Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The contribution of protein kinase C to the contraction by oxytocin of rat uterine longitudinal smooth muscle in Ca(2+)-free solution was investigated. Immunological analysis revealed that type II (beta) and III (alpha) protein kinase C subspecies were present in rat uterine smooth muscle. The pretreatment of a diacylglycerol kinase inhibitor R59022 to accumulate diacylglycerol potentiated the Ca(2+)-independent contraction. The contractile activity was diminished with the depletion of protein kinase C, when the contraction was evoked repeatedly by oxytocin during the prolonged exposure to a tumor-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate. These results suggested the involvement of protein kinase C in oxytocin-induced contraction in Ca(2+)-free solution.
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PMID:Involvement of protein kinase C in Ca(2+)-independent contraction of rat uterine smooth muscle. 188 74

The effects of phorbol 12-myristate 13-acetate (PMA), a potent activator of protein kinase C (PKC), on high-affinity Na(+)-dependent gamma-aminobutyric acid (GABA) uptake were investigated in primary cultures of neurons and glial cells from rat brain cortex. Incubation of glial cells with PMA led to concentration- and time-dependent decreases in the GABA transport in glial cells. This effect could be completely suppressed by addition of the PKC inhibitor H7. The PMA effects could be mimicked by oleoylacetylglycerol, the diacylglycerol kinase inhibitor R59022 and exogenous phospholipase C. Treatment with PMA did not affect GABA transport in neuronal cells.
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PMID:Inhibition of high-affinity gamma-aminobutyric acid uptake in primary astrocyte cultures by phorbol esters and phospholipase C. 190 65

Thrombin stimulation of human platelets is known to result in phosphatidylinositol turnover (PI response), the activation of protein kinase C (C-kinase), and the release of arachidonic acid (AA). The authors studied the effects of chlorpromazine (CPZ) on these responses. At a concentration of 100 microM, CPZ inhibited the phosphorylation of 40,000-dalton protein through C-kinase activation. CPZ failed to inhibit initial transient synthesis of 1,2-diacylglycerol (1,2-DAG) through the PI response, although it slowed the concurrent decreasing process. CPZ inhibited promotion of compensatory synthesis of phosphatidylinositol 4,5-bisphosphate (PIP2), and also inhibited the synthesis of phosphatidic acid (PA). These results suggest that phosphatidylinositol 4-monophosphate kinase and diacylglycerol kinase (DAG-kinase) may be inhibited by CPZ. CPZ also intensified the accumulation of inositol phosphates caused by the PI response, indicating possible inhibition of the phosphatases that metabolize these phosphates. Thus, CPZ partially inhibited the PI response. However, it appears likely that the inhibition of C-kinase activity by CPZ was not due to inhibition of 1,2-DAG production nor to direct inhibition of phospholipase C. CPZ also inhibited AA release. This action might be partially a result of the inhibitory effect of CPZ on PA production.
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PMID:Effects of chlorpromazine on phosphatidylinositol turnover following thrombin stimulation of human platelets. 190 65

Subcellular liver fractions from rats receiving a subcutaneous injection of turpentine, which causes a local inflammation, show an increased synthesis of Prostaglandin E2 and Prostaglandin F2 alpha which reaches a peak 90 minutes and 3 hours after treatment, respectively. Stimulation of phospholipase A2 activity of liver cell preparations seems to be responsible for the supply of arachidonic acid necessary to feed PG synthesis: this stimulation is accompanied by unchanged levels of diacylglycerol lipase, diacylglycerol kinase and protein kinase C activities and by an unchanged content of diacylglycerol in the liver tissue. This picture does not favour the hypothesis of an involvement of phospholipase C in the early stages after turpentine treatment. Determinations of GTP-ase activity in plasma membrane-rich liver preparations give ambiguous results, which do not allow any conclusion on the possible role of G-proteins in phospholipase A2 activation.
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PMID:Rat liver eicosanoid synthesis during turpentine-induced inflammation. 195 99

