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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic glucocorticoid therapy causes rapid bone loss and clinical osteoporosis. We found that although the glucocorticoid, dexamethasone, stimulated osteoblast maturation, it also inhibited proliferation of a preosteoblastic cell line, MBA-15.4. The dexamethasone-induced decline in preosteoblast proliferation correlated with a 30-40% reduction in protein kinase C/TPA-stimulated mitogen-activated protein kinase (MAPK) activity. These steroid effects only became evident after 6-24 h treatment, implying that dexamethasone acts on de novo synthesis of proteins. Because MAPK is inactivated by dephosphorylation of tyrosine and threonine residues, cells were treated concomitantly for 24 h with dexamethasone and inhibitors of tyrosine (sodium orthovanadate) and/or serine/threonine phosphatases (sodium fluoride). MAPK activity and cell proliferation were restored when MBA-15.4 cells were treated with vanadate, suggesting that dexamethasone up-regulates tyrosine phosphatase activity. Inactivation of serine/threonine phosphatases with sodium fluoride had no effect. Inhibition of the PKA pathway (which is growth inhibitory in mature osteoblasts) with H-89 did not reverse the effects of dexamethasone. Pretreatment with dexamethasone inhibited both peak- and extended activation plateau-phases of MAPK activity. Both phases were fully restored by pretreatment with vanadate, implicating more than one tyrosine phosphatase. Cycloheximide, alone or in combination with dexamethasone, prevented drop-off from plateau to basal levels, suggesting that an inducible dual-specificity phosphatase regulates the plateau-phase. We conclude that dexamethasone may inhibit preosteoblast growth via a novel tyrosine phosphatase pathway.
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PMID:Inhibition of mitogen-activated protein kinase activity and proliferation of an early osteoblast cell line (MBA 15.4) by dexamethasone: role of protein phosphatases. 956 54

The expression of the rate-limiting enzyme of haem degradation, haem oxygenase-1 (HO-1), can be induced by various stimuli, including lipopolysaccharide, tumour necrosis factor alpha and NO. The NO signal can be transmitted by cGMP, therefore this study was aimed at testing the activation of the HO-1 gene by cGMP. In primary cultures of rat hepatocytes, both HO-1 mRNA and protein were induced by the NO donor sodium nitroprusside and 8-bromo-cGMP. The HO-1 mRNA induction by cGMP was prevented by the specific protein kinase G inhibitor KT5823. The cGMP-dependent HO-1 mRNA induction was dose-dependent and transcriptionally regulated, as determined by studies with actinomycin D and a nuclear run-on assay. Cycloheximide lowered the cGMP-dependent induction of HO-1 mRNA to about one half. Luciferase reporter constructs driven by about 800 bp of the 5'-flanking region of the rat HO-1 gene were transiently transfected into primary rat hepatocytes; 8-bromo-cGMP caused a 6-fold induction, which was obliterated by deletion and mutation of the cAMP response element/activator protein-1 (CRE/AP-1) (-665/-654) site. Thus HO-1 induction by cGMP appears to be stimulated by the protein kinase G pathway and may be mediated mainly via a CRE/AP-1 element in the rat HO-1 promoter.
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PMID:Transcriptional activation of the haem oxygenase-1 gene by cGMP via a cAMP response element/activator protein-1 element in primary cultures of rat hepatocytes. 969 13

Parathyroid hormone (PTH) regulates gene expression in skeletal osteoblasts mainly through the cAMP-protein kinase A (PKA) pathway. In neuroendocrine cells, activation of the cAMP-PKA signaling pathway leads to induction of the inducible cAMP early repressor (ICER), which is transcribed from an intronic promoter of the CREM gene and acts as a transcriptional repressor. To investigate whether PTH induces ICER expression in osteoblastic cells, RNA from MC3T3-E1 cells was subjected to reverse transcriptase-polymerase chain reaction using primers spanning the ICER sequence. Amplified products were subcloned, sequenced, and used as a probe for Northern blot analysis. In MC3T3-E1 cells, PTH induced ICER mRNA levels, which peaked at 2 h and declined to baseline by 8 h. Cycloheximide caused superinduction of ICER mRNA in response to PTH. In cultured mouse calvariae, PTH also induced ICER mRNA accumulation, which peaked at 2 h and returned almost to baseline by 10 h. Overexpression of ICER IIgamma decreased both baseline and PTH-stimulated prostaglandin G/H synthase 2 promoter activity in MC3T3-E1 cells. The induction of ICER represents a novel mechanism by which PTH regulates gene expression in osteoblastic cells.
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PMID:Parathyroid hormone induces expression of the inducible cAMP early repressor in osteoblastic MC3T3-E1 cells and mouse calvariae. 984 2

