Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion molecules mediate inflammatory myocardial injury after ischemia/reperfusion. Cytokine release and hypoxia are features of acute ischemia that may influence expression of these molecules. Accordingly, we studied intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) responses to cytokines and acute hypoxia in cultured myocardial cells. Northern blot analysis and immunoassay showed that the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha stimulated concentration-dependent increases in ICAM and VCAM mRNA and protein. In both cardiac myocytes and fibroblasts, pretreatment with a specific inhibitor of nuclear transcription factor-kappaB (NF-kappaB) prevented cytokine induction of both molecules. We also found that inhibition of tyrosine kinase and p38/RK (stress-activated protein kinase) pathways prevented IL-1beta-induced ICAM and VCAM protein synthesis, whereas extracellular signal-regulated protein kinase (ERK1/ERK2) inhibition did not. Neither hypoxia (0% O2 for 6 hours) alone nor hypoxia/reoxygenation had any significant effect on ICAM and VCAM mRNA. However, hypoxia did enhance IL-1beta-induced ICAM mRNA expression in myocytes. As a possible mechanism of this synergistic action on CAM expression, hypoxia induced a time-dependent increase in the DNA binding activity of both NF-kappaB and activator protein-1 (AP-1), two transcription factors important for cell adhesion molecule expression. In contrast to the enhanced ICAM mRNA induced by IL-1beta during hypoxia, however, protein levels for this adhesion molecule were unchanged beyond IL-1beta-stimulated levels, suggesting posttranscriptional and/or posttranslational control mechanisms. We conclude that cytokines regulate ICAM and VCAM mRNA and protein in both cardiac myocytes and fibroblasts. Furthermore, adhesion molecule induction requires translocation of at least two transcription factors, NF-kappaB and AP-1.
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PMID:Expression and regulation of adhesion molecules in cardiac cells by cytokines: response to acute hypoxia. 952 62

Work from this and other laboratories has identified a role for protein tyrosine kinases in interleukin-1 alpha (IL-1 alpha)- and tumor necrosis factor-alpha (TNF-alpha)-induced responses in endothelial cells. In this study, we show that activation of human umbilical vein endothelial cells (HUVEC) by IL-1 alpha leads to increased tyrosine phosphorylation of several proteins including one with a molecular mass of approximately 42 kDa. This protein was identified as p42mapk by Western blot analysis. Tyrosine phosphorylation and catalytic activation of p42mapk by IL-1 alpha was transient, reaching maximal levels after 30 min and returning to basal levels by 120-300 min. Activation of p42mapk in HUVEC was also observed in response to TNF-alpha or to the protein kinase C (PKC)-activating phorbol ester phorbol 12-myristate 13-acetate (PMA). Pretreatment of HUVEC with IL-1 alpha or TNF-alpha prevented reactivation of p42mapk by either cytokine but did not affect subsequent activation in response to PMA. Activation of p42mapk by PMA was significantly reduced by the PKC inhibitor Ro-31-8220 and completely inhibited by the protein tyrosine kinase inhibitor genistein. Genistein, but not Ro-31-8220, attenuated IL-1 alpha- and TNF-alpha-induced p42mapk activation. Taken together, the results of this study demonstrate 1) that p42mapk is transiently activated in HUVEC by IL-1 alpha and TNF-alpha, 2) that this activation is PKC independent, and 3) that a genistein-inhibitable tyrosine kinase may be an upstream regulator of cytokine-induced p42mapk activation in human endothelium.
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PMID:Activation of p42mapk in human umbilical vein endothelial cells by interleukin-1 alpha and tumor necrosis factor-alpha. 953 Jan 11

Human monocytic leukemia U937 cells undergo apoptosis when treated with antitumor drugs, such as etoposide, camptothecin and mitomycin C. The molecular mechanism of the drug-induced apoptosis is not well understood. In this study, we found that 2-deoxyglucose (2DG), an analog of D-glucose and an inducer of glucose-regulated stress, inhibited anticancer drug-induced but not tumor necrosis factor-alpha-induced apoptosis of U937 cells. 2DG did not reduce initial cellular damage caused by etoposide, an inhibitor of topoisomerase II, suggesting that 2DG affected subsequent cellular responses involved in apoptosis. 2DG inhibited the etoposide-induced activation of c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK) and the subsequent activation of CPP32, both of which are positive regulators for etoposide-induced apoptosis of U937 cells. Our results indicate that 2DG inhibits apoptosis by blocking the signals from cellular DNA damage for JNK1/SAPK activation.
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PMID:2-Deoxyglucose inhibits chemotherapeutic drug-induced apoptosis in human monocytic leukemia U937 cells with inhibition of c-Jun N-terminal kinase 1/stress-activated protein kinase activation. 953 66

