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)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) activates several kinases and transcription factors through interaction with a heterodimeric receptor complex. We previously demonstrated that phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, occurs through a protein kinase A-independent pathway and is required for GM-CSF-induced transcriptional activation of the immediate early gene, early growth response-1 (egr-1). Recent reports indicate that receptor tyrosine kinases can induce CREB phosphorylation through activation of pp90RSK. We performed immune complex kinase assays in the human myeloid leukemic cell line, TF-1, which revealed that GM-CSF induced pp90RSK activation and phosphorylation of CREB within 5 minutes of stimulation. Transfection with the kinase-defective pp90RSK expression plasmid demonstrated a statistically significant decrease in transcriptional activation of a -116 CAT/egr-1 promoter construct in response to GM-CSF. Furthermore, activation of pp90RSK, CREB and egr-1 in GM-CSF-treated cells was inhibited by the presence of the inhibitor, PD98059. In this study, we report that GM-CSF induces CREB phosphorylation and egr-1 transcription by activating pp90RSK through an MEK-dependent signaling pathway. (Blood. 2000;95:2552-2558)
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PMID:Granulocyte-macrophage colony-stimulating factor stimulation results in phosphorylation of cAMP response element-binding protein through activation of pp90RSK. 1075 34

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is a 28-kDa plasma protein that binds to IGF-I and IGF-II with high affinity. IGFBP-1 is elevated in the blood as a result of sepsis, AIDS, excessive alcohol consumption, and diabetes and may, in part, be responsible for the wasting observed during these pathophysiological conditions. The liver is the principal site of IGFBP-1 synthesis, and we have previously shown that proinflammatory cytokines can directly stimulate IGFBP-1 secretion in a human hepatoma cell line (HepG2). The purpose of the present study was to investigate the role of the MAP kinase pathway in regulating IGFBP-1 synthesis by IL-1beta. We show that IL-1beta stimulates the phosphorylation of ERK-1 and -2 in a time- and dose-dependent manner. In addition, the MAP kinase-kinase MEK-1 and the ribosomal S6-kinase RSK-1 are also phosphorylated in response to IL-1beta. The transcription factor CREB, a potential substrate of both protein kinase A (PKA) and RSK-1, is phosphorylated in response to IL-1beta and cAMP in HepG2 cells. The ability of IL-1beta to stimulate the expression of IGFBP-1 and the phosphorylation of the above kinases was specifically inhibited by PD98059, a MEK-1 inhibitor. cAMP also stimulated IGFBP-1 synthesis, but PD98059 failed to block the cAMP effect. Conversely, a PKA inhibitor (H-89) inhibited the ability of cAMP, but not IL-1beta to stimulate IGFBP-1 synthesis. The effect of IL-1beta and cAMP on IGFBP-1 messenger RNA (mRNA) accumulation was additive. IL-1beta, cAMP, PD98059, and H-89 had similar effects on the accumulation of IGFBP-1 protein and mRNA. IL-1beta and cAMP did not change the half-life of IGFBP-1 mRNA, but PD98059 and SB202190, a p38 MAP kinase inhibitor, destabilized IGFBP-1 mRNA and blocked the phosphorylation of RSK-1 in response to IL-1beta. Our data demonstrate that the MAP kinase signal transduction pathway plays an important role in the regulation of IGFBP-1 synthesis by IL-1beta.
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PMID:Stimulation of insulin-like growth factor binding protein-1 synthesis by interleukin-1beta: requirement of the mitogen-activated protein kinase pathway. 1096 86

In the human breast cancer cell line MCF-7, the nucleotides ATP gamma S and UTP, acting extracellularly through the purinergic receptor P2Y(2), lead to elevated intracellular calcium levels and increased proliferation. ATP gamma S and UTP treatment of MCF-7 cells activated transcription of the immediate early gene c-fos, an important component in the response to proliferative stimulation. c-fos induction was enhanced by co-treatment with ATP gamma S and a variety of proliferative agents including growth factors, tumour promoters and stress. Stimulation with ATP gamma S or epidermal growth factor (EGF) led to extracellular signal-regulated kinase (ERK) activation and phosphorylation of the transcription factors CREB and Elk-1. Co-stimulation synergistically activated fos expression and notably led to increased levels of ERK, CREB and EGF receptor phosphorylation, as well as hyperphosphorylation of ternary complex factor. Nevertheless, the ERK pathway does not fully account for this synergy, since fos induction was differentially sensitive to the MEK inhibitor U0126, indicating that these two agonists signal differently to this immediate early gene. Thus, extracellular nucleotides co-operate with growth factors to activate genes linked to the proliferative response in MCF-7 cells through activation of specific purinergic receptors, which thereby represent important potential targets for arresting the neoplastic progression of breast cancer cells.
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PMID:Extracellular ATP activates multiple signalling pathways and potentiates growth factor-induced c-fos gene expression in MCF-7 breast cancer cells. 1113 6

