Ras myoblasts. Recently, NFkappaB, another Ras signaling target, has been shown to inhibit myogenesis presumably by stimulating cyclin D1 accumulation and cell cycle progression. In this study, we address the involvement of NFkappaB activation in the Ras-induced inhibition of myogenesis. Using H-Ras G12V and three G12V effector-loop variants, we detect high levels of NFkappaB transcriptional activity in C3H10T1/2-MyoD cells treated with differentiation medium. Myogenesis is blocked by all Ras proteins tested, yet only in the case of H-Ras G12V are cyclin D1 levels increased and cell cycle progression maintained. Expression of IkappaBalpha SR, an inhibitor of NFkappaB, does not reverse the differentiation-defective phenotype of Ras expressing cultures, but does induce differentiation in cultures treated with tumor necrosis factor (TNFalpha) or in cultures expressing the RelA/p65 subunit of NFkappaB. These data confirm that NFkappaB is a target of Ras and suggest that the cellular actions of NFkappaB require additional signals that are discriminated by the Ras effector-loop variants. Results with IkappaBalpha SR convincingly demonstrate that H-Ras G12V does not rely on NFkappaB activity to block myogenesis, an observation that continues to implicate another unidentified signaling pathway(s) in the inhibition of skeletal myogenesis by Ras.
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PMID:Differential effects of Ras signaling through NFkappaB on skeletal myogenesis. 1131 72

Our previous works demonstrated that ligands of macrophage scavenger receptor (MSR) induce protein kinases (PKs) including protein-tyrosine kinase (PTK) and up-regulate urokinase-type plasminogen activator expression (Hsu, H. Y., Hajjar, D. P., Khan, K. M., and Falcone, D. J. (1998) J. Biol. Chem. 273, 1240--1246). To continue to investigate MSR ligand-mediated signal transductions, we focus on ligands, oxidized low density lipoprotein (OxLDL), and fucoidan induction of the cytokines tumor necrosis factor-alpha (TNF) and interleukin 1 beta (IL-1). In brief, in murine macrophages J774A.1, OxLDL and fucoidan up-regulate TNF production; additionally, fucoidan but not OxLDL induces IL-1 secretion, prointerleukin 1 (proIL-1, precursor of IL-1) protein, and proIL-1 message. Simultaneously, fucoidan stimulates activity of interleukin 1-converting enzyme. We further investigate the molecular mechanism by which ligand binding-induced PK-mediated mitogen-activated protein kinase (MAPK) in regulation of expression of proIL-1 and IL-1. Specifically, fucoidan stimulates activity of p21-activated kinase (PAK) and of the MAPKs extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38. Combined with PK inhibitors and genetic mutants of Rac1 and JNK in PK activity assays, Western blotting analyses, and IL-1 enzyme-linked immunosorbent assay, the role of individual PKs in the regulation of proIL-1/IL-1 was extensively dissected. Moreover, tyrosine phosphorylation of pp60Src as well as association between pp60Src and Hsp90 play important roles in fucoidan-induced proIL-1 expression. We are the first to establish two fucoidan-mediated signaling pathways: PTK(Src)/Rac1/PAK/JNK and PTK(Src)/Rac1/PAK/p38, but not PTK/phospholipase C-gamma 1/PKC/MEK1/ERK, playing critical roles in proIL-1/IL-1 regulation. Our current results indicate and suggest a model for MSR ligands differentially modulating specific PK signal transduction pathways, which regulate atherogenesis-related inflammatory cytokines TNF and IL-1.
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PMID:Ligands of macrophage scavenger receptor induce cytokine expression via differential modulation of protein kinase signaling pathways. 1139 Mar 74

Treatment of MC3T3E-1 osteoblast cultures with combined interferon- gamma(IFN- gamma), lipopolysaccharide (LPS) and tumor necrosis factor- alpha(TNF- alpha) induces expressions of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), resulting in sustained releases of large amounts of nitric oxide and IL-6. However IFN- gamma, LPS and TNF- alpha individually induces non-detectable or small amounts of NO and IL-6 in MC3T3E-1 osteoblasts. The role of mitogen-activated protein kinase (MAPK) activation in the early intracellular signal transduction involved in iNOS and IL-6 transcription in the combined agents-stimulated osteoblasts has been investigated. The p38 MAPK pathway is specifically involved in the combined agents-induced NO and IL-6 release, since NO and IL-6 release in the presence of a specific inhibitor of p38 MAPK, 4-(4-fluorophenyl)-2-(4-metylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580), are significantly diminished. In contrast, PD98059, a specific inhibitor of MEK1, had no effect on NO and IL-6 release. Northern blot analysis showed that the p38 MAPK pathway controlled iNOS and IL-6 transcription levels. These data suggest that p38 MAPK plays an important role in the secretion of NO and IL-6 in LPS/IFN- gamma or TNF- alpha /IFN- gamma -treated MC3T3E-1 osteoblasts.
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PMID:Blockade of the p38 mitogen-activated protein kinase pathway inhibits inducible nitric oxide synthase and interleukin-6 expression in MC3T3E-1 osteoblasts. 1140 20

