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)

We have previously reported that progesterone synthesis in the bovine placenta is regulated by Ca2+ dependent and cyclic nucleotide independent mechanism. In studies conducted to further define the role of Ca2+ in the synthesis of progestins in bovine placental tissue, it was found that both protein kinase C (PKC), as determined by phosphorylation, and cytochrome P-450 side chain cleavage, as determined by Western blot analysis, were detectable in the steroidogenetically active portion of the placentome. To determine the site of action of PKC, fetal cotyledon cells were incubated in media containing 25-hydroxycholesterol in the absence or or presence of 10 ng/ml 12-O-tetradecanoyl-phorbol-13-acetate (TPA). It was found that TPA significantly (P less than 0.05) increased the conversion of the exogenous cholesterol analog to progesterone. To determine if the TPA could act synergistically with calcium activators, fetal cotyledon cells were incubated with either methyl isobutyl xanthine (MIX), an activator of intracellular calcium, or the calcium ionophore, A23187, which increases extracellular calcium influx, or both of these agents, in the presence or absence of TPA. It was found that TPA synergistically increased the conversion of sterol to progestins induced by submaximal concentrations of either MIX or A23187. In the presence of both compounds, TPA induced an even more dramatic increase in progestin synthesis. In experiments in which cyanoketone, an agent that inhibits the conversion of pregnenolone to progesterone, was added, TPA addition resulted in increased pregnenolone production, indicating that side chain cleavage of cholesterol is the site of action. The data, therefore, suggest that: (a) Ca2+ affects mechanisms regulating placental steroidogenesis; (2) one locus of Ca2+ is the cholesterol side chain cleavage reaction; and (3) PKC found in this tissue has a role in the Ca activated progestin production.
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PMID:Control of bovine placental progestin synthesis: calcium dependent steroidogenesis is modulated at the site of the cholesterol side chain cleavage enzyme. 246 34

The structural gene encoding aromatase cytochrome P-450 (P-450AROM) was isolated from human genomic DNA. The gene spans at least 52 kilobases and is composed of 10 exons, the first of which is untranslated. Analysis of the transcription initiation site of human P-450AROM mRNA reveals the differential use of 1 of 3 consecutive G residues at the cap site. DNA sequence analysis indicates that the gene has a putative TATA (ATAAAA) sequence at -23 base pairs (bp) and putative CAAT binding sequences beginning at -41, -67, and -83 bp. The 5'-flanking region contains sequences similar to consensus sequences of cis-acting elements defined as regulators of aromatase gene expression. These putative sequences include a cAMP regulatory element at -211 bp, an AP1 (protein kinase C) site at -54 bp, and glucocorticoid regulatory elements at -352 bp and within the first intron at +346 bp. There appears to be only one gene encoding P-450AROM in the human genome. Two major species of human P-450AROM mRNA (3.4 and 2.9 kilobases) are derived from the use of two polyadenylation signals.
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PMID:Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. 280 31

The effect of tetradecanoylphorbol acetate (TPA) on follicle-stimulating hormone (FSH)-induced synthesis of the cholesterol side-chain cleavage (SCC) enzyme complex was studied in rat ovarian granulosa cells cultured for 48 h in serum-free medium. Cell proteins were radiolabeled with [35S]methionine, followed by immunoprecipitation of cholesterol side-chain cleavage cytochrome P-450 (P-450SCC) as well as the iron-sulfur protein adrenodoxin. Polyacrylamide gel electrophoresis and fluorography of the immunoprecipitates showed that TPA, when added in combination with FSH (50 ng/ml) or dibutyryl cAMP (Bt2cAMP; 1 mM), suppressed the stimulatory effects of these compounds on the synthesis of the SCC components in a concentration-dependent fashion. The effect of TPA was accompanied by decreased progesterone formation and decreased cAMP accumulation. The structural analog of TPA, phorbol-4 alpha-didecanoate, which does not activate protein kinase C (Ca2+/phospholipid-dependent enzyme), had no effect on the FSH- or Bt2cAMP-stimulated synthesis of SCC and progesterone or on cAMP formation. In addition to inhibiting the synthesis of these proteins, TPA greatly reduced the FSH- and Bt2cAMP-induced increase in levels of mRNA encoding the precursor form of P-450SCC. It is concluded that the effect of the phorbol ester TPA to inhibit FSH-stimulated progesterone formation in cultured ovarian granulosa cells of the rat involves decreased synthesis of the components of the SCC enzyme complex due to reduced levels of mRNA encoding the precursor forms of these proteins. The results are indicative that TPA not only inhibits FSH-mediated stimulation of cAMP formation but also may block cAMP-mediated induction of SCC synthesis. It is postulated that the effects of TPA may reflect the physiological role of protein kinase C in the regulation of ovarian steroidogenesis.
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PMID:Tetradecanoyl phorbol acetate suppresses follicle-stimulating hormone-induced synthesis of the cholesterol side-chain cleavage enzyme complex in rat ovarian granulosa cells. 288 36

