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 early effects (0-120 s) of the beta-adrenergic secretagogue isoproterenol (2.10(-5) M) and the muscarinic secretagogue carbamoylcholine (2.10(-6) M) on various parameters of lipid and phospholipid metabolism were studied in isolated guinea pig parotid acinar cells. Both agonists enhanced within 10-20 s the incorporation of radioactive palmitate into the diacylglycerol, the triglyceride, and the phosphatidylinositol fractions but significantly diminished radioactive palmitate recovered in the acyl-CoA fraction. Carbamoylcholine decreased and isoproterenol increased the recovery of radioactive palmitate in the free fatty acid fraction. All changes had returned almost to control levels after 120 s. In cells prelabeled with [3H]arachidonate, carbamoylcholine exerted similar effects, whereas isoproterenol was almost ineffective. Both agonists stimulated the incorporation of radioactive glycerol into diacylglycerols 2-3-fold, while only carbamoylcholine stimulated the incorporation of [32P]phosphate into phosphatidylinositol and phosphatidate. Both agonists induced an increase in total diacylglycerols, carbamoylcholine being about twice as effective as isoproterenol. A lower concentration of carbamoylcholine (6.5.10(-7) M) had the same quantitative effect as 2.10(-5) M isoproterenol on the increase of total diacylglycerols. Even under these conditions carbamoylcholine, but not isoproterenol led to a significant translocation of protein kinase C from the soluble to the particulate fraction. Isoproterenol remained ineffective in this respect also when intracellular free calcium was increased with a calcium ionophore. This is explained by the finding that isoproterenol stimulates preferentially the formation of 2,3-sn-diacylglycerol, and carbamoylcholine preferentially stimulates the formation of 1,2-sn-diacylglycerol. The results indicate that in the guinea pig parotid acinar cell the two agonists do not only lead to activation of a triglyceride lipase (isoproterenol) or phosphoinositide-specific phospholipase(s) (carbamoylcholine), but also to a rapid change of flux through a number of other enzyme-catalyzed reactions involved in diacylglycerol turnover.
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PMID:Early effects of beta-adrenergic and muscarinic secretagogues on lipid and phospholipid metabolism in guinea pig parotid acinar cells. Stimulation of 2,3-sn-diacylglycerol formation by isoproterenol. 289 Jun 41

Exogenous 1-oleoyl-2-acetylglycerol (OAG) is known to mimic the action of tumour-promoting phorbol esters in various cell types. However, in isolated rat hepatocytes OAG depressed the rate of de novo fatty acid synthesis and the activity of the key enzyme acetyl-CoA carboxylase (EC 6.4.1.2), in contrast to the pronounced stimulation of both parameters by phorbol 12-myristate 13-acetate (PMA). The inhibition by OAG appeared to be dose- and time-dependent. On the other hand, medium-chain 1,2-diacylglycerols like 1,2-dioctanoyl-sn-glycerol did mimic the stimulatory action of PMA. The anomalous effect of OAG may well be explained by its metabolic breakdown leading to liberation of oleate and subsequent inhibition of acetyl-CoA carboxylase activity by endogenously formed oleoyl-CoA. The stimulatory effects of both PMA and medium-chain diacylglycerols are likely to be mediated by protein kinase C.
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PMID:Dissimilar effects of 1-oleoyl-2-acetylglycerol and phorbol 12-myristate 13-acetate on fatty acid synthesis in isolated rat-liver cells. 289 28

Acyl-Coenzyme A thioesters of the hypolipidaemic and cancerinogenic peroxisome proliferators clofibric acid, nafenopin, ciprofibrate, bezafibrate and tibric acid were found to greatly increase the activity of rat brain protein kinase C. Maximal activation required the simultaneous presence of Ca+2, phosphatidylserine and diolein, thus differentiating their action from that of other tumor promoters such as phorbol esters. Under similar conditions the unesterified drugs were comparatively ineffective. Similar results were obtained using the rat liver enzyme. The data suggest that acylcoenzyme A thioesters of hypolipidaemic drugs, may play a role in the induction of liver tumors by these compounds, through the potentiation of protein kinase C.
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PMID:Potentiation of diacylglycerol-activated protein kinase C by acyl-coenzyme A thioesters of hypolipidaemic drugs. 293 May 49

The addition of the analogue of diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG), to resident macrophages isolated from the peritoneal cavity of mice led to a dose and time dependent increase in the synthesis of prostaglandin E. This was likely due to an enhanced amount of arachidonic acid available for eicosanoid synthesis as OAG suppressed the incorporation of arachidonic acid into cellular phospholipids by inhibiting acyl-CoA:lysophosphatide acyltransferase. Since OAG has been shown to activate protein kinase C in various cells, these data lead us to suggest that synthesis of eicosanoids in peritoneal macrophages is mediated by the activation of protein kinase C.
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PMID:A possible role of protein kinase C in regulating prostaglandin synthesis of mouse peritoneal macrophages. 309 19