We report the cloning of a novel human activator of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 7 (MKK7). The mRNA for MKK7 is widely expressed in humans and mice and encodes a 47-kDa protein (419 amino acids), as determined by immunoblotting endogenous MKK7 with an antibody raised against its N terminus. The kinase domain of MKK7 is closely related to a Drosophila JNK kinase dHep (69% identity) and to a newly identified ortholog from Caenorhabditis elegans (54% identity), and was more distantly related to MKK4, MKK3, and MKK6. MKK7 phosphorylated and activated JNK1 but failed to activate p38 MAPK in co-expression studies. In hematopoietic cells, endogenous MKK7 was activated by treatment with the growth factor interleukin-3 (but not interleukin-4), or by ligation of CD40, the B-cell antigen receptor, or the receptor for the Fc fragment of immunoglobulin. MKK7 was also activated when cells were exposed to heat, UV irradiation, anisomycin, hyperosmolarity or the pro-inflammatory cytokine tumor necrosis factor-alpha. Co-expression of constitutively active mutants of RAS, RAC, or CDC42 in HeLa epithelial cells or of RAC or CDC42 in Ba/F3 factor-dependent hematopoietic cells also activated MKK7, suggesting that MKK7 will be involved in many physiological pathways.
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PMID:Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. 953 30

In addition to its role as a survival factor, nerve growth factor (NGF) has been implicated in initiating apoptosis in restricted cell types both during development and after terminal cell differentiation. NGF binds to the TrkA tyrosine kinase and the p75 neurotrophin receptor, a member of the tumor necrosis factor cytokine family. To understand the mechanisms underlying survival versus death decisions, the TrkA receptor was introduced into oligodendrocyte cell cultures that undergo apoptosis in a p75-dependent manner. Here we report that activation of the TrkA NGF receptor in oligodendrocytes negates cell death by the p75 receptor. TrkA-mediated rescue from apoptosis correlated with mitogen-activated protein kinase activation. Concurrently, activation of TrkA in oligodendrocytes resulted in suppression of c-jun kinase activity initiated by p75, whereas induction of NFkappaB activity by p75 was unaffected. These results indicate that TrkA-mediated rescue involves not only activation of survival signals but also simultaneous suppression of a death signal by p75. The selective interplay between tyrosine kinase and cytokine receptors provides a novel mechanism that achieves alternative cellular responses by merging signals from different ligand-receptor systems.
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PMID:Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. 954 36

Apoptosis signal-regulating kinase (ASK) 1 was recently identified as a mitogen-activated protein (MAP) kinase kinase kinase which activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)-alpha-induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1-binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)-regulatory protein thought to have anti-apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N-terminal portion of ASK1 in vitro and in vivo. Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1-dependent apoptosis. Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis.
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PMID:Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. 956 42

This study describes the activation conditions for tumor necrosis factor-alpha (TNF alpha) production in myelomonocytic U937 cells and human primary peripheral blood monocytes in response to lipopolysaccharide (LPS) and/or phorbol 12-myristate 13-acetate (PMA). PMA itself induced only low levels of TNF alpha production with delayed kinetics (e.g. 0.758 +/- 0.128 ng/ml from U937 cells after 48 h) while LPS induced greater levels of TNF alpha production in less time (e.g. 2.083 +/- 0.96 ng/ml from monocytes in 24 h). Pharmacological agents with various molecular sites of action were used to validate the two systems, with the protein serine-threonine kinase inhibitors staurosporine and Ro-31-8220, the protein tyrosine kinase inhibitor herbimycin A (HBA) and dexamethasone exhibiting the greatest potency (IC50S 5-350 nM). In contrast to the effect on TNF alpha production, PMA induced strong phosphorylation/activation of p42/p44mapk in monocytes by 10 min determined in a mobility shift assay, while LPS was a weaker inducer. Additionally, staurosporine (to LPS and PMA) and HBA (to LPS only) inhibited the activation of these mitogen-activated protein kinase (MAPK) isoforms at doses 10-100 fold higher than those required to inhibit maximal TNF alpha production. These data indicate the involvement of the p42/p44mapk signalling pathway in LPS-induced pro-inflammatory cytokine production but suggest that other signalling pathways are also implicated in this phenomenon.
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PMID:Differential effects on TNF alpha production by pharmacological agents with varying molecular sites of action. 956 51

