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)

Adenylate/uridylate-rich element (ARE)-mediated mRNA turnover is an important regulatory component of gene expression for innate and specific immunity, in the hematopoietic system, in cellular growth regulation, and for many other cellular processes. This diversity is reflected in the distribution of AREs in the human genome, which we have established as a database of more than 900 ARE-containing genes that may utilize AREs as a means of controlling cellular mRNA levels. The p38 mitogen-activated protein kinase (MAP kinase) pathway has been implicated in regulating the stability of nine ARE-containing transcripts. Here we explored the entire spectrum of ARE-containing genes for p38-dependent regulation of ARE-mediated mRNA turnover with a custom cDNA array containing probes for 950 ARE mRNAs. The human monocytic cell line THP-1 treated with lipopolysaccharide (LPS) was used as a reproducible cellular model system that allowed us to precisely control the conditions of mRNA induction and decay in the absence and presence of the p38 inhibitor SB203580. This approach allowed us to establish an LPS-induced ARE mRNA expression profile in human monocytes and determine the half-lives of 470 AU-rich mRNAs. Most importantly, we identified 42 AU-rich genes, previously unrecognized, that show p38-dependent mRNA stabilization. In addition to a number of cytokines, several interesting novel AU-rich transcripts likely to play a role in macrophage activation by LPS exhibited p38-dependent transcript stabilization, including macrophage-specific colony-stimulating factor 1, carbonic anhydrase 2, Bcl2, Bcl2-like 2, and nuclear factor erythroid 2-like 2. Finally, the identification of the p38-dependent upstream activator MAP kinase kinase 6 as a member of this group identifies a positive feedback loop regulating macrophage signaling via p38 MAP kinase-dependent transcript stabilization.
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PMID:p38 Mitogen-activated protein kinase-dependent and -independent signaling of mRNA stability of AU-rich element-containing transcripts. 1250 43

So far some nuclear receptors for bile acids have been identified. However, no cell surface receptor for bile acids has yet been reported. We found that a novel G protein-coupled receptor, TGR5, is responsive to bile acids as a cell-surface receptor. Bile acids specifically induced receptor internalization, the activation of extracellular signal-regulated kinase mitogen-activated protein kinase, the increase of guanosine 5'-O-3-thio-triphosphate binding in membrane fractions, and intracellular cAMP production in Chinese hamster ovary cells expressing TGR5. Our quantitative analyses for TGR5 mRNA showed that it was abundantly expressed in monocytes/macrophages in human and rabbit. Treatment with bile acids was found to suppress the functions of rabbit alveolar macrophages including phagocytosis and lipopolysaccharide-stimulated cytokine productions. We prepared a monocytic cell line expressing TGR5 by transfecting a TGR5 cDNA into THP-1 cells that did not express TGR5 originally. Treatment with bile acids suppressed the cytokine productions in the THP-1 cells expressing TGR5, whereas it did not influence those in the original THP-1 cells, suggesting that TGR5 is implicated in the suppression of macrophage functions by bile acids.
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PMID:A G protein-coupled receptor responsive to bile acids. 1252 22

A mouse IgG(1)-producing hybridoma, CSC-31, was isolated and characterized. The monoclonal antibody (MAb) was originally raised against monkey kidney cell-surface molecules. FACS analysis further showed that CSC-31 exhibited broad tissue and species reactivity. Although most human T- and B-cell lines failed to react with CSC-31, myeloid, and erythroleukemia cells lines such as THP-1 and K562 expressed the CSC-31 cell surface marker. Furthermore, in vitro differentiation of HL-60, U-937, and K562 showed that expression of the CSC-31 marker is associated with monocytic or megakaryocytic differentiation. However, up-regulation of the CSC-31 marker expression was not detected during granulocytic or erythroid differentiation. Through the in vitro differentiation of K562, it was demonstrated that up-regulation of the CSC-31 marker required novel PKCs and might be regulated by the MAPK signaling pathway. Last, limited biochemical analysis demonstrated that the CSC-31-specific epitope is sensitive to digestion by papain yet highly resistant to other proteases.
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PMID:Characterization of a pan-species reactive monoclonal antibody specific for a cell surface epitope which could serve as a marker for human monocytic and megakaryocytic differentiation. 1257 8