Oleoyl coenzyme A and other acyl-CoA derivatives inhibited ADP or thrombin-induced aggregation of platelets. Arachidonic acid-induced aggregation was also inhibited, but not the slower aggregation caused by 1-oleoyl-2-acetylglycerol or tetradecanoyl-phorbol-13-acetate. Coenzyme A and free fatty acids had little or no effect, and transfer of labeled oleate from oleoyl Co-A to other lipid classes was not detected. Because acyl Co-A compounds have recently been shown to modulate protein kinase C activity, acyl Co-A may provide a useful tool for investigating activation sequences in platelets and other membranes.
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PMID:Platelet aggregation is inhibited by long chain acyl-CoA. 314 60

Methyl lidocaine is an experimental anti-arrhythmic drug which has been shown to enhance the biosynthesis of phosphatidyl-inositol (PI) in the hamster heart. In this study, the effect of methyl lidocaine on enzymes involved in the biosynthesis of PI in the heart was examined. When the hamster heart was perfused with labelled methyl lidocaine, the majority of the compound was not metabolized after perfusion. The direct action of methyl lidocaine on an enzyme was studied by the presence of the drug in enzyme assays, whereas its indirect action was studied by assaying the enzyme activity in the heart after methyl lidocaine perfusion. CTP:phosphatidic acid cytidylyl-transferase, a rate-limiting enzyme in PI biosynthesis, was stimulated by methyl lidocaine in a direct manner. Kinetic studies revealed that methyl lidocaine caused a change in the affinity between the enzyme and phosphatidic acid and resulted in the enhancement of the reaction. Alternatively, acyl-CoA:lysophosphatidic acid acyltransferase, another key enzyme for PI biosynthesis, was not activated by the presence of methyl lidocaine. However, the enzyme activity was stimulated in hearts perfused with methyl lidocaine. The enhancement of the acyl-transferase by methyl lidocaine perfusion was found to be mediated via the adenylate cyclase cascade with the elevation of the cyclic AMP level. The stimulation of protein kinase A activity by cyclic AMP resulted in the phosphorylation and activation of the acyltransferase. Interestingly, the activity of protein kinase C was not stimulated by methyl lidocaine perfusion. We conclude that the enhancement of PI biosynthesis by methyl lidocaine in the hamster heart resulted from the direct activation of the cytidylyltransferase, as well as the phosphorylation and subsequent activation of the acyltransferase.
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PMID:The modulation of phosphatidylinositol biosynthesis in hamster hearts by methyl lidocaine. 763 4

Peroxisome proliferator-activated receptor (PPAR) and retinoid x receptor (RXR) play important roles in fatty acid metabolism. The present study examined the regulation of retinoic acid receptor (RAR alpha, beta, and gamma), RXR (alpha, beta, and gamma), PPAR, cytochrome P450 2E1 (CYP2E1), catalase, and beta-actin gene expression in chronic alcoholic liver disease in the rat. The results demonstrated that the expression of genes for RAR and RXR isoforms and catalase were not altered by ethanol in the fatty liver. In contrast, the levels of PPAR and CYP2E1 mRNAs were down- and up-regulated by ethanol in the liver, respectively. The levels of CYP2E1 mRNAs correlated positively with blood alcohol levels (BAL). In addition, ethanol induced expression of beta-actin mRNA was also proportional to the BAL. The level of PPAR mRNA and the content of polyunsaturated fatty acid decreased in ethanol-fed rat livers. Decreased PPAR gene expression in ethanol-fed rats might result from a decrease in the content of polyunsaturated fatty acid in the liver. However, the activities of enzymes involved in hepatic lipid metabolism, including acyl CoA synthetase, acyl CoA oxidase, catalase, and protein kinase C, were not changed by ethanol treatment. The significance of down-regulation of PPAR gene in alcohol liver disease is discussed.
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PMID:Expression of the peroxisome proliferator-activated receptor gene is decreased in experimental alcoholic liver disease. 783 30

