Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differences between the influences of phorbol esters (such as 4 beta-12-O-tetradecanoylphorbol 13-acetate) and of fatty acids (such as oleic acid) on the synthesis and turnover of phosphatidylcholine (PtdCho) and other phospholipids have been studied in glioma (C6), neuroblastoma (N1E-115), and hybrid (NG108-15) cells in culture using [methyl-3H]choline, [32P]Pi, [1,2-14C]ethanolamine, or 1-14C-labeled fatty acids as lipid precursors. 100-500 microM oleic acid stimulated PtdCho synthesis 3- to 5-fold in all three cell lines, but had little influence on chase of choline label following a 24-h pulse. Phorbol ester (50-200 nM) stimulated PtdCho synthesis 1.5- to 3-fold in C6 cells, was without effect in N1E-115 cells, and had intermediate effects on NG108-15 cells. Phorbol ester stimulated both uptake of extracellular choline and synthesis of PtdCho, whereas fatty acid stimulated only synthesis. Release of radioactivity from 24-h pulse-labeled PtdCho to the medium was enhanced by phorbol ester in C6 cells. Incorporation of [32P]Pi, primarily into PtdCho, was stimulated, whereas utilization of [1,2-14C]ethanolamine or 1-14C-fatty acid was little altered by phorbol ester. C6 cells "down-regulated" with phorbol ester lost the stimulatory response of subsequent treatment with phorbol esters on PtdCho synthesis, but the response to fatty acid was enhanced. Fatty acid had little influence on the relative binding of phorbol ester or "translocation" of phorbol ester binding sites. Accordingly, metabolism of phospholipids in these cultured cells of neural origin is markedly influenced by cell type, phospholipid class, condition of incubation medium, and nature of stimulator. Phorbol esters and fatty acids appear to enhance phospholipid synthesis and turnover by distinct intracellular mechanisms.
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PMID:Alterations of phospholipid metabolism by phorbol esters and fatty acids occur by different intracellular mechanisms in cultured glioma, neuroblastoma, and hybrid cells. 291 28

The phorbol ester tumor promoter phorbol-12-myristate-13-acetate (PMA) was found to have differential inhibitory effects on the expression of morphological and biochemical differentiation of N-18 mouse neuroblastoma cells. PMA completely inhibited neurite extension and associated growth characteristics and partially inhibited the increased expression of R1 cAMP-binding protein; PMA had no effect on the induction of acetylcholinesterase activity in cells prompted to differentiate either by treatment with 1 mM dibutyryl cAMP or by serum deprivation. 4-alpha-Phorbol-12, 13-didecanoate, an inactive analogue of phorbol ester tumor promoter, was without effect. The implications of these findings concerning the mechanism of action of phorbol ester tumor promoters in the control of cell differentiation are discussed.
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PMID:Differential effects of the tumor promoter phorbol-12-myristate-13-acetate on the morphological and biochemical differentiation of N-18 mouse neuroblastoma cells. 299 62

The binding characteristics of [3H]phorbol-12,13-dibutyrate ([3H]PDBu) in mouse neuroblastoma N1E-115 cells were studied. The specific binding of [3H]PDBu to intact cells was saturable and to a homogeneous class of binding sites, with a Kd of 21 nM. Phorbol 12-myristate-13-acetate and PDBu competed for [3H]PDBu binding whereas 4 alpha-phorbol did not. The binding of [3H]PDBu to the cells was selective, as it was not affected by several agents that interact with various neurotransmitter receptors in N1E-115 cells. The density of the phorbol ester binding site decreased as the cell passage increased, although the Kd of [3H]PDBu binding remained relatively constant. Upon exposure of the cells to 100 nM PDBu for 1 hr at 37 degrees C, a translocation of the binding sites from the cytosol to the particulate fraction was observed. A similar pretreatment of the cells with 1 mM carbamylcholine, however, was ineffective. The specific binding of [3H]PDBu was down-regulated in both a time- and a concentration-dependent fashion by exposure of the cells to PDBu. When the cells were treated with 100 nM PDBu for 24 hr, the maximum binding site density of [3H]PDBu was decreased to 47% of control, with no change in the Kd. Recovery of [3H]PDBu binding after exposure to the phorbol ester for 24 hr was slow and incomplete, and was dependent on protein synthesis. The down-regulation of [3H]PDBu binding after pretreatment of the cells with PDBu for 24 hr was accompanied by an attenuation of the ability of phorbol 12-myristate-13-acetate to inhibit carbamylcholine-induced cyclic GMP formation as well as inositol phosphates accumulation in these cells, indicating desensitization of protein kinase C function.
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PMID:Regulation of [3H]phorbol-12,13-dibutyrate binding sites in mouse neuroblastoma cells: simultaneous down-regulation by phorbol esters and desensitization of their inhibition of muscarinic receptor function. 342 96