We investigated the expression pattern of three 1-aminocyclopropane-1-carboxylate (ACC) synthase genes, CS-ACS1, CS-ACS2 and CS-ACS3 in cucumber (Cucumis sativus L.) fruit under CO2 stress. CO2 stress-induced ethylene production paralleled the accumulation of only CS-ACS1 transcripts which disappeared upon withdrawal of CO2. Cycloheximide inhibited the CO2 stress-induced ethylene production but superinduced the accumulation of CS-ACS1 transcript. At higher concentrations, cycloheximide also induced the accumulation of CS-ACS2 and CS-ACS3 transcripts. In the presence of CO2 and cycloheximide, the accumulation of CS-ACS2 transcript occurred within 1 h, disappeared after 3 h and increased greatly upon withdrawal of CO2. Inhibitors of protein kinase and types 1 and 2A protein phosphatases which inhibited and stimulated, respectively, CO2 stress-induced ethylene production had little effect on the expression of these genes. The results presented here identify CS-ACS1 as the main ACC synthase gene responsible for the increased ethylene biosynthesis in cucumber fruit under CO2 stress and suggest that this gene is a primary response gene and its expression is under negative control since it is expressed by treatment with cycloheximide. The results further suggest that the regulation of CO2 stress-induced ethylene biosynthesis by reversible protein phosphorylation does not result from enhanced ACC synthase transcription.
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PMID:Expression characteristics of CS-ACS1, CS-ACS2 and CS-ACS3, three members of the 1-aminocyclopropane-1-carboxylate synthase gene family in cucumber (Cucumis sativus L.) fruit under carbon dioxide stress. 1020 12

1. Human myometrial smooth muscle cells (HMSMCs) in culture were exposed to recombinant human interleukin-1beta (IL-1beta, 10 ng ml-1) for 1 to 24 h. Cyclooxygenase-2 (COX-2) mRNA and protein were rapidly induced, with expression sustained at 24 h. 2. Cycloheximide (10 microg ml-1, 6 h) blocked IL-1beta-induced COX-2 protein expression and super-induced COX-2 mRNA expression. Induction of COX-2 mRNA and protein was blocked by dexamethasone (1 microm, 6 h). 3. IL-1beta-induced COX-2 expression was accompanied by a 3-fold increase of prostaglandin E2 release into the culture medium. 4. IL-1beta induced a transient (5-30 min) activation of p42/44 and p38 mitogen-activated protein kinase (MAPK) enzymes in HMSMCs. Activity of p38 MAPK was monitored by in-gel activity of its substrate MAP kinase-activated protein kinase-2 (MAPKAP kinase-2). Induction of MAPKAP kinase-2 activity was prevented by the p38 MAPK inhibitor SB 203580 (10 microm, 5-30 min). 5. COX-2 protein expression detected after 6 h IL-1beta stimulation was blocked by SB 203580 (10 microM). Exposure of HMSMCs to 10 ng ml-1 IL-1beta for only 30 min induced a level of COX-2 protein expression at 6 h culture similar to that detected in cells exposed to the cytokine for 6 h. 6. Exposure of cells to SB 203580 (10 microM during only the first 30 min of IL-1beta stimulation was effective in blocking COX-2 protein expression assayed after 6 h in culture. 7. This study has established that a transient activation of the p38 MAPK cascade is involved in IL-1beta-stimulated COX-2 expression in human myometrial smooth muscle cells. Induction of COX-2 by IL-1beta in HMSMCs provides support for the hypothesis that autocrine prostaglandin signalling in the myometrium, initiated by elevated intrauterine cytokine concentrations, plays a role in regulating myometrial contractility during labour.
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PMID:Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase. 1052 9

