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)

Ceramide has been implicated as an intermediate in the signal transduction of several cytokines including tumor necrosis factor (TNF). Both ceramide and TNF activate a wide variety of cellular responses, including NF-kappaB, AP-1, JNK, and apoptosis. Whether ceramide transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56(lck) in ceramide- and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, isogeneic Lck-deficient T cells. Treatment with ceramide activated NF-kappaB, degraded IkappaBalpha, and induced NF-kappaB-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56(lck) kinase. These effects were specific to ceramide, as activation of NF-kappaB by phorbol 12-myristate 13-acetate, lipopolysaccharide, H(2)O(2), and TNF was minimally affected. p56(lck) was also found to be required for ceramide-induced but not TNF-induced AP-1 activation. Similarly, ceramide activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. Ceramide also induced cytotoxicity and activated caspases and reactive oxygen intermediates in Jurkat cells but not in JCaM1 cells. Ceramide activated p56(lck) activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56(lck) tyrosine kinase reversed the ceramide-induced NF-kappaB activation and cytotoxicity. Overall our results demonstrate that p56(lck) plays a critical role in the activation of NF-kappaB, AP-1, JNK, and apoptosis by ceramide but has minimal or no role in activation of these responses by TNF.
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PMID:Protein tyrosine kinase p56lck is required for ceramide-induced but not tumor necrosis factor-induced activation of NF-kappa B, AP-1, JNK, and apoptosis. 1078 36

Human chorionic gonadotropin (hCG) suppresses cell-mediated allogeneic reactions, viral replication, tumorigenesis, and metastasis, most of which require activation of nuclear transcription factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In the present report, we investigated the effect of hCG on NF-kappaB and AP-1 activated by tumor necrosis factor (TNF). Treatment of the CaCOV3 human ovarian cell line with hCG blocked TNF-induced activation of NF-kappaB, IkappaBalpha degradation, and NF-kappaB-dependent reporter gene transcription. hCG also blocked NF-kappaB activation induced by ceramide. The effect of hCG on NF-kappaB was mediated through inhibition of phosphorylation of IkappaBalpha. Because hCG also blocked TNF receptor-associated factor-2 and NF-kappaB-inducing kinase reporter gene expression, hCG must act at a step that causes phosphorylation of IkappaBalpha. AP-1 activation induced by TNF and ceramide was also suppressed by hCG. hCG abrogated the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase required for NF-kappaB and AP-1, respectively. Dideoxyadenosine and H-8 reversed the effect, and dibutyryl cAMP mimicked the effect, suggesting that hCG suppresses the transcription factors through cAMP-induced protein kinase A pathway. Overall, our results indicate that hCG inhibits the activation of NF-kappaB and AP-1, which may be the molecular basis by which hCG suppresses viral replication, cell proliferation, tumorigenesis, and metastasis.
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PMID:Human chorionic gonadotropin suppresses activation of nuclear transcription factor-kappa B and activator protein-1 induced by tumor necrosis factor. 1078 37

The signal transduction pathways regulating smooth-muscle gene expression and production of cytokines in response to proinflammatory mediators are undefined. Cultured human bronchial smooth-muscle cells were treated for 20 h with a cytokine cocktail containing interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. A complementary DNA expression array containing 588 genes was used to follow cytokine-stimulated gene expression. The expression and secretion of the cytokines IL-1beta, IL-6, and IL-8 significantly increased after 20 h of stimulation as measured by relative reverse transcriptase/ polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blotting techniques. Expression of IL-6 and IL-8 was sensitive to SB203580, the specific inhibitor of p38 mitogen-activated protein (MAP) kinase and PD98059, an inhibitor of MAP kinase kinase. Expression of IL-1beta was sensitive only to PD98059. Together, these results demonstrate that the p38 and extracellular signal-regulated protein kinase MAP kinase pathways are required for proinflammatory mediator- induced cytokine expression in airway myocytes. The generation of chemokines and cytokines in airway smooth muscle also provides evidence that smooth-muscle cells have the ability to contribute to the inflammatory response.
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PMID:Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. 1087 57

There is accumulating evidence of complicated interactions among vascular cells, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages, in the regulation of vascular function and remodeling. We have investigated the mechanisms responsible for matrix metalloproteinase (MMP)-1 expression by interactions between monocytes and vascular endothelial cells. THP-1 cells (human monocytic cell line) and human umbilical vein endothelial cells (HUVECs) were cocultured. MMP-1 levels in the culture medium were measured by enzyme-linked immunosorbent assays. Collagenolytic activity in the culture medium was measured by fluorescence labeled-collagen digestion. Immunohistochemistry using an anti-MMP antibody was carried out to determine which types of cell produce MMP-1. The addition of THP-1 cells to HUVECs for 48 h induced increases in MMP-1 levels and collagenolytic activity, which were 5- and 2-fold relative to those of HUVECs alone, respectively. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced MMP-1 production in the cocolture. Immunohistochemical analysis revealed that both types of cell produce MMP-1 in the coculture. Neutralizing anti-interleukin-1 beta and tumor necrosis factor- alpha antibodies inhibited MMP-1 production by the coculture. The Src kinase and MEK inhibitors significantly inhibited MMP-1 production by the coculture. Coculture of THP-1 cells and HUVECs induced significant increases in Src and mitogen activated protein (MAP) kinase activities. Enhanced MMP-1 expression induced by monocyte-endothelial cell interactions may play an important role in the pathogenesis of atherosclerosis and plaque rupture.
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PMID:Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells. 1090 Jan 72