The effects of calphostin A on cytoplasmic calcium levels, receptor-mediated calcium release, and membrane input resistance were measured in neuroblastoma cells. Calphostin A is a lipophilic, light-sensitive perylenequinone that generates singlet oxygen when illuminated. It inhibits the activity of protein kinase C (IC50 = 250 nM), but only in the presence of light. Phorbol esters normally attenuate carbachol-evoked calcium release. This effect was blocked by simultaneous exposure to light and calphostin A (40 nM) for 30 min. At higher doses (0.5-1 microM) calphostin A also approximately doubled the resting calcium level and decreased cell input resistance by 51%. These toxic effects did not occur in the dark or after preincubation with the antioxidant alpha-tocopherol. These data support the hypothesis that the calphostins act by partitioning into the membrane and producing singlet oxygen and endoperoxides which then irreversibly modify protein kinase C and other membrane proteins and lipids.
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PMID:Membrane toxicity of the protein kinase C inhibitor calphostin A by a free-radical mechanism. 769 61

The effects of calphostin A on cytoplasmic calcium levels, receptor-mediated calcium release, and membrane input resistance were measured in neuroblastoma cells. Calphostin A is a lipophilic, light-sensitive perylenequinone that generates singlet oxygen when illuminated. It inhibits the activity of protein kinase C (IC50 = 250 nM), but only in the presence of light. Phorbol esters normally attenuate carbachol-evoked calcium release. This effect was blocked by simultaneous exposure to light and calphostin A (40 nM) for 30 min. At higher doses (0.5-1 microM) calphostin A also approximately doubled the resting calcium level and decreased cell input resistance by 51%. These toxic effects did not occur in the dark or after preincubation with the antioxidant alpha-tocopherol. These data support the hypothesis that the calphostins act by partitioning into the membrane and producing singlet oxygen and endoperoxides which then irreversibly modify protein kinase C and other membrane proteins and lipids.
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PMID:Membrane toxicity of the protein kinase C inhibitor calphostin A by a free-radical mechanism. 769 90

The protein kinase C (PKC) alpha, beta and epsilon isoforms have distinct nuclear localizations in neuroblastoma x glioma hybrid cells NG 108-15. We found by immunoblotting that PKC alpha, beta II, delta and epsilon are the predominant isoforms in these cells. In contrast to other neuronal cell lines, none of these isoforms is down-regulated during differentiation. Confocal immunofluorescence microscopy revealed that in undifferentiated cells PKC alpha is located in the cytoplasm and in the nucleus excluding nucleoli. In differentiated cells PKC alpha was almost exclusively located in the cytoplasm. Stimulation of the cells with phorbol ester resulted in translocation to the plasma membrane. PKC beta II was not detectable in the nuclei. PKC delta was found in the nucleoli and in the cytoplasm, in differentiated cells particularly in the neurites. Phorbol ester failed to induce a translocation to other compartments. PKC epsilon was localized with the nuclear-pore complexes at the nuclear envelope. In differentiated cells after stimulation with phorbol ester, partial translocation to the plasma membrane was observed.
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PMID:Differential nuclear localization of protein kinase C isoforms in neuroblastoma x glioma hybrid cells. 802 Apr 72

The effects of protein kinase C (PKC) activation on muscarinic receptor-mediated phosphoinositide and Ca2+ signalling were examined in the human neuroblastoma, SH-SY5Y. Carbachol evoked rapid transient elevations of Ins(1,4,5)P3 and intracellular [Ca2+] followed by lower sustained elevations. Phorbol 12,13-dibutyrate (PDBu) preferentially attenuated transient phases. Removal of the transplasmalemmal Ca2+ gradient coupled with depletion of intracellular Ca2+ stores with thapsigargin also reduced carbachol-mediated Ins(1,4,5)P3 accumulation. Under these conditions, PDBu virtually abolished Ins(1,4,5)P3 responses to carbachol thereby implicating both Ca(2+)- and PKC-sensitive components. PDBu also reduced agonist-mediated accumulation of inositol phosphates and depletion of lipids, thereby eliminating an effect of PKC on Ins(1,4,5)P3 metabolism or phosphoinositide synthesis. In electroporated cells, PDBu inhibited Ins(1,4,5)P3 accumulation mediated by carbachol or guanosine 5'-[gamma-thio]-triphosphate, the latter indicating that some PDBu-sensitive elements were downstream of the receptor. The PKC inhibitor, Ro-318220, protected against PDBu but did not enhance responses to maximal concentrations of carbachol, indicating no feedback inhibition by agonist-activated PKC. Muscarinic antagonist activity of Ro-318220 complicated such assessment at low agonist concentrations. Carbachol or PDBu induced cytosol to membrane translocation of PKC alpha. This was faster and possibly greater with PDBu, which may explain the lack of feedback by agonist-activated PKC. These results indicate that, in SH-SY5Y cells, PDBu activation of PKC preferentially inhibits rapid muscarinic receptor-mediated phosphoinositide and Ca2+ responses via suppression of PtdIns(4,5)P2 hydrolysis. This is at least partially through inhibition of Gq-protein/phosphoinositidase C coupling. However, at least at high agonist concentrations, a major agonist-mediated PKC feedback is not present in these cells.
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PMID:Contrasting effects of phorbol ester and agonist-mediated activation of protein kinase C on phosphoinositide and Ca2+ signalling in a human neuroblastoma. 867 Jan 70

