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)

O2 plays a dominant role in the metabolism and viability of cells; changes in O2 supply lead to many physiological responses in the cell. Recent reports have shown that hypoxia induces the transcription of a number of genes, among them those for the glycolytic enzymes. We have investigated signalling events that may lead to enhanced activity of lactate dehydrogenase (LDH) in cultured vascular smooth muscle (VSM) cells derived from rat aorta, grown under hypoxic conditions (1% versus 20% O2). LDH was chosen because this enzyme exhibits one of the largest increases in activity among the glycolytic enzymes after hypoxic stimulation of cells. Hypoxic exposure of VSM cells for 24 h resulted in a 2-fold increase in LDH activity and in a 2.5-fold increase in intracellular cAMP levels. Agents that activate adenylate cyclase, such as forskolin, cholera toxin and 1-methyl-3-isobutylxanthine (IBMX), and thus increase cAMP production, significantly induced LDH activity. Moreover, induction of LDH activity by hypoxia was prevented in the presence of the protein kinase A inhibitor N-[2-(methyl-amino)ethyl]-5-isoquinolinsulphonamide dihydrochloride (H-8), and the cyclooxygenase inhibitor indomethacin. In contrast to the cAMP-stimulating agents, stable cGMP analogues (dibutyryl-cGMP, 8-bromo-cGMP), activators of protein kinase C [12-O-tetradecanoylphorbol-13-acetate (TPA), and 1-oleoyl-2-acetyl-glycerol (OAG), and the calcium ionophore ionomycin did not alter LDH activity in VSM cells kept at 20% O2. A dose-dependent increase in LDH activity was also observed in normoxic cells exposed to cobalt chloride (50-200 microM), indicating that a metal binding protein might be involved in this signalling cascade.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypoxia and cobalt stimulate lactate dehydrogenase (LDH) activity in vascular smooth muscle cells. 789 7

FMRFamide evokes long-term inhibition of the sensorimotor connection of Aplysia that includes structural alterations in the presynaptic sensory cell. FMRFamide also evokes a down-regulation of the adhesion molecule apCAM from the surface of the postsynaptic motor cell L7. We examined the second messenger pathways mediating the long-term actions of FMRFamide on both the pre- and postsynaptic cells and determined whether the activation of each pathway is required for the expression of long-term functional and structural plasticity. Inhibition of the lipoxygenase pathway of arachidonic acid metabolism, but not the cyclooxygenase pathway, blocks the long-term changes in the presynaptic sensory cell evoked by FMRFamide. The down-regulation of apCAM in L7 appears to be mediated by cAMP-dependent activation of protein kinase A. Blocking the cAMP-dependent changes also blocks FMRFamide-induced long-term functional and structural changes. These results suggest that the expression of long-term heterosynaptic inhibition in Aplysia may require concomitant presynaptic and postsynaptic changes, each transduced by specific second messenger systems.
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PMID:Pre- and postsynaptic changes mediated by two second messengers contribute to expression of Aplysia long-term heterosynaptic inhibition. 790 29

Although a principal pharmacological action of nonsteroidal anti-inflammatory drugs (NSAIDs) is to blunt eicosanoid synthesis by inhibiting cyclooxygenase, recent evidence indicates that NSAIDs may also interact directly with proteins that control the activity of adenylyl cyclase. Since the only physiological mechanism governing the action of cyclic AMP occurs via activation of its receptor, cyclic AMP-dependent protein kinase (cAMPPk; Kinase A), we determined whether NSAIDs affect intracellular substrate phosphorylation dependent on cAMPPk. The incorporation of 32Pi into cellular proteins that are substrates for cAMPPk was determined in intact human non-arthritic, aged non-arthritic and osteoarthritic chondrocytes in the presence or absence of NSAIDs, namely, sodium meclofenamate, indomethacin, tiaprofenic acid and sodium salicyclate. The transfer of [32P]-ATP was employed to identify phosphoproteins in a membrane fraction prepared from chondrocyte homogenates in the presence or absence of these NSAIDs. The lowest concentration of NSAID was similar to NSAID concentrations achieved during therapy for the arthritides. In intact human chondrocyte strains, activation of cAMPPk by dibutyryl cAMP (dBcAMP) resulted in the phosphorylation of intracellular substrates with an apparent M(r) of 55kD, 42kD, 26kD, 25kD, 22kD, 21.5kD, 20.5kD, and 17kD when examined by autoradiography after 12.5% SDS/PAGE. The NSAIDs augmented or potentiated phosphorylation of these proteins which were cAMPPk-dependent. In the chondrocyte membrane fraction, protein phosphorylation by cAMP was mimicked by isobutylmethylxanthine or by the purified catalytic subunit of bovine cAMPPk. NSAIDs augmented chondrocyte phosphorylation in the chondrocyte membrane fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of nonsteroidal anti-inflammatory drugs on cAMP-dependent protein kinase-mediated phosphorylation by human chondrocytes in culture. 803 82