We tested hypothesis that the interaction of fibrinogen (Fg) with intercellular adhesion molecule 1 (ICAM-1) mediates cellular adhesion and cell proliferation. Our results demonstrate that Fg : ICAM-1 ligation mediates endothelial cell survival and has an anti-apoptotic effect via activation of the MAP kinase pathway. Fg : ICAM-1 ligation in endothelial cells treated with tumor necrosis factor (TNF)alpha resulted in the hyperphosphorylation of extracellular signal-regulated kinase (ERK)-1/2 (eightfold to 10-fold) at 5-30 min. The specificity of ERK-1/2 phosphorylation was verified using the recognition peptides Fg-gamma-(117-133) and ICAM-1(8-22). ERK-1/2 hyperphosphorylation was dependent on intact cytoskeleton, as treatment with cytochalasin B and nocodazole blocked this activity. The attachment of TNFalpha-treated endothelial cells to fibrinogen or Fg-gamma-(117-133) resulted in cell survival, as assessed by an annexin V binding assay. ICAM-1(8-22) blocked the survival process. The MEK-1 inhibitor PD 98059 blocked ERK-1/2 phosphorylation, and treatment of endothelial cells with PD 98059 resulted in apoptosis even upon Fg : ICAM-1 ligation. Cells transfected with dominant-negative ERK-1/2 underwent apoptosis upon Fg : ICAM-1 ligation. Cell survival factor A1 was specifically upregulated upon adhesion of TNFalpha-stimulated endothelial cells to Fg. A1 expression was blocked by ICAM-1(8-22) and PD 98059. The Fg : ICAM-1 endothelial cell survival pathway appears to be mediated via the activation and upregulation of ERK-1/2 and A1.
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PMID:Fibrinogen interactions with ICAM-1 (CD54) regulate endothelial cell survival. 1090 2

Brain microglia are a major source of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), which have been implicated in the progression of neurodegenerative diseases. Recently, microglia were revealed to be highly responsive to ATP, which is released from nerve terminals, activated immune cells, or damaged cells. It is not clear, however, whether released ATP can regulate TNF-alpha secretion from microglia. Here we demonstrate that ATP potently stimulates TNF-alpha release, resulting from TNF-alpha mRNA expression in rat cultured brain microglia. The TNF-alpha release was maximally elicited by 1 mM ATP and also induced by a P2X(7) receptor-selective agonist, 2'- and 3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, suggesting the involvement of P2X(7) receptor. ATP-induced TNF-alpha release was Ca(2+)-dependent, and a sustained Ca(2+) influx correlated with the TNF-alpha release in ATP-stimulated microglia. ATP-induced TNF-alpha release was inhibited by PD 098059, an inhibitor of extracellular signal-regulated protein kinase (ERK) kinase 1 (MEK1), which activates ERK, and also by SB 203580, an inhibitor of p38 mitogen-activated protein kinase. ATP rapidly activated both ERK and p38 even in the absence of extracellular Ca(2+). These results indicate that extracellular ATP triggers TNF-alpha release in rat microglia via a P2 receptor, likely to be the P2X(7) subtype, by a mechanism that is dependent on both the sustained Ca(2+) influx and ERK/p38 cascade, regulated independently of Ca(2+) influx.
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PMID:Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. 1093 77

We previously reported tumor necrosis factor-alpha (TNF) modulates transcriptional and post-transcriptional down-regulation of macrophage scavenger receptor (MSR) (Hsu, H. Y., Nicholson, A. C., and Hajjar, D. P. (1996) J. Biol. Chem. 271, 7767-7773); however, TNF-mediated signaling mechanisms are unknown. Here, we demonstrate that ligation of TNF receptor stimulates activity of p21-activated protein kinase (PAK) and mitogen-activated protein kinases (MAPK) as follows: ERK, JNK, and p38 in murine macrophage J774A.1 cells. Upon activation of protein kinases (PK), TNF rapidly increases MSR message and protein; later it markedly reduces MSR expression. Studies using PK inhibitors and dominant negative constructs demonstrate phosphatidylinositol 3-kinase/Rac1/PAK/JNK and phosphatidylinositol 3-kinase/Rac1/PAK/p38 pathways contribute to important roles in the late stage of TNF down-regulation of MSR expression and taking up of OxLDL. Alternatively, the PKC/MEK1/ERK pathway in the early stage plays a significant role in up-regulation of the MSR gene. By using anti-TNF-R1 agonist antibody, we further confirm TNF-R1-mediated MAPK in regulation of MSR. Furthermore, in MSR gene promoter-driven luciferase reporter assays with TNF, PKC activator increases, but antioxidant N-acetylcysteine, PK inhibitors, and dominant negative constructs decrease luciferase activity in MSR gene promoter-transfected cells. Our current results show the first evidence of crucial roles for TNF-mediated MAPK pathways in the transcriptional regulation of MSR gene and increase MSR expression; in contrast, with TNF longer treatment the pathways down-regulate MSR and foam cell formation probably via post-transcriptional process.
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PMID:Tumor necrosis factor-alpha -mediated protein kinases in regulation of scavenger receptor and foam cell formation on macrophage. 1096 71