Phorbol myristate acetate (PMA), a protein kinase C (PKC) activator significantly decreased in a time- and dose-dependent manner taurine uptake by rat astroglial but not neuronal cells. The PMA-induced inhibition of taurine uptake by rat astrocytes was prevented by chelerythrine, a potent and selective inhibitor of PKC. The differential effect of PMA on rat neuronal and astroglial taurine transport was also obtained with the protein phosphatase inhibitor okadaic acid. This was not only the feature of rat cells since the same differential effects were obtained with human glioma GL15 and human neuroblastoma IMR32 cell lines. The results suggest that the neuronal and astroglial taurine transporter may be structurally different.
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PMID:Activation of protein kinase C down-regulates glial but not neuronal taurine uptake. 884 83

Phorbol esters such as 12-O-tetradeonyl phorbol-13 acetate (TPA) induce a time-dependent biphasic effect on protein kinase C (PKC)-mediated events by fostering translocation of cytosolic (latent) PKC to the plasma membrane (where it is activated). Continued treatment, however, depletes the cell's entire PKC complement and induces a functional stake of PKC inhibition. Previous studies from several laboratories have demonstrated that long-term TPA treatment, like treatment with PKC inhibitors, induces neuronal differentiation. Bryostatin-1 also induces translocation and overall downregulation of PKC following long-term treatment, yet, unlike TPA or PKC inhibitors, does not induce neuronal differentiation, promoting controversy regarding the role of PKC inhibition in neuronal differentiation. We demonstrate herein that, despite overall downregulation in human neuroblastoma cells, membrane-associated levels of one PKC isoform (PKC epsilon) are actually increased following long-term bryostatin-1 treatment. Since previous studies have implicated this PKC isoform in phosphorylation of the microtubule-associated protein tau and in neuritogenesis, we examined the consequences of long-term bryostatin treatment on these phenomena. Treatment with 25 n-100 M bryostatin-1 for 72 h increased tau phosphorylation and inhibited neuritogenesis. By contrast, treatment with either TPA or the PKC inhibitor staurosporine did not induce tau phosphorylation and induced neurite elaboration. Bryostatin-1 antagonized neurite induction by staurosporine. These findings provide additional evidence for a unique role of PKC epsilon in the regulation of tau phosphorylation and neuronal differentiation, and demonstrate that bryostatin-1 can function under certain conditions as a selective PKC epsilon activator even following long-term treatment.
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PMID:Selective activation by bryostatin-1 demonstrates unique roles for PKC epsilon in neurite extension and tau phosphorylation. 956 34

Dopamine D4 receptors (D4 receptors) mediate dopamine-stimulated, folate-dependent phospholipid methylation. To investigate possible regulation of this multi-step D4 receptor-mediated phospholipid methylation cycle by protein kinases, specific kinase activators and inhibitors were studied in SK-N-MC human neuroblastoma cells, using [14C] formate to label folate-derived single-carbon groups. Phorbol dibutyrate (PDB), an activator of protein kinase C, stimulated basal phospholipid methylation and also shifted the dose-response curve for dopamine-stimulated phospholipid methylation to the right by more than an order of magnitude. Calphostin C, an inhibitor of protein kinase C, had little effect on basal phospholipid methylation but significantly inhibited dopamine-stimulated phospholipid methylation and also blocked the stimulatory response to PDB. Chelerythrine, which inhibits protein kinase C and other kinases, strongly inhibited both basal and dopamine-stimulated phospholipid methylation. Forskolin, an activator of protein kinase A, inhibited basal and dopamine-stimulated phospholipid methylation, but only at high concentrations while Rp-cAMP, an inhibitor of protein kinase A, did not block this effect. Inhibition of protein kinase G produced a modest decrease in dopamine-stimulated phospholipid methylation, but neither sodium nitroprusside, which increases nitric oxide (NO) production and activates protein kinase G, nor the NO synthase inhibitor N-nitro-L-arginine had any effect on basal or dopamine-stimulated phospholipid methylation. These observations indicate that protein kinase C is an important regulator of basal and D4 receptor-mediated folate-dependent phospholipid methylation, whereas protein kinase A and protein kinase G have a lesser or minimal role.
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PMID:Protein kinase C regulates dopamine D4 receptor-mediated phospholipid methylation. 1155 58


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