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)

The murine calcium-binding protein S100A8 is a potent chemoattractant for neutrophils and monocytes in vivo and in vitro but may also play a protective role. We show that the kinetics of induction of S100A8 mRNA in elicited murine macrophages (Mac) by LPS, IFN-gamma, and TNF were distinct from the C-C chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage-inflammatory protein-1alpha (MIP-1alpha), and RANTES. Monomeric S100A8 was predominantly secreted. IFN substantially increased S100A8 mRNA levels after 1 h with optimal induction after 12 h; induction by TNF was slower and more sustained. TNF did not up-regulate MCP-1 and MIP-1alpha mRNA in these cells. Luciferase reporter assays confirmed that LPS and IFN induce S100A8 gene transcription and mRNA in LPS-treated Mac showed little decay over 16 h, whereas transcripts induced by IFN and TNF were markedly less stable. Newly synthesized proteins may be required for mRNA transcription and stabilization in response to LPS. S100A9 associates with A8 in neutrophils, but was not coinduced with S100A8. S100A8 gene induction in Mac stimulated with LPS and IFN may be modulated by mobilization of intracellular Ca2+ concentration from distinct intracellular stores and/or the extracellular compartment and by distinct pathways involving protein kinase C and leading to activation of mitogen-activated protein kinase.
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PMID:IFN-gamma and TNF regulate macrophage expression of the chemotactic S100 protein S100A8. 1077 2

HIV-tat protein, like TNF, activates a wide variety of cellular responses, including NF-kappa B, AP-1, c-Jun N-terminal kinase (JNK), and apoptosis. Whether HIV-tat 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 p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an isogeneic lck-deficient T cell line. Treatment with HIV-tat protein activated NF-kappa B, degraded I kappa B alpha, and induced NF-kappa B-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56lck kinase. These effects were specific to HIV-tat, as activation of NF-kappa B by PMA, LPS, H2O2, and TNF was minimally affected. p56lck was also found to be required for HIV-tat-induced but not TNF-induced AP-1 activation. Similarly, HIV-tat activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. HIV-tat also induced cytotoxicity, activated caspases, and reactive oxygen intermediates in Jurkat cells, but not in JCaM1 cells. HIV-tat activated p56lck activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56lck tyrosine kinase reversed the HIV-tat-induced NF-kappa B activation and cytotoxicity. Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-kappa B, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF.
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PMID:Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosis. 1079 74

Two relatively well characterised kinase signalling pathways are those involving MAPK/ERK and p38/SAPK2, that are known to be activated in vitro by various factors known to increase following stroke, such as glutamate, IL-1 and TNF. The present study was designed to investigate the activation and cellular distribution of phosphorylated-ERK1/2, -p38 and the transcription factor CREB following focal cerebral ischaemia using phosphospecific antibodies. Up to 24 h following transient MCAO (90 min) and 6 h following permanent MCAO, phospho-ERK1/2 staining was markedly increased within the cytoplasm of neuronal perikarya in 'penumbral-like' regions. In contrast, phospho-p38 immunostaining was markedly increased in cells with astrocyte-like morphology in both 'core' and 'penumbral-like' regions. Phospho-p38 staining was also detected in some neurones within 'penumbral-like' regions up to 24 h following transient MCAO. CREB activation was confined to neurones in 'penumbral-like' regions. Increased phospho-p38 immunoreactivity was detected in astrocyte-like cells present in the subcortical white matter ipsilateral to the occluded MCAO, while phospho-CREB and -ERK1/2 staining was localised to cells with the morphological appearance of oligodendrocytes. This study demonstrates phosphorylation, indicative of activation, of both the MAPK and p38 pathways following transient and permanent MCAO. However, each pathway shows a distinct cellular and spatial distribution within ischaemic tissue. Together these data indicate that neuroprotection offered by agents directed towards the ERK1/2 pathway may act directly through protection of neurones and oligodendrocytes, while those directed towards the p38 pathway kinase signalling pathways may be indirectly via inhibition of cytokines and other mediators involved in the brains response to injury.
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PMID:Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. 1081 33

