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)

Treatment of HeLa cells or human skin fibroblast cells with hemin led to a time- and dose-dependent rapid induction of c-fos mRNA. This induction was absent in the cells treated with actinomycin D, indicating that the c-fos induction by hemin occurs at the level of transcription. Metalloporphyrins, including zinc-, cobalt-, and tin-protoporphyrin, ferric ion, and protoporphyrin also induced c-fos mRNA. Transient reporter assay with the reporter constructs of the human c-fos gene promoter up to -404 bp connected to the luciferase gene showed high activity but no induction by hemin, suggesting that cis-acting elements, including the serum response element located about -310 bp upstream of the human c-fos gene promoter, may not contribute to the heme-dependent induction. With in-gel assay of protein kinases, the activity of the mitogen-activated protein (MAP) kinases such as extracellular signal-regulated kinase 12 or p38 MAP kinase in hemin-treated HeLa cells was not stimulated. Stimulation of c-Jun N-terminal kinase by hemin was nil. Furthermore, PD58059 and SB203580, inhibitors for MAP kinases, did not affect the hemin-dependent c-fos induction. Of the inhibitors for protein kinases so far tested, KN-62, a specific inhibitor for calmodulin-dependent protein kinase II (CaMK II), inhibited the induction of c-fos mRNA by hemin. Phosphorylation of CaMK II in hemin-treated cells increased. With gel mobility assay, the DNA AP-1 binding activity transiently increased when treating HeLa cells with hemin. Therefore, induction of c-fos led to an activation of AP-1 in the presence of hemin. We suggest that calmodulin-dependent protein kinase II rather than the MAP kinase family regulates the induction of the human c-fos gene expression by hemin.
 ...
PMID:MAP kinase-independent induction of proto-oncogene c-fos mRNA by hemin in human cells. 1038 81

Egr-1 is one of the immediate early transcription factors that are induced after brain insults. However, the mechanism and the role of Egr-1 induction are not yet determined. In the present study, using mouse cortical cultures, we examined the ionic mechanism of Egr-1 induction and its role in neuronal death. Although zinc, NMDA, or ionomycin induced comparable neuronal death in cortical culture, only zinc increased Egr-1 expression, which was attenuated by blocking zinc influx. It is intriguing that brief exposure to zinc induced sustained extracellular signal-regulated kinase (Erk) activation. PD098059, an inhibitor of the Erk 1/2 upstream kinase mitogen-activated protein kinase kinase 1 (MEK1), blocked Erk 1/2 activation, Egr-1 induction, and neuronal death by zinc. The present study has demonstrated that zinc, rather than calcium, induces lasting Egr-1 expression in cortical culture by activating Erk 1/2, which is part of a cascade that may play an active role in zinc neurotoxicity. We propose that translocation of endogenous zinc may be the key mechanism of Egr-1 induction and neuronal death in brain ischemia.
 ...
PMID:Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death. 1042 39

The lethal toxin (LeTx) of Bacillus anthracis is the major virulence factor responsible for the death of infected animals and for cytolysis of cultured macrophages. Its catalytic component, LF, contains the characteristic zinc-binding motif of metalloproteases, it binds zinc and indirect evidence suggests that this hydrolytic activity is essential for LeTx cytotoxicity (Limpel et al. 1994; Kochi et al. 1994). To identify substrates of LF, we have used the yeast two-hybrid system, employing an LF inactive mutant as bait. This approach has led to the identification of the MAP kinase kinases (MAPKKs) Mek1 and Mek2 as proteins capable of specific interaction with LF. LF cleaves Mek1 and Mek2 within their N-terminus in vitro and in vivo, hydrolysing a Pro8-Ile9 and a Pro10-Arg11 peptide bond in Mek1 and Mek2, respectively (Vitale et al. 1998), similarly to that found with a different approach by Duesbery et al. (1998). The removal of the amino terminus of MAPKKs eliminates the 'docking site' involved in the specific interaction with MAPKs and interferes with the phospho-activation of the MAPKs ERK1 and ERK2, which become phosphorylated in cultured macrophages following toxin challenge. We are currently investigating the relevance of MAPKKs cleavage for LeTx cytotoxicity and the consequences for the activity of the MAP pathway.
 ...
PMID:Anthrax lethal factor cleaves the N-terminus of MAPKKS and induces tyrosine/threonine phosphorylation of MAPKS in cultured macrophages 1047 70