1. We have investigated the modification of catecholamine efflux and inositol phosphate formation in cultured adrenal chromaffin cells by tetradecanoyl phorbol acetate (TPA) and inhibitors of diacylglycerol kinase (R 59,022) and diacylglycerol lipase (RG 80267), the two principal pathways of diacylglycerol metabolism. 2. TPA (1 nM to 1 microM) elicited a slow, calcium-dependent, sustained release of noradrenaline, which was partially blocked by the dihydropyridine calcium channel blocker (-)-202,791 and potentiated by the channel enhancer (+)-202,791. 3. R 59,022 enhanced noradrenaline efflux at 30 and 50 microM, while the lipase inhibitor RG 80267 failed to elicit release. 4. Neither R 59,022 nor RG 80267 affected bradykinin- or histamine-stimulated release, but both drugs substantially attenuated nicotine- and high K(+)-stimulated release. 5. Pretreatment for 10 min with TPA (but not the relatively inactive 4-methoxy TPA) or the non-phorbol protein kinase C stimulator mezerein potently inhibited bradykinin- and histamine-stimulated accumulation of total [3H]-inositol phosphate; inhibition of [3H]-inositol phosphate formation was also seen with 24 h TPA treatment. 6. Neither R 59,022 nor RG 80267, separately or together, affected bradykinin-stimulated [3H]-inositol phosphate formation. 7. Thus while the mechanism exists for inhibition of formation of inositol phosphates by stimulation of protein kinase C, these studies failed to show that this mechanism is activated by agonists acting on phospholipase C linked receptors.
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PMID:Influence of phorbol esters, and diacylglycerol kinase and lipase inhibitors on noradrenaline release and phosphoinositide hydrolysis in chromaffin cells. 196 97

The nontumorigenic, immortal line of murine melanocytes, Mel-ab, requires the continual presence of biologically active phorbol esters for growth (R.E. Wilson et al., Cancer Res., 49:711-716, 1989). Comparable treatments of B16 murine melanoma cells result in partial inhibition of cell proliferation. The role of protein kinase C (PKC) in the modulation of growth of cells from these two melanocytic cell lines has been investigated. Significant levels of PKC were present in quiescent Mel-ab cells as determined by Western blotting, whereas no immunoreactive protein was detected in cell extracts from either proliferating Mel-ab or B16.F1 cells. Phosphorylation of a Mr 80,000 protein, which by one- and two-dimensional gel analysis comigrated with the known Mr 80,000 protein substrate of PKC in fibroblasts, was induced in 12-O-tetradecanoylphorbol-13-acetate-stimulated quiescent Mel-ab cells but not in proliferating Mel-ab cells or B16.F1 melanoma cells. Direct measurement of PKC activity in these cells demonstrated a 10-fold greater level of activity in quiescent Mel-ab cells (262 +/- 50 pmol/min/mg SD) compared with growing cells (22.8 +/- 11.8 pmol/min/mg SD). An intermediate level of activity was detected in proliferating B16.F1 melanoma cells (148.5 +/- 20.4 pmol/min/mg SD). The subcellular distribution of PKC was dependent upon the growth state of the cells such that quiescent Mel-ab cells displayed a higher level of activity in the cytosol, whereas growing Mel-ab cells displayed greater activity in the particulate fraction. Like many other transformed lines, B16.F1 melanoma cells constitutively expressed the majority of enzyme activity in the particulate fraction. Measurement of [3H]phorbol ester binding in intact cells paralleled the PKC activation data such that quiescent Mel-ab cells displayed binding of 1612 +/- 147 cpm/10(6) cells, whereas proliferating Mel-ab and B16.F1 melanoma cells displayed binding of 652 +/- 28 and 947 +/- 81 cpm/10(6) cells, respectively. Membrane-permeant diacylglycerol analogues, which activated but did not down-regulate PKC, were devoid of growth-stimulating effects on melanocytes, even in the presence of the specific diacylglycerol kinase inhibitor, R59022. Together, these data show that PKC down-regulation, and not activation, correlates with the growth of melanocytes in culture.
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PMID:Protein kinase C down-regulation, and not transient activation, correlates with melanocyte growth. 204 3

vav is a human locus that appears to be specifically expressed in cells of hematopoietic origin regardless of their differentiation lineage. This gene was first identified as a result of its malignant activation during the course of gene transfer assays (Katzav, S., Martin-Zanca, D., and Barbacid, M. EMBO J., 8: 2283-2290, 1989). In this study, we report the isolation of complementary DNA clones containing the entire coding sequence of the mouse vav protooncogene. Antisera raised against a peptide corresponding to a predicted hydrophilic domain have allowed us to identify the product of the vav gene as a 95,000 Da protein. Analysis of the deduced amino acid sequence of p95vav revealed an amino-terminal leucine-rich region not present in the activated vav oncogene. This region consists of an amphipathic helix-loop-helix followed by a leucine zipper, a structure reminiscent of the carboxy-terminal region of myc proteins and the steroid binding domain of nuclear receptors. In vitro mutagenicity studies have indicated that removal of the amphipathic helix-loop-helix is sufficient to activate the transforming potential of human and mouse vav protooncogenes. vav proteins also possess a cysteine-rich domain whose sequence predicts the formation of two putative metal binding-like domains, Cys-X2-Cys-X13-Cys-X2-Cys and His-X2-Cys-X6-Cys-X2-His. Replacement of some of these cysteine and histidine residues completely abolished the transforming activity of vav genes. Further examination of the alignment of cysteine residues in this region revealed an alternative structure, Cys-X2-Cys-X13-Cys-X2-Cys-X7-Cys-X6-Cys, which is reminiscent of the phorbol ester binding domain of protein kinase C. A similar domain has been recently identified in a second enzyme, diacylglycerol kinase. These structural similarities, along with its expression pattern, suggest that the vav protooncogene codes for a new type of signal-transducing molecule that may play an important role in controlling hematopoiesis.
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PMID:Mechanism of activation of the vav protooncogene. 206 73