We studied the effects of LPS on cysteinyl leukotriene (LT) synthesis and LTC(4) synthase expression in mononuclear phagocytes. Conditioning of the monocyte-like cell line, THP-1, with LPS for 7 days resulted in significantly decreased ionophore-stimulated LTC(4) release. The putative LPS receptor, Toll-like receptor 4, was expressed in THP-1 cells. LPS down-regulated LTC(4) synthase mRNA in THP-1 cells in a dose- and time-dependent manner, with down-regulation observed as early as 4 h. Conditioning of actinomycin D-treated cells with LPS resulted in no change in the rate of LTC(4) synthase mRNA decay. LPS treatment of THP-1 cells, transiently transfected with a LTC(4) synthase promoter (1.35 kb)-reporter construct, decreased promoter activity. Neutralization of TNF-alpha and inhibition of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase did not inhibit the effect of LPS. Treatment of cells with a Toll-like receptor 4-blocking Ab and an inhibitor of NF-kappaB activation resulted in inhibition of the LPS effect, while activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism.
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PMID:Lipopolysaccharide down-regulates the leukotriene C4 synthase gene in the monocyte-like cell line, THP-1. 1257 84

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
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PMID:A mechanism converting psychosocial stress into mononuclear cell activation. 1257 63

In the present study, we focused on the molecular events involved in tumor necrosis factor-alpha (TNF-alpha) production in response to the amyloidogenic 105-amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a candidate alternative toxic element in Alzheimer's disease pathology, and the mechanisms by which cyclic AMP regulates the relating inflammatory signal cascades. CT105 at nanomolar concentrations strongly activated multiple signaling pathways involving tyrosine kinase-dependent extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Moreover, phosphatidylinositol 3-kinase/Akt signal was required for excess TNF-alpha production in human macrophages derived from THP-1 cells. Interferon-gamma significantly potentiated the induction of the CT105-mediated signal cascade. These multiple signaling pathways in turn converged, at least in part, at the nuclear transcription factor known as cAMP response element binding protein (CREB), which acts on the TNF-alpha gene promoter through the cAMP response element. The cell-permeable cAMP analog dibutyryl cAMP partially and almost simultaneously suppressed all of these CT105-induced signaling pathways through excessive CREB phosphorylation, which led to decreased CREB DNA binding activity and reduced TNF-alpha expression. Furthermore, dibutyryl cAMP decreased the interaction of the p65 nuclear factor-kappa B with CREB binding protein, thus further inhibiting CT105-mediated TNF-alpha expression. Collectively, the detailed molecular mechanisms of amyloidogenic CT-induced TNF-alpha production as negatively regulated by cAMP may advance the possibility of targeted treatment in Alzheimer's disease.
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PMID:Cyclic AMP inhibition of tumor necrosis factor alpha production induced by amyloidogenic C-terminal peptide of Alzheimer's amyloid precursor protein in macrophages: involvement of multiple intracellular pathways and cyclic AMP response element binding protein. 1260 79

Monocyte chemoattractant protein (MCP-1) is a major chemoattractant for monocytes and T-lymphocytes although it can cause migration of the HUVECs. We used monocytic cell line THP-1, monocytes of human peripheral blood, and HUVECs to study MCP-1 receptor-mediated cell migration. We showed that THP-1 and the monocytes chemotaxis was decreased in presence of specific inhibitors of p 38 MAP-kinase. Furthermore, it was almost completely diminished by inhibitor of tyrosine kinases. In contrast, MCP-1-stimulated migration of HUVECs was abrogated by specific inhibitor of ERK1/2 MAP-kinases and, to a lesser extent, by blocking tyrosine kinases. These results suggest that intracellular signal pathways activated by MCP-1 in monocytes and HUVECs, are distinct.
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PMID:[Effect of the mitogen-activated kinase inhibitors on monocyte protein-1-stimulated chemotaxis of cells]. 1266 92