The satratoxins are members of the trichothecene mycotoxin family that are produced by the fungus Stachybotrys and that have been etiologically associated with building-related health problems. The purpose of this study was to relate cytotoxic and apoptotic capacities of satratoxins and other trichothecenes to the activation of three groups of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated protein kinase (ERK), p38 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)). Two myeloid models, RAW 264.7 murine macrophage and U937 human leukemic cells were used. Upon evaluating representative trichothecenes in the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) cleavage assay, cytotoxicity was evident according to the following rank order: satratoxin G, roridin A, and verrucarin A > T-2 toxin, satratoxin F, H > nivalenol, and vomitoxin. Comparable results were found when measuring trichothecene-mediated apoptosis using DNA fragmentation and fluorescence microscopy assays, thus suggesting that cytotoxicity was mediated through an apoptotic process. Assessment of MAPK activation using Western blot analysis revealed that trichothecenes activated not only SAPK/JNK and p38 MAPK but also ERK. Activation of MAPKs by satratoxins and other trichothecenes correlated with and preceded apoptosis. The concentration of satratoxin G sufficient for protein synthesis inhibition correlated with that required for apoptosis and activation of all three MAPKs. Cycloheximide had similar effects to trichothecenes, suggesting that ribosome binding or protein synthesis inhibition may play roles in MAPK activation and apoptosis induction. Apoptosis induction by satratoxin G and vomitoxin was markedly enhanced when ERK activation was selectively inhibited by ERK-specific inhibitor PD98059, thus indicating a negative role for ERK. Inhibition of p38 MAPK activity with the p38-specific inhibitor SB203580 had no effect on apoptosis induction by the highly toxic satratoxin G. However, SB203580 moderately inhibited apoptosis induction by the less toxic trichothecene vomitoxin, thus implying a partial role of p38 MAPK in trichothecene-induced apoptosis. The results suggest that the satratoxins are among the most potent trichothecenes and that MAPKs may play integral roles in the diverse toxic manifestations of these mycotoxins.
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PMID:Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. 1076 28

Conflicting data for the effects of colchicine on cholesterol transport and steroidogenesis raise the question of the role of microtubules in cholesterol transport from the lipid droplet to mitochondria in steroidogenic cells. In this study, using corticosterone radioimmunoassay and immunofluorescence microscopy, we re-evaluated the effects of colchicine on hormone production and morphological changes of lipid droplets' and studied the signaling pathway involved in colchicine-induced steroidogenesis. Colchicine stimulated steroid production in a dose- and time-dependent manner. The structural integrity of both the microtubules and the lipid droplet capsule was destroyed by colchicine treatment. Disruption of the lipid droplet capsule occurred later than microtubule depolymerization. After cessation of colchicine treatment and a 3 h recovery in fresh medium, capsular protein relocated to the droplet surface before the cytoplasmic microtubule network was re-established. beta-lumicolchicine, an inactive analogue of colchicine, disrupted the capsule and increased hormone production without affecting microtubular structure. Thus, microtubule depolymerization is not required for the increase in steroid production and capsular disruption. To explore the signaling pathway involved in colchicine-induced steroidogenesis, we measured intracellular cAMP levels. Unlike ACTH, colchicine did not increase cAMP levels, suggesting that the cAMP-PKA system is not involved. Colchicine and ACTH had additive effects on corticosterone production, whereas colchicine and PMA did not, implying that part of the PKC signaling mechanism may be involved in colchicine-induced steroidogenesis. Cycloheximide, a protein synthesis inhibitor, completely inhibited colchicine-induced steroidogenesis and capsular disruption. These results demonstrate that the steroid production and lipid droplet capsule detachment induced by colchicine are both protein neosynthesis-dependent and microtubule-independent.
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PMID:Mechanism of colchicine-induced steroidogenesis in rat adrenocortical cells. 1118 Apr 6