Differentiated osteoclasts have a short life span. We tested various cytokines and growth factors for the effects on the survival of purified mature osteoclasts. In the absence of any added factors, osteoclasts exhibited the survival rate of less than 25% after a 24-h incubation. Among the tested factors, tumor necrosis factor-alpha (TNF-alpha) was found to increase the survival rate to approximately 80%. The TNF-alpha-enhanced survival of osteoclasts appeared to be associated with reduction in apoptosis and suppression of caspase activation. The antiapoptotic signaling pathways involved in the TNF-alpha-induced osteoclast survival were investigated. TNF-alpha treatment increased the phosphorylation of Akt in osteoclasts, which was suppressed by a phosphatidylinositol 3-kinase inhibitor LY294002 and an Src family kinase-selective inhibitor PP1. These inhibitors also attenuated the TNF-alpha stimulation of osteoclast survival. In addition an increase in the phosphorylation of ERK was observed upon TNF-alpha stimulation. PD98059, a specific inhibitor of the ERK-activating kinase MEK-1, abolished the TNF-alpha-induced ERK phosphorylation and osteoclast survival, and in these responses the involvement of Grb2 and ceramide was observed. These results suggest that TNF-alpha promotes the survival of osteoclasts by engaging the phosphatidylinositol 3-kinase Akt and MEK/ERK signaling pathways.
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PMID:Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK. 1167 79

First published September 5, 2001; 10.1152/ajpcell.00077.2001.-Protective mechanisms for lysophosphatidic acid (LPA) against cell death caused by Clostridium difficile toxin, or tumor necrosis factor-alpha (TNF-alpha) plus D-galactosamine, were investigated in a murine hepatocyte cell line AML12 expressing Edg2 LPA receptor. In these models of hepatocellular injury, LPA prevented hepatocyte damage, suppressed apoptosis, and enhanced cell survival in a dose-dependent fashion. The protective effects of LPA were abolished by wortmannin and LY-294002, specific inhibitors of phosphatidylinositol 3-phosphate kinase (PI 3-kinase), and by PD-98059 and U-0126, inhibitors of MEK1/MEK2. In nontreated hepatocytes, LPA elicited a gradual and sustained increase in phosphorylation of Erk1/Erk2 over 180 min of stimulation and downstream phosphorylation of p90RSK and transcription factor Elk-1. In C. difficile toxin-treated cells, LPA-induced phosphorylation of Erk1/Erk2 was rapid but transient, while p90RSK and Elk-1 phosphorylation did not change significantly. LPA stimulated phosphorylation of Akt in a time-dependent manner in both intact and toxin-treated AML12 hepatocytes. Wortmannin and LY-294002 abolished phosphorylation of Akt, further supporting activation of PI 3-kinase/Akt as a signaling pathway, which mediates hepatocyte protection by LPA. Taken together, these results demonstrate that LPA prevents cell apoptosis induced by C. difficile toxin and TNF-alpha/D-galactosamine in the AML12 murine hepatocyte cell line. Cell protection by LPA involves activation of the mitogen-activated protein kinase Erk1/Erk2 cascade and PI 3-kinase-dependent phosphorylation of Akt.
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PMID:Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line. 1169 60

Helicobacter pylori and proinflammatory cytokines have a direct stimulatory effect on gastrin release from isolated G cells, but little is known about the mechanism by which these factors regulate gastrin gene expression. We explored whether tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 directly regulate gastrin gene expression and, if so, by what mechanism. TNF-alpha and IL-1 significantly increased gastrin mRNA in canine G cells to 181 +/- 18% and 187 +/- 28% of control, respectively, after 24 h of treatment. TNF-alpha and IL-1 stimulated gastrin promoter activity to a maximal level of 285 +/- 12% and 415 +/- 26% of control. PD-98059 (a mitogen-activated protein kinase kinase inhibitor), SB-202190 (a p38 kinase inhibitor), and GF-109203 (a protein kinase C inhibitor) inhibited the stimulatory action of both cytokines on the gastrin promoter. In conclusion, both cytokines can directly regulate gastrin gene expression via a mitogen-activated protein kinase- and protein kinase C-dependent mechanism. These data suggest that TNF-alpha and IL-1 may play a direct role in Helicobacter pylori-induced hypergastrinemia.
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PMID:TNF-alpha and interleukin 1 activate gastrin gene expression via MAPK- and PKC-dependent mechanisms. 1170 45