The potent mitogen and tumor promoter, phorbol 12-myristate 13-acetate (PMA), has a primary action via activation of calcium-dependent protein kinase C. The treatment of monolayer cultures of human fetal adrenal neocortex (HFA) cells with PMA (50-250 nM) stimulated basal dehydroepiandrosterone sulfate (DS) secretion 2-3 fold. ACTH-treated HFA cells secreted amounts of DS and cortisol (F) 10-50 fold greater than basal secretions. PMA (250 nM) addition with ACTH to HFA cells decreased DS and F secretions at least 75% on days 2 and 3 of treatment. Treatment of HFA cells with 4 alpha-phorbol, which does not activate calcium-dependent protein kinase C, did not inhibit steroidogenesis. The attenuated rates of steroidogenesis after PMA treatment correlated with the decreased amounts of steroid 11 beta, 17 alpha- and 21-hydroxylase cholesterol side-chain cleavage steroid dehydrogenase and sulfotransferase activities. The decrease of steroid 17 alpha-hydroxylase activity correlated with the decreased amount of cytochrome P-450(17) alpha as determined after protein immunoblotting of NaDodSO4 cell lysates. After PMA treatment the ACTH-promoted increases of hydroxysteroid sulfotransferase and dehydrogenase activities of HFA cells were suppressed. PMA (50 nM) inhibited cAMP accumulation in ACTH-treated HFA cells, while 4 alpha-phorbol had no effect. Importantly, dibutyryl cAMP (0.2 mM) treatment of HFA cells did not reverse phorbol ester-promoted attenuation of steroidogenesis. We conclude that, in the presence of ACTH, phorbol ester chronically inhibits both cAMP synthesis and cAMP-dependent protein kinase action with resultant decreased steroidogenic enzyme synthesis and steroid production. This may be a consequence of activation, migration and a slow degradation of protein kinase C activity. These multifaceted actions of phorbol ester and associated protein kinase C activation may have critical effects on the ontogeny of fetal adrenal function.
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PMID:The action of phorbol ester on steroidogenesis in cultured human fetal adrenal cells. 303 Jul 21

Exposure of various cell types (rat-1 fibroblasts, bovine adrenocortical cells, human lymphoid cells) to nanomolar concentrations of TPA, resulted in a rapid, apparent loss of cellular protein kinase C content, when the enzyme was assayed by its phospholipid and Ca2+-dependent histone (H1)-kinase activity, following solubilization and DEAE-cellulose chromatography isolation. By contrast, no loss of protein kinase C was detected when the enzyme was probed by its high affinity PDBu binding capacity nor when the kinase activity was assayed with protein substrates other than histones, such as vinculin and a cytochrome P-450. It is concluded that, in addition to the previously reported enzyme subcellular redistribution, following TPA treatment, the phorbol ester induces striking alterations of the cellular protein kinase C catalytic activities. The molecular mechanisms of these changes and their implication in the tumor promotion process remain to be clarified.
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PMID:Altered catalytic properties of protein kinase C in phorbol ester treated cells. 394 56