NIH 3T3 fibroblasts were transfected with the chloramphenicol-acetyltransferase (CAT) gene under the control of the SV40 early promoter, which can be stimulated by IL-1. CAT activity in cell lysates and PGE2 release in the supernatants were measured in control and stimulated cell cultures in parallel. Human IL-1 beta (180 pM) and human rTNF-alpha (3 nM) significantly stimulated both CAT activity and PGE2 release. The combined incubation of the two cytokines resulted in a synergistic effect on PGE2 release. The addition of AA (30 microM) greatly stimulated PGE2 release without affecting CAT activity. Similarly, drugs interfering with AA metabolism were without effect on CAT activity although profoundly reducing PGE2 release. Forskolin (0.1 microM) did not modify either parameter. The glucocorticoid fluocinolone (20 nM) was able to decrease both parameters. Protein kinase inhibitors H7 (5-50 microM) and sphingosine (50 microM) inhibited only IL-1-induced CAT activity, whereas H8 (5-50 microM) and HA1004 (50 microM) were ineffective on both parameters. PMA (0.5 microM) and R59 022, a diacylglycerol kinase inhibitor (10 microM), did not modify either control or IL-1-induced CAT activity. IL-1-stimulated PGE2 release was potentiated by PMA, although this effect was not inhibited by H7. The data suggest that: 1) in NIH 3T3 cells the activation of AA metabolism by IL-1 is not involved in IL-1-induced gene expression; 2) protein kinase C activity is required but not sufficient for IL-1-induced gene expression; and 3) PMA may stimulate AA metabolism by a mechanism in part independent of protein kinase activity.
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PMID:Induction of gene expression by IL-1 in NIH 3T3 cells. Possible requirement of protein kinase C activity and independence from arachidonic acid metabolism. 212 35

The effect of protein kinase C activation and dibutyryl cyclic AMP on oxytocin secretion by ovine luteal tissue slices was investigated. Several putative regulators of luteal oxytocin secretion were also examined. Oxytocin was secreted by luteal tissue slices at a basal rate of 234.4 +/- 32.8 pmol/g per h (n = 24) during 60-min incubations. Activators of protein kinase C: phorbol 12, 13-dibutyrate (n = 8), phorbol 12-myristate, 13-acetate (n = 4) and 1,2-didecanoylglycerol (n = 5), caused a dose-dependent stimulation of oxytocin secretion in the presence of a calcium ionophore (A23187; 0.2 mumol/l). Phospholipase C (PLC; 50-250 units/l) also caused a dose-dependent stimulation of oxytocin secretion by luteal slices. Phospholipase C-stimulated oxytocin secretion was potentiated by the addition of an inhibitor of diacylglycerol kinase (R59 022; n = 4). These data suggest that the activation of protein kinase C has a role in the stimulation of luteal oxytocin secretion. The results are also consistent with the involvement of protein kinase C in PLC-stimulated oxytocin secretion. The cyclic AMP second messenger system does not appear to be involved in the control of oxytocin secretion by the corpus luteum.
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PMID:Regulation of oxytocin secretion by the ovine corpus luteum: effect of activators of protein kinase C. 215 85

Cell stimulation causes diacylglycerol kinase (DGK) to convert the second messenger diacylglycerol into phosphatidate, thus initiating the resynthesis of phosphatidylinositols and attenuating protein kinase C activity. Of the DGK isoforms so far reported, only porcine DGK from lymphocytes has been characterized in detail. Here we report the isolation and sequencing of complementary DNA clones that together cover the entire region encoding porcine DGK (relative molecular mass 80,000 (80K)). The deduced primary structure of this DGK contains the putative ATP-binding sites, two cysteine-rich zinc finger-like sequences similar to those found in protein kinase C, and two E-F hand motifs, typical of Ca2(+)-binding proteins like calmodulin. Indeed, we find that the activity of this DGK isoform is enhanced by micromolar concentrations of Ca2+ in the presence of deoxycholate or sphingosine. These properties of 80K DGK indicate that its action is probably linked with both of the second messengers diacylglycerol and inositol 1,4,5-trisphosphate.
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PMID:Porcine diacylglycerol kinase sequence has zinc finger and E-F hand motifs. 215 69


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