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)

It has recently been demonstrated that exogenous addition of low concentrations (< 15 microM) of lysophosphatidyl choline (LPC, palmitic acid in the sn-1 position) induces a transient increase in taurine efflux from HeLa cells in a process that seems to involve generation of reactive oxygen species (ROS) and tyrosine phosphorylation (J. Membrane Biol. 176 (2000) 175-185). We now demonstrate that LPC also induces release of taurine under isotonic conditions in mouse fibroblast (NIH/3T3) and Ehrlich ascites tumor cells. Furthermore, we show that in the case of HeLa cells addition of the calmodulin antagonist W-7 (50 microM) or the calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 (10 microM) reduces the LPC-induced taurine release under isotonic conditions. Conversely, addition of a standard protein kinase C (PKC) inhibitor chelerythrine (10 microM) leads to a potentiation of the LPC-induced taurine efflux, whereas direct activation of PKC by the phorbol ester PMA has no effect. It is suggested that the putative generation of ROS following addition of LPC is modulated by calmodulin/CaMKII, and that the effect of chelerythrine is more likely related to the ROS production than to PKC inhibition.
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PMID:Lysophosphatidylcholine-induced taurine release in HeLa cells involves protein kinase activity. 1191 68

Ultraviolet irradiation is a major environmental cause of skin cancers, whereas ultraviolet-induced DNA repair and apoptosis are defense mechanisms that rescue and/or protect keratinocytes from this risk. Multiple pathways are involved in ultraviolet-induced keratinocyte apoptosis, including activation of p38-mitogen-activated protein kinase, protein kinase C, and CD95, each of which are associated with caspase activation. Alternatively, ceramides could serve as ultraviolet-induced, second messenger lipids, because they induce cell cycle arrest and apoptosis in a variety of cell types, including keratinocytes. We investigated the role of ceramide versus caspase, and the responsible pathway for ceramide generation in ultraviolet B-induced apoptosis of cultured normal human keratinocytes maintained in low calcium (0.07 mm) medium. Ultraviolet B (40 mJ per cm2) significantly inhibited cultured normal human keratinocyte proliferation, assessed as [3H-methyl]thymidine-thymidine incorporation into DNA, 2 h after irradiation. Terminal nick deoxynucleotide end-labeling-positive apoptotic cells (14.8% at 24 h and 34.4% at 48 h) and trypan blue-positive apoptotic cells (8.4% at 24 h and 28.6% at 48 h) became evident in a time-dependent manner after ultraviolet B irradiation, in parallel with activation of caspase-3. The ceramide content of irradiated cultured normal human keratinocytes increased significantly by 8 h, whereas glucosylceramide only modestly increased, and sphingomyelin content remained unaltered. Metabolic studies with radiolabeled serine, palmitic acid, and phosphorylcholine revealed that the ultraviolet B-induced increase in ceramide results primarily from increased de novo synthesis rather than accelerated sphingomyelin hydrolysis. Increased ceramide synthesis, in turn, could be attributed to increased activity of ceramide synthase (i.e., 1.7-fold increase 8 h after ultraviolet B irradiation), whereas serine palmitoyltransferase activity did not change. Both fumonisin B1, an inhibitor of ceramide synthase, and ISP-1, myriocin an inhibitor of serine palmitoyltransferase, significantly attenuated the ultraviolet B-induced apoptosis in a caspase-3-independent fashion, whereas co-incubation with a caspase-3 inhibitor (Ac-DEVD-chloromethyl-ketone) further attenuated the ultraviolet B-induced apoptosis. Thus, increased de novo ceramide synthesis signals ultraviolet B-induced apoptosis, by a pathway independent of, but in concert with, caspase-3 activation.
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PMID:De novo ceramide synthesis participates in the ultraviolet B irradiation-induced apoptosis in undifferentiated cultured human keratinocytes. 1264 32

[3H]Palmitic acid accumulates in neuroblastoma NB-2a cells, being incorporated in lipids (90%) and proteins (10%) fractions. Addition of palmitoylcarnitine, known to modulate activity of protein kinase C and to promote differentiation of neurons, was observed to decrease incorporation of palmitic acid to sphingomyelin, phosphatidylserine, and phosphatidylcholine, with a parallel increase of palmitic acid bound to proteins through a thioester bond (palmitoylation). In the presence of palmitoylcarnitine, one of the palmitoylated proteins expressed at growing neural cones, GAP-43, was observed to co-localize with caveolin-1, what was correlated with the beginning of differentiation. A new function of palmitoylcarnitine in controlling palmitoylation of proteins and their targeting to cholesterol-rich domains has been proposed.
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PMID:Palmitoylcarnitine modulates palmitoylation of proteins: implication for differentiation of neural cells. 1267 56