Stimulation of Ca2+ mobilization and entry by agonists such as ADP, thrombin, and thromboxane is an early step of platelet activation. Here, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP)-elevating prostaglandins, guanosine 3',5'-cyclic monophosphate (cGMP)-elevating nitrovasodilators, membrane-permeant selective activators of cAMP- or cGMP-dependent protein kinases, and physiological endothelium-derived factors on the agonist-evoked Ca2+ mobilization and entry in human platelets. Prostaglandin E1, the prostacyclin analogue Iloprost, the nitric oxide (NO) donor 3-morpholinosydnonimine hydrochloride, and selective activators of cGMP- or cAMP-dependent protein kinase strongly inhibited the agonist-evoked Ca2+ mobilization from intracellular stores and associated late Ca2+ entry but had little effects on the rapid (1st) phase of ADP-evoked Ca2+ entry. During coincubation of platelets with endothelial cells, endothelium-derived factors that were released strongly inhibited platelet agonist-evoked Ca2+ mobilization and only moderately affected the rapid phase of ADP-evoked Ca2+ entry. These effects were partially prevented when endothelial cells were preincubated with cyclooxygenase and/or NO synthase inhibitors. Endothelial cells therefore produce sufficient quantities of labile platelet inhibitors whose effects on the platelet Ca2+ response resemble those observed with selective cAMP- and cGMP-dependent protein kinase activators.
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PMID:Regulation of calcium mobilization and entry in human platelets by endothelium-derived factors. 804 83

Two-dimensional (2-D) gel electrophoresis has been used to map proteins from various cell types in an effort to eventually link such maps to the sequencing of the entire human genome. While this analysis indicates the cellular disposition and expression of proteins, another application of 2-D gels, the analysis of phosphoproteins, can provide much information as to the assembly and "wiring" of the signal transduction circuits within cells which appear to be enervated by phosphate exchange. The preparation and separation of 32P-labeled proteins is described, as well as various analytical methods, including: the variety of gel systems available for specialist types of analyses, comparing 33P- and 32P-labeling of proteins, imaging techniques, phosphoamino analysis, phosphopeptide separation, identifying the amino acid groups that are phosphorylated, and the identification of phosphoproteins on 2-D gels by immunoprecipitation, corunning of purified proteins, comparative mapping and microsequencing, and by Western blotting. Examples (in brackets) are given of applications in which 2-D phosphogels can be applied, which offer advantages over other techniques. These include: (i) identifying in vivo substrates for kinases (protein kinase C activated by phorbol myristate acetate), (ii) investigating cytokine signaling pathways (tumor necrosis factor and interleukin-1), (iii) investigating the effects of drugs on signaling pathways (okadaic acid, menadione and cyclooxygenase inhibitors), (iv) characterization of specific phosphoproteins (heat-shock protein Hsp27 and stathmin), (v) comparing normal and transformed cells (MRC-5 human lung fibroblasts and their SV-40-transformed counterparts, MRC-5 SV1 cells), (vi) purifying phosphoproteins, (vii) investigating the relationship of protein phosphorylation to stages in the cell cycle (stathmin), (viii) investigating protein/protein interactions, (ix) mapping in vitro kinase substrates (protein kinase C, protein kinase A, and mitogen activated protein kinase activated protein kinase 2), and (x) locating and identifying cellular phosphatases (Hsp27 phosphatase). It is possible that the mapping of phosphoproteins can be linked to other 2-D gel databases and that information derived from these can be used in the future to better understand the signaling mechanisms of normal and cancerous cells.
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PMID:Analysis of cellular phosphoproteins by two-dimensional gel electrophoresis: applications for cell signaling in normal and cancer cells. 805 70

We have investigated the changes in intracellular calcium concentration ([Ca2+]i) in human endothelial cells induced by mechanical stretch due to osmotic cell swelling. Hypotonic solutions also activate a Cl- conductance that has been described elsewhere and mainly serves to clamp the membrane potential at negative values to provide a driving force for Ca2+ influx. The increase in [Ca2+]i caused by hypotonic solutions is due to release from inositol-1,4,5-trisphosphate-sensitive Ca2+ pools and a subsequent Ca2+ influx, apparently activated by store depletion. These changes in [Ca2+]i are completely abolished if the phospholipase A2 (PLA2) activity is inhibited by either 4-bromophenacyl bromide or cyclosporin A. Arachidonic acid, applied either extracellularly or intracellularly via the patch pipette, mimics the mechanosensitive response even in cells with blocked PLA2. Metabolites of the lipo- and cyclooxygenase pathways can be excluded. Phospholipase C activation and the protein kinase A pathway are not involved in this mechanical response. Although no specific pharmacological tools for probing the role of PLA2 are available, our evidence suggests that mechanosensitivity in endothelial cells may be modulated by arachidonic acid.
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PMID:Mechanosensitive Ca2+ transients in endothelial cells from human umbilical vein. 815 84