PEA-15 is a small, death effector-domain (DED)-containing protein that was recently demonstrated to inhibit tumor necrosis factor-alpha-induced apoptosis and to reverse the inhibition of integrin activation due to H-Ras. This led us to investigate the involvement of PEA-15 in Ras signaling. Surprisingly, PEA-15 activates the extracellular signal receptor-activated kinase (ERK) mitogen-activated protein kinase pathway in a Ras-dependent manner. PEA-15 expression in Chinese hamster ovary cells resulted in an increased mitogen-activated protein kinase kinase and ERK activity. Furthermore, PEA-15 expression leads to an increase in Ras guanosine 5'-triphosphate loading. PEA-15 bypasses the anchorage dependence of ERK activation. Finally, the effects of PEA-15 on integrin signaling are separate from those on ERK activation. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to activate ERK. The ability of PEA-15 to simultaneously inhibit apoptosis and potentiate Ras-to-Erk signaling may be of importance for oncogenic processes.
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PMID:Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism. 1098 86

Extracellular matrix facilitates anchorage-dependent cell survival via interaction of its arginine-glycine-aspartate (RGD) motif with integrins. In this report, we describe an unexpected, apoptosis-promoting the effect of immobilized RGD (iRGD) on tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis. Mesangial cells cultured on RGD-coated plates showed enhanced susceptibility to TNF-alpha-induced apoptosis. iRGD alone did not affect cell survival. In contrast, iRGD did not facilitate but inhibited apoptosis induced by H(2)O(2). Mitogen-activated protein (MAP) kinases and tyrosine kinases are important mediators for the RGD-integrin signaling. Pretreatment with MAP kinase kinase inhibitor PD098059, c-Jun N-terminal kinase (JNK)-c-Jun/AP-1 inhibitor curcumin or p38 MAP kinase inhibitor SB203580 did not attenuate the apoptosis-promoting effect of iRGD. Consistently, transfection with dominant-negative mutants of extracellular signal-regulated kinases, JNK or p38 MAP kinase did not inhibit the effect of iRGD. In contrast, protein tyrosine kinase inhibitors, genistein, and herbimycin A, abrogated the apoptosis-promoting effect of iRGD. Of note, TNF-alpha-induced apoptosis on uncoated plates was not attenuated by tyrosine kinase inhibitors. These data provide the first evidence that iRGD accelerates certain apoptosis. We identified that the effect was mediated by the tyrosine kinase-dependent, MAP kinase-independent mechanism.
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PMID:Enhancement of TNF-alpha-induced apoptosis by immobilized arginine-glycine-aspartate: involvement of a tyrosine kinase-dependent, MAP kinase-independent mechanism. 1103 20

The intensity and duration of an inflammatory response depends on the balance of factors that favor perpetuation versus resolution. At sites of inflammation, neutrophils adherent to other cells or matrix components are exposed to tumor necrosis factor-alpha (TNFalpha). Although TNFalpha has been implicated in induction of pro-inflammatory responses, it may also inhibit the intensity of neutrophilic inflammation by promoting apoptosis. Since TNFalpha is not only an important activator of the stress-induced pathways leading to p38 MAPk and c-Jun N-terminal kinase (JNK) but also a potent effector of apoptosis, we investigated the effects of TNFalpha on the JNK pathway in adherent human neutrophils and the potential involvement of this pathway in neutrophil apoptosis. Stimulation with TNFalpha was found to result in beta2 integrin-mediated activation of the cytoplasmic tyrosine kinases Pyk2 and Syk, and activation of a three-part MAPk module composed of MEKK1, MKK7, and/or MKK4 and JNK1. JNK activation was attenuated by blocking antibodies to beta2 integrins, the tyrosine kinase inhibitors, genistein, and tyrphostin A9, a Pyk2-specific inhibitor, and piceatannol, a Syk-specific inhibitor. Exposure of adherent neutrophils to TNFalpha led to the rapid onset of apoptosis that was demonstrated by augmented annexin V binding and caspase-3 cleavage. TNFalpha-induced increases in annexin V binding to neutrophils were attenuated by blocking antibodies to beta2 integrins, and the caspase-3 cleavage was attenuated by tyrphostin A9. Hence, exposure of adherent neutrophils to TNFalpha leads to utilization of the JNK-signaling pathways that may contribute to diverse functional responses including induction of apoptosis and subsequent resolution of the inflammatory response.
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PMID:Tumor necrosis factor-alpha activation of the c-Jun N-terminal kinase pathway in human neutrophils. Integrin involvement in a pathway leading from cytoplasmic tyrosine kinases apoptosis. 1105 15


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