We have investigated the effects of inhibiting sphingomyelin (SM) biosynthesis on cellular diacylglycerol (DAG) content and protein kinase C (PKC) activation during growth initiation in Madin-Darby canine kidney cells. We utilized beta-chloroalanine (BCA) to inactivate serine C -palmitoyltransferase, the first enzyme in the sphingolipid biosynthesis pathway. This inactivation prevented growth, but did not affect viability. When the inhibitor was replaced with fresh culture medium, the cells continued their proliferation in a normal way. BCA (2 mM) inhibited [(32)P]P(i), [(3)H]palmitic acid and [ methyl -(3)H]choline incorporation into SM, but did not influence the synthesis of other major phospholipids. SM synthesis and DAG generation were decreased by 51% and 47.6% respectively. Particulate PKC activity was not observed in cells incubated with BCA, in contrast with a 5-fold increase in control cells. BCA inhibited 75% of the [(3)H]thymidine incorporation, and the cells were arrested before the S phase of the cell cycle. Moreover, exogenous D-erythrosphingosine restored SM synthesis, DAG generation and cell proliferation. These data indicate that the contribution of DAG generated during SM synthesis plays an important role in PKC activation and cell proliferation.
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PMID:Diacylglycerol generated during sphingomyelin synthesis is involved in protein kinase C activation and cell proliferation in Madin-Darby canine kidney cells. 1269 4

Insulin resistance is defined as the decrease in the glucose disposal in response to insulin by the target tissues. High concentrations of nonesterified fatty acids (NEFA) in plasma have been implicated with many insulin resistance states. We evaluated several aspects of the insulin resistance induced by palmitic acid in rats and found that after treatment with 0.09 g/kg of palmitic acid there is a delay in the curve of tolerance to glucose. We measured the changes in protein phosphorylation in samples from abdominus rectus muscle and there was a decrease of 64 and 75% in the levels of phosphorylation in tyrosine of the insulin receptor and insulin receptor substrate-1, respectively. This diminution in the tyrosine phosphorylation is consistent with a decrease in the main pathway known to be activated after insulin treatment, the mitogen activated protein kinases (MAPKs). If the animals were treated with inhibitors of PKC, like sphingosine, there was a prevention of the effect of palmitic acid determined at the level of tyrosine phosphorylation. According with this result, we found an increase in the phosphorylations in serine of the insulin receptor after the treatment with palmitate. These results suggest that PKC has a role as negative regulator (by phosphorylation in serine) of the insulin receptors activation in the insulin resistance induced by palmitic acid.
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PMID:High levels of palmitic acid lead to insulin resistance due to changes in the level of phosphorylation of the insulin receptor and insulin receptor substrate-1. 1284 57

The Ca2+-sensing receptor (CaR) couples to multiple G proteins involved in distinct signaling pathways: Galphai to inhibit the activity of adenylyl cyclase and activate ERK, Galphaq to stimulate phospholipase C and phospholipase A2, and Gbetagamma to stimulate phosphatidylinositol 3-kinase. To determine whether the receptor also couples to Galpha12/13, we investigated the signaling pathway by which the CaR regulates phospholipase D (PLD), a known Galpha12/13 target. We established Madin-Darby canine kidney (MDCK) cell lines that stably overexpress the wild-type CaR (CaRWT) or the nonfunctional mutant CaRR796W as a negative control, prelabeled these cells with [3H]palmitic acid, and measured CaR-stimulated PLD activity as the formation of [3H]phosphatidylethanol (PEt). The formation of [3H]PEt increased in a time-dependent manner in the cells that overexpress the CaRWT but not the CaRR796W. Treatment of the cells with C3 exoenzyme inhibited PLD activity, which indicates that the CaR activates the Rho family of small G proteins, targets of Galpha12/13. To determine which G protein(s) the CaR couples to in order to activate Rho and PLD, we pretreated the cells with pertussis toxin to inactivate Galphai or coexpressed regulators of G protein-signaling (RGS) proteins to attenuate G protein signaling (RGS4 for Galphai and Galphaq, and a p115RhoGEF construct containing the RGS domain for Galpha12/13). Overexpression of p115RhoGEF-RGS in the MDCK cells that overexpress CaRWT inhibited extracellular Ca2+-stimulated PLD activity, but pretreatment of cells with pertussis toxin and overexpression of RGS4 were without effect. The involvement of other signaling components such as protein kinase C, ADP-ribosylation factor, and phosphatidylinositol biphosphate was excluded. These findings demonstrate that the CaR couples to Galpha12/13 to regulate PLD via a Rho-dependent mechanism and does so independently of Galphai and Galphaq. This suggests that the CaR may regulate cytoskeleton via Galpha12/13, Rho, and PLD.
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PMID:The Ca2+-sensing receptor couples to Galpha12/13 to activate phospholipase D in Madin-Darby canine kidney cells. 1295 3