Most chemical carcinogens require activation by polysubstrate monooxygenase. The phosphorylation of essential components of this cytochrome P-450 monooxygenase system, isolated from rabbit liver microsomes, cytochrome P-450 (LM2) and cytochrome reductase, was tested using two different protein kinases. One of the kinases, a cyclic AMP-independent phosvitin kinase (kinase P), was inactive in all systems tested. However, the catalytic subunit of a cyclic AMP-dependent protein kinase (kinase C) catalyzed phosphoryl group transfer to both proteins, but to different extents. Cytochrome P-450 was phosphorylated when added as sole component and also when in the presence of P-450 reductase and phosphatidylcholine. In contrast, the weak phosphorylation of P-450 reductase was reduced considerably in a complete reconstituted system containing P-450 and phosphatidylcholine. The inclusion of kinase P did not alter these results which excludes the possibility that these kinases participate in a sequential phosphorylation mechanism. The monooxygenase constituents themselves were without kinase activity. When hepatic microsomes were isolated in presence of the phosphatase inhibitor sodium fluoride no significant change in monooxygenase (7-ethoxycoumarin O-deethylation) activity was observed, whilst after preincubation with either acid or alkaline phosphatase a significant reduction in monooxygenase activity was measured. Thus, cytochrome P-450 (LM2) is phosphorylatable by protein kinase C and the catalytic activity of polysubstrate monooxygenase decreases after preincubation of microsomes with phosphatases.
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PMID:Phosphorylation of cytochrome-P-450-dependent monooxygenase components. 685 Sep 89

Elevations in transmural pressure increase active vascular tone in arteries from most vascular beds, and this myogenic response has been shown to play an important role in the regulation of blood flow in the kidney and other organs. The myogenic response in isolated perfused arteries is associated with depolarization of vascular smooth muscle cells and a rise in intracellular calcium concentration, which is dependent on calcium influx through voltage-sensitive calcium channels. Recent studies have indicated that the myogenic response in renal arteries is associated with the activation of phospholipase C and that arachidonic acid potentiates, whereas inhibitors of cytochrome P-450 and protein kinase C attenuate, this response. Renal arteries produce 20-hydroxyeicosatetraenoic acid (20-HETE) via the cytochrome P-450 pathway when incubated with arachidonic acid. 20-HETE is a potent constrictor of canine and rat renal arterioles. It inhibits K+ channel activity, depolarizes renal vascular smooth muscle cells, and produces a sustained increase in intracellular calcium concentration. In this regard, the vasoconstrictor response to 20-HETE mimics the myogenic activation of renal arteries after elevations in transmural pressure. These studies suggest that the activation of phospholipase C and subsequent increases in the intracellular levels of diacylglycerol, 1,4,5 inositol triphosphate, and cytochrome P-450 metabolites of arachidonic acid may participate in the myogenic response of renal arteries and in the regulation of renal vascular tone.
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PMID:Cellular and ionic signal transduction mechanisms for the mechanical activation of renal arterial vascular smooth muscle. 750 44

The dynamics and mechanisms of extracellular release of hydrogen peroxide (H2O2) from bovine pulmonary artery endothelial cells (EC) subjected to anoxia, hypoxia, and hypoxia followed by reoxygenation were examined using various inhibitors of enzymatic systems in intact cells and by direct measurement of H2O2 production from isolated EC plasma membranes. Extracellular H2O2 was measured with a fluorometric assay. EC exposed to hypoxia (3% O2) and anoxia (0% O2) released less H2O2 (29.6 +/- 1.3% and 4.2 +/- 0.7%, respectively) compared with EC exposed to normoxia (20% O2). The extracellular release of H2O2 from EC previously exposed to hypoxia for 24 h increased immediately after reoxygenation (20% O2) to 272 +/- 48%, as compared with EC exposed continuously to normoxia (100% release). Inhibition of xanthine oxidase (XO) by allopurinol did not reduce the release of H2O2 from cells exposed to normoxia or hypoxia followed by reoxygenation. Furthermore, inhibitors of cyclooxygenase (indomethacin), phospholipase A2 (quinacrine and chlorpromazine), nitric oxide synthase (L-arginine analogs), the mitochondrial electron transport chain (rotenone and cyanide), and cytochrome P-450 (methoxypsoralen) had no or minimal effect on this release. On the other hand, inhibitors of protein kinase C (calphostin and staurosporine) and NADPH oxidase (diphenyliodonium) reduced the release of H2O2 from EC in a dose-dependent manner in both exposure groups. In separate experiments, plasma membranes isolated from EC were found to produce H2O2 in the presence of NADH or NADPH as electron donors. This was inhibited by diphenyliodonium but not by allopurinol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of hydrogen peroxide in response to hypoxia-reoxygenation: role of an NAD(P)H oxidase-like enzyme in endothelial cell plasma membrane. 752 30