We studied the effect of fatty acids and their acyl-CoA esters on protein kinase C (PK-C) activity in human skin fibroblasts. Butyrate, octanoate, palmitate and oleate did not alter PK-C activity in either cytosolic or particulate fraction. In the presence of calcium, phosphatidylserine and diacylglycerol, both palmitoyl-CoA (Pal-CoA) and oleoyl-CoA (Ole-CoA) enhanced particulate PK-C activity by approx. 70% and octanoyl-CoA (Oct-CoA) by approx. 35%. Partially purified cytosolic PK-C activity was enhanced by 60-70% by 13.5 microM of either Pal-CoA or Ole-CoA. Basal histone phosphorylation (i.e., PK-C-independent phosphorylation) was decreased in the particulate fraction in the presence of these esters in a concentration-dependent manner. Both Pal-CoA and Ole-CoA fully substituted diacylglycerol in activating the kinase in both the cytosolic and particulate fractions, whereas Oct-CoA had a moderate effect. The pattern of endogenous cytosolic and particulate protein phosphorylation was altered in the presence of either Pal-CoA or Ole-CoA. We conclude that long-chain fatty acyl-CoA esters may activate PK-C in non-stimulated fibroblasts, i.e., in the absence of physiological diacylglycerol formation. Activation of PK-C in stimulated fibroblasts, i.e., in the presence of an elevated diacylglycerol concentration, is less pronounced. These results support the hypothesis that activation of PK-C and alteration of endogenous protein phosphorylation may play a role in the pathogenesis of diseases in which there is intracellular accumulation of fatty acyl-CoA esters, such as in inborn fatty-acid oxidation defects.
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PMID:Effect of fatty acids and their acyl-CoA esters on protein kinase C activity in fibroblasts: possible implications in fatty acid oxidation defects. 813 Feb 78

The mechanism by which hypolipidemic drugs and industrial plasticizers cause hepatic tumors in rodents remains unknown. It is known, however, that protein kinase C is elevated during hepatic cell turnover, and sustained cellular replication is correlated with an increased incidence of hepatic tumors. Therefore, several peroxisomal proliferators varying in their tumorigenic potency in chronic feeding studies were examined for their ability to increase protein kinase C activity. Intragastric administration of (4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio)acetic acid (Wy-14,643; 100 mg/kg) increased protein kinase C activity threefold in 5 hr and fivefold in 10 hr. Perfluorooctanoate also increased protein kinase C activity significantly in microsomes at 5 hr. Wy-14,643 and perfluorooctanoate also diminished acyl CoA synthetase activity significantly, with Wy-14,643 exhibiting competitive type kinetics. Other peroxisomal proliferators were examined [e.g., ciprofibrate, clofibrate, 2-ethylhexanol, valproate, and di(ethylhexyl)phthalate (DEHP)] and collectively an inverse relationship between their ability to stimulate protein kinase C activity and inhibit acyl CoA synthetase was observed (r = -0.80). All chemicals examined had no direct effect on protein kinase C activity in vitro. Interestingly, those compounds which are more potent as hepatocarcinogens (e.g., Wy-14,643) in long-term feeding studies decreased acyl CoA synthetase and elevated protein kinase C activity to a greater extent than their weaker counterparts (e.g., DEHP). It is proposed that inhibition of acyl CoA synthetase by peroxisomal proliferators elevates free fatty acids which stimulate protein kinase C activity and ultimately promote tumor formation.
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PMID:Peroxisomal proliferators inhibit acyl CoA synthetase and stimulate protein kinase C in vivo. 820 76

We have in this study examined the effects of sphingosine, a possible secondary degradation product following sphingomyelin hydrolysis, on cholesterol homeostasis in cultured human fibroblasts treated with sphingomyelinase. The activation of cholesterol esterification, which resulted from the degradation of plasma membrane sphingomyelin (by sphingomyelinase), was observed to be effectively blocked by sphingosine (half-maximal dose 6-7 microM). The inhibitory action of sphingosine could not be reproduced with other amines (e.g., dodecyl amine or imipramine). The onset of inhibition of cholesteryl ester formation by sphingosine was rapid (maximal effect within 15 min). Sphingosine itself had no spontaneous effects on the distribution of cellular cholesterol. At concentrations below 10 microM, sphingosine was not cytotoxic, as determined by cellular trypan blue permeability. The inhibitory action of sphingosine on cholesteryl ester formation apparently did not result from a direct inhibition of acyl-CoA cholesterol acyltransferase (ACAT), since the activity of this enzyme was unaffected by sphingosine (10 microM) in a cell-free homogenate, using [14C]oleoyl-CoA as a co-substrate. Sphingosine was also unable to prevent the formation of activated fatty acids (oleoyl-CoA), since acyl-CoA synthetase activity in a cell-free homogenate was not inhibited by sphingosine (at 5 microM). The cellular cholesteryl ester cycle (i.e., the neutral cholesteryl ester hydrolase) was unaffected by sphingosine (at 5 microM). Down-regulation of PKC activity (24 h exposure of cells to 100 nM (62 ng/ml) phorbol ester) did not affect the sphingomyelinase-induced stimulation of [3H]cholesteryl ester formation. In addition, the sphingosine-induced inhibition of [3H]cholesteryl ester formation was not reversed in the presence of phorbol ester (short-term exposures), suggesting that the effect of sphingosine was not mediated via PKC. In conclusion, we have shown that sphingosine is an inhibitor of cholesteryl ester formation in fibroblasts. The inhibition is only seen with intact cells, which may suggest that a secondary metabolite of sphingosine was responsible for the observed inhibition of cholesteryl ester formation.
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PMID:Sphingosine inhibits sphingomyelinase-induced cholesteryl ester formation in cultured fibroblasts. 825 25


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