2,3,5-Tris(glutathion-S-yl)hydroquinone [TGHQ] is a potent nephrotoxicant and nephrocarcinogen, and induces a spectrum of mutations in human and bacterial cells consistent with those attributed to reactive oxygen species (ROS). Studies were conducted to determine whether the oxidative stress induced by TGHQ in renal proximal tubule epithelial cells (LLC-PK(1)) modulates transcriptional activities widely implicated in transformation responses, namely 12-O-tetradecanoyl phorbol 13-acetate (TPA) responsive element (TRE)- and nuclear factor kappa B (NF-kappaB)-binding activity. TGHQ increased TRE- and NF-kappaB-binding activity in a concentration- and time-dependent manner. Catalase fully inhibited peak TGHQ-mediated TRE- and NF-kappaB-binding activity. In contrast, although deferoxamine fully inhibited TGHQ-mediated TRE-binding activity, it had only a marginal effect on NF-kappaB-binding activity. Collectively, these data indicate that TGHQ modulates TRE- and NF-kappaB-binding activity in an ROS-dependent fashion. Cycloheximide and actinomycin D fully inhibited TGHQ-mediated TRE-binding activity, but in the absence of TGHQ increased NF-kappaB-binding activity. Although protein kinase C (PKC) is widely implicated in stress response signaling, pretreatment of cells with PKC inhibitors (H-89, calphostin C) did not modulate TGHQ-mediated DNA-binding activities. In contrast, pretreatment of cells with (PD098059), a mitogen activated protein kinase kinase (MEK) inhibitor, markedly reduced TGHQ-mediated TRE-binding activity, but enhanced TGHQ-mediated NF-kappaB-binding activity. We conclude that TGHQ-mediated TRE- and NF-kappaB-binding activities are ROS-dependent. Although there is a common requirement for hydrogen peroxide (H(2)O(2)) in the regulation of these DNA-binding activities, there appears to be divergent regulation after H(2)O(2) generation in renal epithelial cells.
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PMID:Differential regulation of redox responsive transcription factors by the nephrocarcinogen 2,3,5-Tris(glutathion-S-yl)hydroquinone. 1145 27

The induction of fructosylsucrose-synthesizing activity (FSS) by sugars was tested using detached primary leaf blades of several wheat (Triticum aestivum L.) cultivars, immersed in different sugars solutions for 24 h in the dark. The highest induction was brought about by sucrose, while glucose, fructose and maltose also caused significant induction. 5-Ketofructose, 3-methylglucose and 6-deoxyglucose, which cannot be metabolized by plants, produced no induction at all. The fact that mannose also failed to induce FSS and that mannoheptulose did not inhibit the induction by sucrose suggests that the hexokinase-sensing system may not be involved. The protein phosphatase inhibitor okadaic acid and the calmodulin-dependent protein kinase antagonist W7 inhibited FSS induction while some types of protein kinase inhibitors, such as staurosporine and genistein, had less or no effect, respectively. Cycloheximide and cordycepin completely inhibited the induction response, indicating that transcription and translation are necessary for the FSS induction. Northern blot experiments using a sucrose:fructan-6-fructosyl transferase probe gave a clear indication that the mRNA for this enzyme, which is almost absent in control leaves, is dramatically increased after a 24-h treatment with 500 mM sucrose, and confirmed the inhibition produced by protein kinase and protein phosphatase inhibitors. Our data indicate that protein kinase and protein phosphatase activities take part in the chain of events that intervenes in the induction of fructan synthesis by sugars.
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PMID:Protein kinase and phosphatase activities are involved in fructan synthesis initiation mediated by sugars. 1155 97

The effects of forskolin (FSK) and phobol 12-myristate-13-acetate (PMA) on c-fos and c-jun mRNA expressions in rat C6 glioma cells were studied. Both FSK and PMA increased the c-fos mRNA level. The C-jun mRNA level was decreased by FSK, whereas it was increased by PMA. The elevated c-fos mRNA level, induced by FSK or PMA, was significantly inhibited by dexamethasone (DEX). In contrast, DEX did not affect the FSK- and PMA-induced response of the c-jun mRNA level. Cycloheximide (CHX) caused a superinduction of the FSK- or PMA-induced c-fos mRNA level. Furthermore, CHX also potentiated the PMA-induced c-jun mRNA level. However, CHX did not affect the FSK-induced down-regulation of the c-jun mRNA level. When C6 glioma cells were incubated with PMA and FSK, the PMA-induced c-jun mRNA level was inhibited by FSK, whereas FSK did not affect the PMA-induced c-fos mRNA level. Our results suggest that the activations of PKA and PKC pathways have different roles in the regulation of the c-jun mRNA expression in rat C6 glioma cells. PKA activation can inhibit induction of the c-jun mRNA expression by PMA. In addition, DEX appears to have a selective inhibitory action against c-fos, but not c-jun, -mRNA expression that is regulated by PKA and PKC. On-going protein synthesis inhibition is required for the superinduction of the c-fos expression that is induced by PMA, or FSK and the PMA-induced c-jun mRNA level.
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PMID:Differential effects of forskolin and phobol 12-myristate-13-acetate on the c-fos and c-jun mRNA expression in rat C6 glioma cells. 1156 18


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