Circadian-time dependent differences of protein kinase C (PKC) activities as well as its susceptibility to a phenobarbital caused suppression in vivo (40 mg/kg b.i.d. for 3 days) were studied in outbred male Wistar rats weighing 280-360 g. The well-known phenobarbital induction of cytochrome P-450 and 7-pentylresorufin-O-depentylase (PROD) was associated with inhibition of the hepatic PKC. The activities of the cytosolic and membrane-bound PKC were significantly lower than in the respective controls. Statistically significant circadian-time differences were found. The activities of both cytosolic and membrane-bound PKC of control rats were highest in the evening (158% and 131%, respectively, of the morning values). Furthermore, phenobarbital inhibited the enzyme more strongly at 19.00 h than at 07.00 h. Our results suggest that increase of hepatic cytochrome P-450 content as well as induction of PROD are inversely related with the function of PKC.
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PMID:Circadian-time rhythm of hepatic protein kinase C of rats pretreated with phenobarbital. 773 53

Studying Swiss 3T3 fibroblasts, we report that arachidonic acid strongly stimulates mRNA levels of the growth-associated immediate early genes c-fos and Egr-1. Structurally related compounds like arachidonic acid methyl ester, arachidonyl alcohol, or eicosatetraynoic acid are ineffective, indicating a specific role of free unesterified arachidonic acid or an arachidonic acid metabolite in c-fos and Egr-1 mRNA accumulation. Blocking the conversion of arachidonic acid to prostaglandins by inhibiting cyclooxygenase abolishes arachidonic acid-induced accumulation of c-fos and Egr-1 mRNA. Inhibition of the lipoxygenase or cytochrome P-450 epoxygenase pathways has no significant effect on arachidonic acid-induced c-fos and Egr-1 mRNA levels, indicating that prostaglandin synthesis is necessary for the increase in c-fos and Egr-1 mRNA. Reversed phase high performance liquid chromatography revealed prostaglandin E2 (PGE2) as the major arachidonic acid metabolite in Swiss 3T3 fibroblasts. When added to the cells, PGE2 stimulates c-fos and Egr-1 mRNA levels to the same degree as arachidonic acid. Also, the inhibition of arachidonic acid-stimulated c-fos and Egr-1 mRNA accumulation by indomethacin is reversed by PGE2. Contrary to reports that PGE2 caused an increase in cAMP levels in Swiss 3T3 fibroblasts, we found that arachidonic acid and PGE2 only minimally increase cAMP levels as compared with untreated cells. In contrast, inhibition of protein kinase C by calphostin C and chelerythrine or down-regulation with phorbol 12-myristate 13-acetate drastically reduces PGE2 and arachidonic acid-induced c-fos and Egr-1 mRNA levels. These data indicate that arachidonic acid exerts its stimulatory effect on c-fos and Egr-1 mRNA via synthesis of PGE2 and subsequent activation of protein kinase C, probably through a PGE2 receptor coupled to phospholipase C.
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PMID:Arachidonic acid increases c-fos and Egr-1 mRNA in 3T3 fibroblasts by formation of prostaglandin E2 and activation of protein kinase C. 796 34


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