The patterned branching in the Drosophila tracheal system is triggered by the FGF-like ligand Branchless that activates a receptor tyrosine kinase Breathless and the MAP kinase pathway. A single fusion cell at the tip of each fusion branch expresses the zinc-finger gene escargot, leads branch migration in a stereotypical pattern and contacts with another fusion cell to mediate fusion of the branches. A high level of MAP kinase activation is also limited to the tip of the branches. Restriction of such cell specialization events to the tip is essential for tracheal tubulogenesis. Here we show that Notch signaling plays crucial roles in the singling out process of the fusion cell. We found that Notch is activated in tracheal cells by Branchless signaling through stimulation of &Dgr; expression at the tip of tracheal branches and that activated Notch represses the fate of the fusion cell. In addition, Notch is required to restrict activation of MAP kinase to the tip of the branches, in part through the negative regulation of Branchless expression. Notch-mediated lateral inhibition in sending and receiving cells is thus essential to restrict the inductive influence of Branchless on the tracheal tubulogenesis.
 ...
PMID:Interplay of Notch and FGF signaling restricts cell fate and MAPK activation in the Drosophila trachea. 1049 81

The gene early growth response gene-1 (egr-1) encodes a zinc transcription factor involved in cell proliferation. Increased expression of egr-1 has been linked to heart and kidney disease. In mouse mesangial cells, insulin stimulated egr-1 expression more than angiotensin II, suggesting that insulin may play an important role in stimulating cell proliferation, leading to glomerulonephritis and diabetic nephropathy. Angiotensin II inhibited insulin-induced egr-1 expression but not c-fos expression, and the decrease in egr-1 expression was concurrent with a decrease in insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation. These results suggest that insulin-induced egr-1 expression in mouse mesangial cells is downstream of tyrosine phosphorylation of IRS-1 and activation of the MAP kinase pathway and that crosstalk between angiotensin II and insulin signaling pathways led to an inhibition of IRS-1 tyrosine phosphorylation and egr-1 expression.
 ...
PMID:Angiotensin II inhibits insulin-induced egr-1 expression in mesangial cells. 1051 Feb 89

In serum-starved NIH 3T3 fibroblast cultures, zinc (15-40 microM) enhanced both the individual and combined stimulatory effects of insulin and ethanol (EtOH) on DNA synthesis. Zinc, but not EtOH, also promoted the stimulatory effects of insulin on activating phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases. In the presence of zinc, insulin induced premature expression of cyclin E during early G1 phase; EtOH partially restored the normal timing (late G1 phase) of cyclin E expression. The results suggest that zinc and EtOH promote insulin-induced DNA synthesis by different mechanisms; while zinc acts by enhancing the effects of insulin on MAP kinase activation, EtOH may act by ensuring timely zinc-dependent insulin-induced expression of cyclin E.
 ...
PMID:The possible mechanism of synergistic effects of ethanol, zinc and insulin on DNA synthesis in NIH 3T3 fibroblasts. 1054 34

The lethal toxin of Bacillus anthracis consists of two proteins, PA and LF, which together induce lethal effects in animals and cause macrophage lysis. LF is a zinc-endopeptidase which cleaves two mitogen-activated protein kinase kinases (MAPKKs), Mek1 and Mek2, within the cytosol. Here, we show that also MKK3, another dual-specificity kinase that phosphorylates and activates p38 MAP kinase, is cleaved by LF in macrophages. No direct correlation between LF-induced cell death and cleavage of these MAPKKs was found in macrophage cell lines and primary peritoneal cells exhibiting different sensitivity to LF. However, we present the first evidence that sublytic doses of LF cleave Meks and cause a substantial reduction in the production of NO and tumour necrosis factor-alpha induced by lipopolysaccharide/interferon gamma. We suggest that this effect of LF is relevant during the first stages of B. anthracis infection, when a reduction of the inflammatory response would permit growth and diffusion of the bacterium.
 ...
PMID:Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha. 1058 Jan 19