In this study, the effect of in vitro endotoxin tolerance on LPS-induced mitogen-activated protein kinase activation, transcription factor induction, and cytokine, chemokine, and Toll-like receptor (TLR) 2 and 4 gene expression, as well as the involvement of TNF and IL-1 signaling pathways in tolerance, were examined. Pretreatment of mouse macrophages with LPS inhibited phosphorylation of the extracellular signal-regulated kinases, c-Jun NH2-terminal kinases, and p38 kinase; degradation of I-kappaBalpha (inhibitory protein that dissociates from NF-kappaB) and I-kappaBbeta; and activation of the transcription factors NF-kappaB and AP-1 in response to subsequent LPS stimulation. These changes were accompanied by suppression of LPS-induced expression of mRNA for GM-CSF, IFN-gamma-inducible protein-10, KC, JE/monocyte chemoattractant protein-1, macrophage-inflammatory protein-1beta, and macrophage-inflammatory protein-2, with concurrent inhibition of chemokine secretion. In contrast to control cells, endotoxin-tolerant macrophages exhibited an increased basal level of TLR2 mRNA, and failed to increase levels of TLR2 mRNA or to down-regulate TLR4 gene expression upon restimulation with LPS. As judged by transcription factor activation, LPS and IL-1 were found to induce a state of cross-tolerance against each other, while no such reciprocal effect was seen for LPS and TNF-alpha. In addition, macrophages from TNFR I/II double knockout mice were LPS tolerizable, and blocking of endogenous TNF-alpha with TNFR-Fc fusion protein did not affect the capacity of LPS to tolerize macrophages. These data extend our understanding of LPS-signaling mechanisms that are inhibited in endotoxin-tolerized macrophages and suggest that endotoxin tolerance might result from impaired expression and/or functions of common signaling intermediates involved in LPS and IL-1 signaling.
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PMID:Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. 1082 Feb 30

Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-kappa B in these responses, we hypothesized that vesnarinone must modulate NF-kappa B activation. We investigated the effect of vesnarinone on NF-kappa B activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-kappa B in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-kappa B activation in a variety of cells. NF-kappa B-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-kappa B activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-kappa B-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-kappa B-inducing kinase sites by vesnarinone, thus suppressing NF-kappa B reporter gene expression. Vesnarinone also blocked NF-kappa B activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-kappa B and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone's ability to suppress inflammation, immunomodulation, and growth regulation.
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PMID:Vesnarinone suppresses TNF-induced activation of NF-kappa B, c-Jun kinase, and apoptosis. 1082 Feb 60

Stimulating macrophages with bacterial endotoxin (LPS) activates numerous intracellular signaling pathways that lead to the production of TNF. In this study, we show that four mitogen-activated protein (MAP) kinase pathways are activated in LPS-stimulated macrophages: the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase, p38, and Big MAP kinase (BMK)/ERK5 pathways. Although specific activation of a single MAP kinase pathway produces only a modest effect on TNF promoter activation, activation of each MAP kinase pathway is important for full induction of the TNF gene. Interestingly, a dramatic induction of TNF promoter-driven gene expression was observed when all of the four MAP kinase pathways were activated simultaneously, suggesting a cooperative effect among these kinases. Unexpectedly, cis elements known to be targeted by MAP kinases do not play a major role in multiple MAP kinase-induced TNF gene expression. Rather, a 40-bp sequence harboring the TATA box, is responsible for the gene up-regulation induced by MAP kinases. The proximity of the MAP kinase-responsive element to the transcriptional initiation site suggested that MAP kinases regulate the transcriptional initiation complex. Utilizing alpha-amanitin-resistant RNA polymerase II mutants with or without a C-terminal domain (CTD) deletion, we found that deleting the CTD to 31 tandem repeats (Delta31) led to >90% reduction in MAP kinase-mediated TNF production. Thus, our data demonstrate coordination of multiple MAP kinase pathways in TNF production and suggest that the CTD of RNA polymerase II is required to execute MAP kinase signaling in TNF expression.
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PMID:Regulation of TNF expression by multiple mitogen-activated protein kinase pathways. 1084 89

Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic phytoalexin found in grapes, fruits, and root extracts of the weed Polygonum cuspidatum, exhibits anti-inflammatory, cell growth-modulatory, and anticarcinogenic effects. How this chemical produces these effects is not known, but it may work by suppressing NF-kappaB, a nuclear transcription factor that regulates the expression of various genes involved in inflammation, cytoprotection, and carcinogenesis. In this study, we investigated the effect of resveratrol on NF-kappaB activation induced by various inflammatory agents. Resveratrol blocked TNF-induced activation of NF-kappaB in a dose- and time-dependent manner. Resveratrol also suppressed TNF-induced phosphorylation and nuclear translocation of the p65 subunit of NF-kappaB, and NF-kappaB-dependent reporter gene transcription. Suppression of TNF-induced NF-kappaB activation by resveratrol was not restricted to myeloid cells (U-937); it was also observed in lymphoid (Jurkat) and epithelial (HeLa and H4) cells. Resveratrol also blocked NF-kappaB activation induced by PMA, LPS, H2O2, okadaic acid, and ceramide. The suppression of NF-kappaB coincided with suppression of AP-1. Resveratrol also inhibited the TNF-induced activation of mitogen-activated protein kinase kinase and c-Jun N-terminal kinase and abrogated TNF-induced cytotoxicity and caspase activation. Both reactive oxygen intermediate generation and lipid peroxidation induced by TNF were suppressed by resveratrol. Resveratrol's anticarcinogenic, anti-inflammatory, and growth-modulatory effects may thus be partially ascribed to the inhibition of activation of NF-kappaB and AP-1 and the associated kinases.
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PMID:Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. 1084 9

Anethole, a chief constituent of anise, camphor, and fennel, has been shown to block both inflammation and carcinogenesis, but just how these effects are mediated is not known. One possibility is TNF-mediated signaling, which has also been associated with both inflammation and carcinogenesis. In the present report we show that anethole is a potent inhibitor of TNF-induced NF-kappaB activation (an early response) as monitored by electrophoretic mobility shift assay, IkappaBalpha phosphorylation and degradation, and NF-kappaB reporter gene expression. Suppression of IkappaBalpha phosphorylation and NF-kappaB reporter gene expression induced by TRAF2 and NIK, suggests that anethole acts on IkappaBalpha kinase. Anethole also blocked the NF-kappaB activation induced by a variety of other inflammatory agents. Besides NF-kappaB, anethole also suppressed TNF-induced activation of the transcription factor AP-1, c-jun N-terminal kinase and MAPK-kinase. In addition, anethole abrogated TNF-induced apoptosis as measured by both caspase activation and cell viability. The anethole analogues eugenol and isoeugenol also blocked TNF signaling. Anethole suppressed TNF-induced both lipid peroxidation and ROI generation. Overall, our results demonstrate that anethole inhibits TNF-induced cellular responses, which may explain its role in suppression of inflammation and carcinogenesis. Oncogene (2000).
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PMID:Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. 1087 45

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype is reminiscent of that reported for FADD-/- and caspase-8-/- embryos. However, unlike FADD-/- and caspase-8-/- cells, casper-/- embryonic fibroblasts are highly sensitive to FasL- or TNF-induced apoptosis and show rapid induction of caspase activities. NF-kappaB and JNK/SAPK activation is intact in TNF-stimulated casper-/- cells. These results suggest that Casper has two distinct roles: to cooperate with FADD and caspase-8 during embryonic development and to mediate cytoprotection against death factor-induced apoptosis.
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PMID:Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. 1089 63

TRADD is a multifunctional signaling adaptor protein that is recruited to TNFR1 upon ligand binding. The C-terminal of TRADD comprises the "death domain" that is responsible for association of TNFR1 and other death domain-containing proteins such as FADD and RIP. The N-terminal domain (N-TRADD) promotes the recruitment of TRAF2 to TNFR1 by binding to the C-terminal of TRAF2, leading to the activation of JNK/AP1 and NF-kappa B. The solution structure of N-TRADD was determined, revealing a novel protein fold. A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways.
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PMID:Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway. 1091 99


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