To test whether mitogen-activated protein kinases (MAPKs) are involved in microglial activation, pure microglia prepared from 1- to 3-day-old rat brains were activated with either 100 ng/ml lipopolysaccharide (LPS) or 5 nM synthetic beta-amyloid (Abeta) (25-35). The patterns of MAPK activation following LPS and Abeta treatment were very similar. Three MAPK subtypes, p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) were activated within 15 min and the activities of p38 and ERK were rapidly reduced to background level within 30 min while that of JNK was maintained for over 1 h. Both inhibitors of p38 (SB203580) and ERK pathway (PD098059) reduced LPS-induced nitric oxide (NO) release and Abeta-induced tumor necrosis factor-alpha (TNF-alpha) release. Furthermore, co-treatment of SB203580 and PD098059 additively reduced NO and TNF-alpha release. These results suggest that MAPK, at least p38 and ERK, mediate LPS-, and Abeta-induced microglial activation.
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PMID:Mitogen-activated protein kinases activated by lipopolysaccharide and beta-amyloid in cultured rat microglia. 957 82

CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on T, B, and NK cells. The signal via CD27 plays pivotal roles in T-T and T-B cell interactions. Here we demonstrate that overexpression of CD27 activates NF-kappaB and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). Deletion analysis of the cytoplasmic domain of CD27 revealed that the C-terminal PIQEDYR motif was indispensable for both NF-kappaB and SAPK/JNK activation and was also required for the interaction with TNF receptor-associated factor (TRAF) 2 and TRAF5, both of which have been implicated in NF-kappaB activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-kappaB and SAPK/JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-kappaB-inducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-kappaB and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-kappaB and SAPK/JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-kappaB and SAPK/JNK activation.
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PMID:CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase. 958 83

Reactive oxygen metabolites are increasingly recognized for their ability to stimulate signal transduction pathways. This is important because these oxidants are frequently generated at sites of inflammation. However, little is known about the manner in which reactive oxygen species may selectively stimulate distinct signaling pathways. We have examined this question by stimulating mesothelial cells with hydrogen peroxide (H2O2) as a model oxidant stimulus. The response to H2O2 was examined by measuring the activation of the extracellular signal-regulated kinase (ERK1/2) and the nuclear factor-kappa B (NF-kappa B) signal transduction pathways. We found that H2O2 stimulated activity of the ERK1/2 pathway in a dose- and time-dependent manner. The ability of H2O2 to activate ERK1/2 was similar to that found with tumor necrosis factor (TNF) stimulation. The oxidant effect was inhibited by various reactive oxygen scavengers. An inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase, the upstream kinase that activates ERK1/2, inhibited the oxidant effect. The superoxide anion (O2-) also stimulated ERK1/2 activity. In contrast, H2O2 did not stimulate proteolysis of I kappa B-alpha and induced only a small degree of NF-kappa B nuclear translocation. Stimulation of the cells with O2- also induced a minimal degree of NF-kappa B activation. TNF was a potent stimulus for I kappa B-alpha proteolysis and NF-kappa B activation, demonstrating that the cells did have a functional NF-kappa B pathway. These results suggest that oxidants may selectively stimulate certain pathways, thereby preserving some specificity of the signaling process. Furthermore, different cell types and distinct signaling pathways within cells may demonstrate unique profiles in the manner in which they respond to oxidant stimulation.
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PMID:Differential regulation of extracellular signal-regulated kinase and nuclear factor-kappa B signal transduction pathways by hydrogen peroxide and tumor necrosis factor. 958 14


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