Monocytes from patients with sickle cell disease (SCD) are in an activated state. However, the mechanism of activation of monocytes in SCD is not known. Our studies showed that placenta growth factor (PlGF) activated monocytes and increased mRNA levels of cytokines (tumor necrosis factor-alpha [TNF-alpha] and interleukin-1beta [IL-1beta]) and chemokines (monocyte chemotactic protein-1 [MCP-1], IL-8, and macrophage inflammatory protein-1beta [MIP-1beta]) in both normal monocytes and in the THP-1 monocytic cell line. This increase in mRNA expression of cytochemokines was also reflected in monocytes derived from subjects with SCD. We studied the PlGF-mediated downstream cellular signaling events that caused increased transcription of inflammatory cytochemokines and chemotaxis of THP-1 monocytes. PlGF-mediated cytochemokine mRNA and protein expression was inhibited by PD98059 and wortmannin, inhibitors of mitogen-activated protein kinase kinase (MAPK/MEK) kinase and phosphatidylinositol-3 (PI3) kinase, respectively, but not by SB203580, a p38 kinase inhibitor. PlGF caused a time-dependent transient increase in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK-1/2), which was completely inhibited by wortmannin, indicating that activation of PI3 kinase preceded MEK activation. PlGF also induced transient phosphorylation of AKT. MEK and PI3 kinase inhibitors and antibody to Flt-1 abrogated PlGF-induced chemotaxis of THP-1 monocytes. Overexpression of a dominant-negative AKT or a dominant-negative PI3 kinase p85 subunit in THP-1 monocytes attenuated the PlGF-mediated phosphorylation of ERK-1/2, cytochemokine secretion, and chemotaxis. Taken together, these data show that activation of monocytes by PlGF occurs via activation of Flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. Therefore, we propose that increased levels of PlGF in circulation play an important role in the inflammation observed in SCD via its effects on monocytes.
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PMID:Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. 1268 30

Previous studies have suggested that heterotrimeric G proteins and tyrosine kinases may be involved in lipopolysacchaide (LPS) signaling events. Signal transduction pathways activated by LPS we examined in human pomonocytic THP-l cells. We hypothesized that Gi proteins and Src tyrosine kinase differentially affect mitogen-activated protein (MAP) kinases (MAPK) and nuclear factor kappa(NF-kappaB) activation. Post-receptor coupling to Ga, proteins were examined using pertussis toxin (PTx),which inhibits Galpha i receptor-coupling. The involvement of the Src family of tyrosine kinases was examined using the selective Src tyrosine kinase inhibitor pyrazolopyrimidine-2 (PP2). Pretreatment of THP-1 cells with PTx attenuated LPS-induced activation of c-Jun-N-terminal kinase (JNK) and p38 kinase, and production of tumor necrosis factor-alpha (TN-alpha) and thromboxane B2 (TXB2). Pretreatment with PP2 inhibited TNF-alpha and TxB2 production, but had no effect on p38 kinase or JNK signaling. Therefore, the Ga i-coupled signaling pathways and Src tyrosine kinase-coupled signaling pathways are necessary for LPS-induced TNF-alpha and TxB2 production, but differ in their effects on MAPK activation. Neither PTx nor PP2 inhibited LPS-induced activation of interleukin receptor activated kinase (IRAK) or inhibited translocation of NF-kappaB. However, PP2 inhibited LPS-induced NF-kappaB transactivation of a luciferase reporter gene construct in a concentration-dependent manner. Thus, LPS induction of Src tyrosine kinases may be essential in downstream NF-kappaB tansactivation of genes following DNA binding. PTx had no effect on NF-kaapaB activation of the reporter construct. These data suggest upstream divergence in signaling through Galpha i,pathways leading to MAPK activation and other signaling events leading to IkappaBalpha degradation and NF-kaapaB DNA binding.
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PMID:Implication of Galpha i proteins and Src tyrosine kinases in endotoxin-induced signal transduction events and mediator production. 1270 23

Monocyte activation and adhesion to the endothelium play important roles in inflammatory and cardiovascular diseases. These processes are further aggravated by hyperglycemia, leading to cardiovascular complications in diabetes. We have previously shown that high glucose (HG) treatment activates monocytes and induces the expression of tumor necrosis factor (TNF)-alpha via oxidant stress and nuclear factor-kB transcription factor. To determine the effects of HG on the expression of other inflammatory genes, in the present study, HG-induced gene profiling was performed in THP-1 monocytes using cytokine gene arrays containing 375 known genes. HG treatment upregulated the expression of 41 genes and downregulated 15 genes that included chemokines, cytokines, chemokines receptors, adhesion molecules, and integrins. RT-PCR analysis further confirmed that HG significantly increased the expression of monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, beta(2)-integrin, interleukin-1beta, and others. HG treatment increased transcription of the MCP-1 gene, MCP-1 protein levels, and adhesion of THP-1 cells to endothelial cells. HG-induced MCP-1 mRNA expression and monocyte adhesion were blocked by specific inhibitors of oxidant stress, protein kinase C, ERK1/2, and p38 mitogen-activated protein kinases. These results show for the first time that multiple inflammatory cytokines and chemokines relevant to the pathogenesis of diabetes complications are induced by HG via key signaling pathways.
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PMID:High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. 1271 61


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