To define the molecular mechanism(s) by which interleukin (IL)-4 reversibly inhibits formation of osteoclasts (OCs) from bone marrow macrophages (BMMs), we examined the capacity of this T cell-derived cytokine to impact signals known to modulate osteoclastogenesis, which include those initiated by macrophage colony-stimulating factor (M-CSF), receptor for activation of NF-kappa B ligand (RANKL), tumor necrosis factor (TNF), and IL-1. We find that although pretreatment of BMMs with IL-4 does not alter M-CSF signaling, it reversibly blocks RANKL-dependent activation of the NF-kappa B, JNK, p38, and ERK signals. IL-4 also selectively inhibits TNF signaling, while enhancing that of IL-1. Contrary to previous reports, we find that MEK inhibitors dose-dependently inhibit OC differentiation. To identify more proximal signals mediating inhibition of OC formation by IL-4, we used mice lacking STAT6 or SHIP1, two adapter proteins that bind the IL-4 receptor. IL-4 fails to inhibit RANKL/M-CSF-induced osteoclastogenesis by BMMs derived from STAT6-, but not SHIP1-, knockout mice. Consistent with this observation, the inhibitory effects of IL-4 on RANKL-induced NF-kappa B and mitogen-activated protein kinase activation are STAT6-dependent. We conclude that IL-4 reversibly arrests osteoclastogenesis in a STAT6-dependent manner by 1) preventing I kappa B phosphorylation and thus NF-kappa B activation, and 2) blockade of the JNK, p38, and ERK mitogen-activated protein kinase pathways.
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PMID:Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-kappa B and mitogen-activated protein kinase signaling. 1171 4

Mitogen-activated protein kinase (MAPK) pathways coordinate critical cellular responses to mitogens, stresses, and developmental cues. The coupling of MAPK kinase kinase (MAP3K) --> MAPK kinase (MEK) --> MAPK core pathways to cell surface receptors remains poorly understood. Recombinant forms of MAP3K MEK kinase 1 (MEKK1) interact in vivo and in vitro with the STE20 protein homologue germinal center kinase (GCK), and both GCK and MEKK1 associate in vivo with the adapter protein tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). These interactions may couple TNF receptors to the SAPK/JNK family of MAPKs; however, a molecular mechanism by which these proteins might collaborate to recruit the SAPKs/JNKs has remained elusive. Here we show that endogenous GCK and MEKK1 associate in vivo. In addition, we have developed an in vitro assay system with which we demonstrate that purified, active GCK and TRAF2 activate MEKK1. The RING domain of TRAF2 is necessary for optimal in vitro activation of MEKK1, but the kinase domain of GCK is not. Autophosphorylation within the MEKK1 kinase domain activation loop is required for activation. Forced oligomerization also activates MEKK1, and GCK elicits enhanced oligomerization of coexpressed MEKK1 in vivo. These results represent the first activation of MEKK1 in vitro using purified proteins and suggest a mechanism for MEKK1 activation involving induced oligomerization and consequent autophosphorylation mediated by upstream proteins.
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PMID:Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. 1178 51

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, whereas laminar flow and high shear stress are atheroprotective. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF), have been shown to stimulate expression of endothelial cell (EC) genes that may promote atherosclerosis. Recent data suggest that steady laminar flow decreases EC apoptosis and blocks TNF-mediated EC activation. EC apoptosis is likely important in the process termed "plaque erosion" that leads to platelet aggregation. Steady laminar flow inhibits EC apoptosis by preventing cell cycle entry, by increasing antioxidant mechanisms (e.g., superoxide dismutase), and by stimulating nitric oxide-dependent protective pathways that involve enzymes PI3-kinase and Akt. Conversely, our laboratory has identified nitric oxide-independent mechanisms that limit TNF signal transduction. TNF regulates gene expression in EC, in part, by stimulating mitogen-activated protein kinases (MAPK) which phosphorylate transcription factors. We hypothesized that fluid shear stress modulates TNF effects on EC by inhibiting TNF-mediated activation of MAP kinases. To test this hypothesis, we determined the effects of steady laminar flow (shear stress = 12 dynes/cm2) on TNF-stimulated activity of two MAP kinases: extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK). Flow alone stimulated ERK1/2 activity, but decreased JNK activity compared to static controls. TNF (10 ng/ml) alone activated both ERK1/2 and JNK maximally at 15 minutes in human umbilical vein EC (HUVEC). Pre-exposing HUVEC for 10 minutes to flow inhibited TNF activation of JNK by 46%, but it had no significant effect on ERK1/2 activation. Incubation of EC with PD98059, a specific mitogen-activated protein kinase kinase inhibitor, blocked the flow-mediated inhibition of TNF activation of JNK. Flow-mediated inhibition of JNK was unaffected by 0.1 mM L-nitroarginine, 100 pM 8-bromo-cyclic GMP, or 100 microM 8-bromo-cyclic AMP. Transfection studies with dominant negative constructs of the protein kinase MEK1 and MEK5 suggested an important role for BMK1 in flow-mediated regulation of TNF signals. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms.
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PMID:Endothelial atheroprotective and anti-inflammatory mechanisms. 1179 13


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