Disruption of the RAS-to-mitogen-activated protein kinase (MAPK/ERK) signaling pathway, either directly through activating RAS gene mutations or indirectly through other genetic aberrations, plays an important role in the molecular pathogenesis of myeloid leukemias. Constitutive activation of ERK-1/2 and MEK-1/2, which elicit oncogenic transformation in fibroblasts, has recently been observed in acute myeloid leukemias (AML). In this study, the activation of the RAS-to-MAPK cascade in 14 AML and 5 chronic myeloid leukemia (CML) cell lines is examined and correlated with the effects of a panel of 9 RAS signaling inhibitors on cell viability, colony formation, cell-cycle progression, and induction of apoptosis. Activation of MEK, ERK, and the transcription factors CREB-1, ATF-1, and c-Myc is demonstrated in the majority of the cell lines (9 of 14 AML and 2 of 5 CML cell lines). Although activation of the ERK cascade did not always correlate with the presence of activating RAS mutations or BCR-Abl, it is linked to the G0/G1 and the G2/M phase of the cell cycle. In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met, FPT-2, FTI-276, and FTS), a significant growth inhibition was only observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK inhibitors U0126 (19 of 19) and PD098059 (8 of 19). Treatment of NB-4 cells with FTI-277 primarily resulted in a G2/M block, whereas treatment with FPT-3 and U0126 led to induction of apoptosis. FTI-277 revealed strong toxicity toward normal purified CD34+ cells. The results suggest differences in the mechanisms of action and support a potential therapeutic usefulness of these inhibitors in the treatment of myeloid leukemias.
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PMID:Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. 1123 26

Lysophosphatidylcholine, a component of oxidized low density lipoprotein, is critical for pathological conditions including atherosclerosis. However, the signaling mechanism of lysophosphatidylcholine remains poorly understood. Here we reported that lysophosphatidylcholine induces phosphorylation of p38 and the transcription factors, CREB and ATF-1 with concomitant up-regulation of cyclooxygenase-2 expression in cultured vascular endothelial cells. Lysophosphatidylcholine induced p38 phosphorylation in a time- and concentration-dependent manner partly via pathway depending on protein tyrosine kinase. Both lysophosphatidylcholine-stimulated phosphorylation of CREB and ATF-1 and lysophosphatidylcholine-increased expression of cyclooxygenase-2 mRNA and protein were effectively inhibited by a combination of SB203580 and PD98059, specific inhibitors of p38 and MEK1, respectively, as well as Ro31-8220 and H89, potent inhibitors of MSK1. These results suggest that both p38 and ERK may function as upstream signaling pathways capable of activating CREB and ATF-1 with subsequent induction of cyclooxygenase-2 expression by lysophosphatidylcholine.
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PMID:Signaling mechanism underlying COX-2 induction by lysophosphatidylcholine. 1124 76

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent for adult T-cell leukemia (ATL), as well as for tropical spastic paraparesis (TSP) and HTLV-I associate myelopathy (HAM). A biological understanding of the involvement of HTLV-I and in ATL has focused significantly on the workings of the virally-encoded 40 kDa phospho-oncoprotein, Tax. Tax is a transcriptional activator. Its ability to modulate the expression and function of many cellular genes has been reasoned to be a major contributory mechanism explaining HTLV-I-mediated transformation of cells. In activating cellular gene expression, Tax impinges upon several cellular signal-transduction pathways, including those for CREB/ATF and NF-kappa B. In this paper, we review aspects of Tax's transcriptional potential with particular focus on recent evidence linking Tax to IKK (I kappa B-kinase)-complex and MAP3Ks (mitogen-activated protein kinase kinase kinases).
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PMID:Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kappa B. 1132 3