In serum-starved mouse NIH 3T3 fibroblasts cultured in 1.8 mM Ca2+-containing medium, addition of 0.75-2 mM extra Ca2+ stimulated DNA synthesis in synergism with zinc (15-60 microM), insulin and insulin-like growth factor I. Extra Ca2+ stimulated phosphorylation/activation of p42/p44 mitogen-activated protein kinases by an initially (10 min) zinc-independent mechanism; however, insulin, and particularly zinc, significantly prolonged Ca2+-induced mitogen-activated protein kinase phosphorylation. In addition, extra Ca2+ activated p70 S6 kinase by a zinc-dependent mechanism and enhanced the stimulatory effect of zinc on choline kinase activity. Insulin and insulin-like growth factor I also commonly increased both p70 S6 kinase and choline kinase activities. In support of the role of the choline kinase product phosphocholine in the mediation of mitogenic Ca2+ effects, cotreatments with the choline kinase substrate choline (250 microM) and the choline kinase inhibitor hemicholinium-3 (2 mM) enhanced and inhibited, respectively, the combined stimulatory effect of extra Ca2+ (3.8 mM total) and zinc on DNA synthesis. In various human skin fibroblast lines, 1-2 mM extra Ca2+ also stimulated DNA synthesis in synergism with zinc and insulin. The results show that in various fibroblast cultures, high concentrations of extracellular Ca2+ can collaborate with zinc and certain growth factors to stimulate DNA synthesis. Considering the high concentration of extracellular Ca2+ in the dermal layer, Ca2+ may promote fibroblast growth during wound healing in concert with zinc, insulin growth factor-I insulin, and perhaps other growth factors.
 ...
PMID:Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I in fibroblasts. 1058 89

Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in the expression of a wide range of genes, most of which code for proteins that play a role in immunity and inflammation. Pyrrolidine dithiocarbamate (PDTC) is a well-known inhibitor of NF-kappaB. Although its mechanism of action is conferred by its antioxidant property, other mechanisms by which PDTC can act as a prooxidant, metal chelator, and free thiol group modulator have recently been suggested. Here we report that PDTC caused a dual effect on cell viability in neuronal rat pheochromocytoma (PC12) cells, depending on its concentration. Increase of intracellular zinc and copper ion levels selectively potentiated the cytotoxic PDTC effect in a dose-dependent manner, and thiol reagents, such as glutathione and N-acetylcysteine, as well as divalent metal-chelating reagents, such as EDTA and bathocuproline disulfonic acid, blocked its cell death effect. The differential effect of PDTC on cell viability correlates well with the inhibition of NF-kappaB activities. In addition, PDTC differentially activated microtubule-associated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38, depending on its dose, and the coaddition of glutathione (GSH), other antioxidants, and metal ions also modulated their activities. Furthermore, stable Bcl-2 expression blocked the PDTC-induced cell death. These results suggest that the thiol groups and free zinc and copper ion levels are important for the novel biphasic PDTC effect on cell viability, which is associated with the differential activation of NF-kappaB and MAP kinases.
 ...
PMID:Novel biphasic effect of pyrrolidine dithiocarbamate on neuronal cell viability is mediated by the differential regulation of intracellular zinc and copper ion levels, NF-kappaB, and MAP kinases. 1065 92

In response to various environmental stresses including heavy metals, the c-Jun N-terminal kinase (JNK) is phosphorylated and then it phosphorylates c-Jun protein. In the present study, effects of mercury chloride (HgCl2) on JNK signalling pathway were examined in LLC-PK1 cells. When exposed to 10 or 20 microM HgCl2, the level of phosphorylated JNK and the activity of JNK assayed in vitro using glutathione-S-transferase-c-Jun as substrate increased markedly. The level of phosphorylated JNK increased 30 min after HgCl2 exposure and remained elevated even at 8 h. On the other hand, no changes were found in the total amount of JNK protein. Consistent with the activation of JNK, c-Jun proteins phosphorylated on Ser63 and Ser73 were accumulated in cells exposed to HgCl2. Concomitantly, the levels of c-jun mRNA and c-Jun protein were elevated. When compared to other heavy metal compounds such as manganese chloride, zinc chloride, cadmium chloride, and lead chloride, HgCl2 could phosphorylate JNK more markedly. Neither intracellular Ca2+ nor sulfhydryl groups appeared to play a major role in the activation of JNK by HgCl2 exposure in this porcine renal epithelial cell line.
 ...
PMID:Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells. 1069 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>