The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.
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PMID:Paradoxical inhibition by aspirin of naloxone-induced adrenocorticotropin secretion in myotonic dystrophy. 820 Sep 45

Human myometrium contains receptors for hCG/human LH (hLH). This suggested the possibility that hCG and hLH might regulate human myometrium, which has not previously been considered a direct target of gonadotropin regulation. To investigate such a possibility, highly pure and viable smooth muscle cells were isolated from nonpregnant human myometrium and cultured as monolayers. The cells contained hCG/LH receptor mRNA transcripts and a 50-kDa immunoreactive protein that can bind 125I-hCG in a ligand-specific manner. The presence of hCG during culture resulted in a significant increase of myometrial smooth muscle cell density. The hCG effect was time- and concentration-dependent and was mimicked by hLH but not by human FSH or human FSH or human thyroid-stimulating hormone. Human CG also greatly increased the size of a subpopulation of myometrial smooth muscle cells without affecting their chromosomal ploidy. Antibodies to hCG/LH receptors and hCG blocked hCG effects. Human prolactin and growth hormone, which do not bind to hCG/LH receptors, also increased the myometrial smooth muscle cell density. A protein kinase A inhibitor (H-89) blocked hCG response whereas calphostin (a protein kinase C inhibitor) and lavendustin A (a tyrosine kinase inhibitor) had no effect on hCG response, suggesting that a cAMP/protein kinase A signaling mechanism is involved in hCG action. Eicosanoids from cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism are probably not involved, because the inhibitors of these enzymes had no effect on hCG response. While progesterone and estradiol could not mimic or modify hCG action, epidermal growth factor did mimic hCG in increasing myometrial smooth muscle cell density.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human myometrial smooth muscle cells are novel targets of direct regulation by human chorionic gonadotropin. 828 97

Human chorionic cells in culture synthesized and secreted a large amount of hyaluronate as well as tissue collagenase. When these cells were treated with human recombinant interleukin 1 alpha (hrIL-1), the biosynthesis and secretion of hyaluronate were predominantly accelerated, but those of sulfated glycosaminoglycans were not modulated. This promotive effect of hrIL-1 was not due to the increase in endogenous prostaglandins including prostaglandin E2 since cyclooxygenase inhibitors, indomethacin and diclofenac did not modulate the IL-1-mediated production of hyaluronate. On the other hand, the cotreatment of chorionic cells with hrIL-1 and cycloheximide suppressed the IL-1-mediated hyaluronate production, suggesting that protein, de novo, synthesis required for the enhancement of hyaluronate synthesis. Upon treatment with hrIL-1, the membrane bound-hyaluronate synthase activity was increased up to 5-fold in a time-dependent manner. On the other hand, when chorionic cells were treated with hrIL-1 and/or protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methyl-pyperadine hydrochloride (H7), the IL-1-mediated production of hyaluronate was effectively suppressed. Similarly, H7 effectively suppressed the protein kinase activator, 12-O-tetradecanoyl-phorbol-13-acetate-enhanced production of glycosaminoglycans with a similar extent. These results indicate that IL-1-induced acceleration of hyaluronate production was reflected on the increase in hyaluronate synthase activity, and that protein kinase C participates positively in the IL-1-signal transduction for the increased synthesis of hyaluronate in human chorionic cells.
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PMID:Regulation of hyaluronate production by interleukin 1 in cultured human chorionic cells. 835 36

Fibroblasts of the pulmonary interstitium are intimately involved in the response of the lung to inflammation as well as in repair of injured tissues. The response of fibroblasts within an inflammatory site appears to be directed, in part, by peptide mediators. Neutral endopeptidase (NEP), a metallopeptidase on the surface membrane of fibroblasts, can inactivate various vasoactive peptides, including kinins and tachykinins. Because lung fibroblasts both secrete cytokines and respond to mediators within the immediate environment, NEP might be regulated by locally generated cytokines. We found that several cytokines, including interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor, interleukin-6, and granulocyte macrophage colony-stimulating factor, enhanced activity of NEP on the surface of intact fibroblasts. In contrast, cultured pleural mesothelial cells had much lower levels of NEP than fibroblasts, and the enzyme was not enhanced by either IL-1 or TNF-alpha. Further studies with IL-1 showed that the effect required at least 6 h of exposure to the cytokine and depended upon final cytokine concentration. Combinations of IL-1 with other cytokines increased NEP activity beyond that in cells treated with individual cytokines, but combinations had less than additive effects. Selected pharmacologic agents indicated that the mechanism involves second messenger pathways. The cytokine effect on NEP was attenuated by indomethacin, an inhibitor of cyclooxygenase, by N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride, an inhibitor of protein kinase, and by adenosine 3',5' cyclic monophosphothionate, an analog of cyclic adenosine monophosphate (cAMP) that competitively inhibits the cAMP signal pathway. It was mimicked by dibutyryl cAMP and by forskolin, an activator of adenyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokines increase neutral endopeptidase activity in lung fibroblasts. 838 Feb 49


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