We investigated the effects of different fatty acids (FAs) or with different degrees of unsaturation on cytochrome P450 2E1 (CYP2E1) induction and protein kinase C (PKC) activity in human hepatoma HepG2 cells. As the degree of unsaturation increased, the cell survival rate decreased for FAs with 18 carbons, but linolenic acid (LNA) or docosahexaenoic acid (DHA) groups were similar even through they have different degrees of unsaturation. Treatment with palmitic acid (PA), oleic acid (OA), linoleic acid (LA), LNA, and DHA resulted in respective cellular FA concentrations of C16:0 (43.1%), C18:1 (18.5%), C18:2 (7.4%), LNA (2.85%), and C22:6 (3.13%), which was highest for the FA that was used as the treatment, indicating that their incorporation within the cell is directly proportional to treatment. After 2 hours of cultivation, the lipid peroxide (LPO) in the DHA group increased 600% compared with control, and was much higher than in the groups treated with the other FAs, with LNA > LA > OA > PA. CYP2E1 induction increased with greater effect as the degree of unsaturation of OA, LA, and DHA increased. PA did not affect PKC activity, but DHA treatment increased PKC activity the most. The effects of LNA and LA were similar, but less than that of DHA, and that of OA was lower still, indicating that activity of PKC is proportional to the degree of unsaturation, and not the configuration of the FA. Increased plasma membrane concentrations of n-3 FA, such as DHA, might exert regulatory effects on PKC by increasing membrane fluidity, causing changes in CYP2E1, elevating levels of LPO, or producing oxidative stress.
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PMID:Differential effects of dietary fatty acids on the regulation of CYP2E1 and protein kinase C in human hepatoma HepG2 cells. 1529 68

Following diazoxide (DZ) induced hypoinsulinemia, cardiac luminal lipoprotein lipase (LPL) increases [Cardiovasc. Res. 3 (2003) 788]. To identify circulating mediators that maintain high LPL in vivo, DZ hearts were perfused for 1 h in the presence or absence of glucose, triglyceride (TG), palmitic acid or palmitoyl lysophosphatidylcholine (PLPC). Only PLPC maintained high luminal LPL in DZ hearts, likely through enzyme recruitment from the cardiomyocyte. PLPC perfusion activated whole heart protein kinase C (PKC) epsilon. As calphostin pretreatment blocked PLPC induced PKC activation, and increases in luminal LPL activity, PKC activation is essential for the effects of PLPC. Incubation of myocytes with PLPC had no effects on either surface or intracellular LPL or PKC suggesting that PKC activation occurs in cells other than the myocyte or that metabolism of PLPC is required for its downstream effects. Since exposure of endothelial cells to PLPC activated PKC, whole heart PKC activation likely occurred in these cells. Incubation of myocytes with LPA, a phospholipase D (PLD) mediated breakdown metabolite of PLPC, significantly enhanced basal and heparin-releasable myocyte LPL activity, an effect that was duplicated by co-incubation of control myocytes with exogenous PLD and PLPC. Our data suggest that at least in the whole heart, the LPL augmenting property of PLPC likely requires endothelial PKC activation, formation of LPA, and mobilization of enzyme from the myocyte to the coronary lumen.
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PMID:Palmitoyl lysophosphatidylcholine mediated mobilization of LPL to the coronary luminal surface requires PKC activation. 1552 70

The enantioselective synthesis of an analogue of scyphostatin, a potent inhibitor of the neutral sphingomyelinase, is described. The synthesis starts with cyclohexanone and a protected D-serine derivative. The key step is an asymmetric hydroxylation to access a hydroxycyclohexanone, which is transformed into a substituted hydroxycyclohexenone. This is converted into the scyphostatin analogue 14, a chemically and metabolically stabilised compound lacking the epoxy function of the natural congener and carrying a palmitic acid group instead of the native trienoyl residue. An evaluation of the biological activity of 14 revealed neutral sphingomyelinase inhibition in several in vivo test systems (monocytes, macrophages, hepatocytes) monitoring antiapoptotic effects and the inversion of phorbolester-induced translocation of green fluorescent protein labelled kinase (protein kinase C-alpha).
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PMID:Synthesis and antiapoptotic activity of a novel analogue of the neutral sphingomyelinase inhibitor scyphostatin. 1575 Oct 1

Palmitoylcarnitine was previously shown to promote differentiation of neuroblastoma NB-2a cells. It was also observed to increase palmitoylation of several proteins and to diminish incorporation of palmitic acid to phospholipids, as well as to affect growth associated protein GAP-43 by decreasing its phosphorylation and interaction with protein kinase C. The present study was focused on influence of palmitoylcarnitine on palmitoylation of GAP-43 and lipid metabolism. Althought palmitoylcarnitine did not significantly affect the total phospholipids and fatty acid content, it increased incorporation of palmitate moiety to triacylglicerides and cholesterol esters, with a decrease of free cholesterol content. The presence of palmitoylcarnitine significantly increased the amount of covalently bound palmitate to GAP-43, which can regulate the signal transduction pathways.
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PMID:Palmitoylcarnitine regulates estrification of lipids and promotes palmitoylation of GAP-43. 1766 26


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