We have recently shown that IL-3R occupancy activates a phosphatidylcholine-specific phospholipase C, and the sustained diacylglycerol accumulation subsequently activates protein kinase C (PKC). In human IL-3-dependent myeloid cells (TF-1), the novel PKCepsilon isoform regulates bcl-2 expression and cell survival. The report of a PKC activatable cAMP response element (CRE) in the bcl-2 promoter and a role for PKC in bcl-2 expression in B cells led us to the hypothesis that PKC phosphorylation activates transcription factor CREB after IL-3R engagement. We found that IL-3 and GM-CSF induced phosphorylation of CREB on Ser(133) in TF-1 cells, and this phosphorylation was blocked by two structurally unrelated classes of PKC inhibitors. An inhibitor of cyclic nucleotide-dependent kinases did not block this phosphorylation. IL-4, which is biologically active in these cells but does not use the beta common subunit, did not phosphorylate CREB on Ser(133). Inhibition of mitogen-activated protein kinase kinase activity also inhibited IL3-induced CREB phosphorylation. The PKC inhibitors, but not a cyclic nucleotide-dependent kinase inhibitor, blocked IL-3 activation of CRE-dependent transcription from an egr-1 promoter/chloramphenicol acetyltransferase (CAT) reporter construction transiently transfected into TF-1 cells. Finally, TF-1 cells stably overexpressing PKCepsilon, but not the delta isoform of PKC, enhanced CRE-dependent CAT expression from the promoter/reporter construction. Therefore, it is likely that a PKCepsilon kinase cascade resulting in CREB phosphorylation represents a novel signal transduction cascade for regulating cellular gene expression through the beta common cytokine receptor.
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PMID:betac cytokine receptor-induced stimulation of cAMP response element binding protein phosphorylation requires protein kinase C in myeloid cells: a novel cytokine signal transduction cascade. 1159 53

The involvement of MAPK pathways in differentiation, proliferation and survival was investigated by comparing Epo and GM-CSF signalling in human factor-dependent myeloerythroid TF-1 cells with abnormal Epo-R. GM-CSF withdrawal induced cell-cycle arrest and apoptosis accompanied by increased caspase-3 activity, DNA degradation and reduced expression of the antiapoptotic Bcl-2 and Bcl-xl proteins. Readministration of GM-CSF but not Epo reversed these processes and induced proliferation. The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. In contrast, Epo failed to activate the Raf-1/ERK1/2 MAPK pathway or to induce Egr-1 and/or c-Fos expression, while it induced erythroid differentiation in GM-CSF-deprived cells. In addition, the Epo-induced haemoglobin production was inhibited in the presence of GM-CSF. These results demonstrate that the activation of MAPK cascade is not necessary for Epo-induced haemoglobin production in TF-1 cells and suggest a negative cross-talk between the signalling of GM-CSF-stimulated cell proliferation and Epo-induced erythroid differentiation.
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PMID:Activation of Raf/ERK1/2 MAP kinase pathway is involved in GM-CSF-induced proliferation and survival but not in erythropoietin-induced differentiation of TF-1 cells. 1160 85

Undifferentiated bipolar CG-4 cell line oligodendrocytes provide a model system for the O-2A progenitor cell from which oligodendrocytes are derived both in vivo and in vitro. The exchange of neuroblastoma conditioned basal media for basal media causes differentiation of undifferentiated bipolar CG-4 cells into multipolar oligodendrocyte-like cells whilst replacement with basal media containing 20% foetal bovine serum favours the formation of type-2 astrocyte-like cells. Here, we demonstrate that activation of these differentiation pathways correlates with distinct changes both in cell metabolism and in signal transduction. Exchange of neuroblastoma conditioned media for basal media correlates with stimulation of basal metabolic activity, reduced phosphorylation of p44/42 MAP kinase and reduced phosphorylation of the transcription factor CREB. In contrast, differentiation with basal medium containing 20% foetal bovine serum (FBS), into type 2 astrocyte-like cells, correlates with reduction in basal metabolic activity, increased phosphorylation of p44/42 MAP kinase and increased phosphorylation of the transcription factor CREB. Inhibition of protein kinase C blocked both the metabolic and morphological changes associated with differentiation towards mature multipolar oligodendrocyte-like cells. Inhibition of PKA and MEK did not effect metabolic activity. The rapid return of neuroblastoma conditioned basal media to cells treated with basal media, increased phosphorylation of CREB and MAP kinase. These results demonstrate that protein kinase C and p44/42 MAP kinase signalling pathways are modulated during bipolar CG-4 cell differentiation and demonstrate that the transcription factor CREB may play a pivotal role in differentiation along oligodendrocyte-or astrocyte-lineages.
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PMID:Differentiation of bipolar CG-4 line oligodendrocytes is associated with regulation of CREB, MAP kinase and PKC signalling pathways. 1167 34

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.
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PMID:Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. 1168 1


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