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)

Inositol phospholipid turnover is part of a signal transduction mechanism which mobilize intracellular calcium and activate a calcium- and phospholipid-dependent protein kinase, protein kinase C. Phosphatidylinositol turnover has recently been implicated in the regulation of cell proliferation and transformation. Its role in differentiation has now been investigated using LAN-1 cells, a human neuroblastoma cell line which can be induced to differentiate along the neuronal pathway by RA. Treatment of LAN-1 cells with RA was followed by a rapid decrease of inositol phospholipid metabolism, as determined by isotopic methodology employing myo-[1,2-3H] inositol or [1(3)-3H] glycerol. Analysis of labelled phosphatidylinositol metabolites from prelabelled cells indicated a rapid decrease of inositol (1,4,5)trisphosphate and (1,2)diacylglycerol within 1 min. of induction of LAN-1 cell differentiation. These findings suggest that inositol phospholipid-derived metabolites (i.e. diacylglycerol and inositol trisphosphate) may be part of the mechanism by which certain RA signals are transduced, playing a key role in control of neuroblastoma cell differentiation.
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PMID:[A rapid decrease in the phosphatidylinositol cycle during neuroblastoma cell differentiation induced by retinoic acid]. 327 73

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

In the mouse neuroblastoma x dorsal root ganglion hybrid cell line F-11, bradykinin receptor stimulation induced the release of inositol-1,4,5-trisphosphate (IP3) and inositol-1,4-bisphosphate (IP2). Maximal stimulation of [2-3H]IP3 and [2-3H]IP2 release by bradykinin in the absence of LiCl occurred at 7 (or less) and 15 s, respectively, with average levels of 5.7-(IP3) and 3.4-(IP2) fold of control values. The EC50 for bradykinin was 33 +/- 5 nM. IP3 and IP2 concentrations returned to basal levels approximately 1 min after bradykinin addition. Bradykinin-induced IP3 release was blocked by several novel bradykinin analogues. In particular, [D-Arg0]-Hyp3-Thi5,8-[D-Phe7]-bradykinin [Hyp, hydroxyproline; Thi, beta-(2-thienyl)-L-alanine] blocked IP3 production in a dose-dependent fashion. Several of these analogues alone showed little or no agonist activity. The bradykinin receptor may be coupled to phospholipase C via a GTP-sensitive protein (Gi or Go), as preincubation for 18-20 h with pertussis toxin decreased IP3 concentrations by 45%. Bradykinin is also known to modulate the concentrations of other second messengers in neurons, increasing the concentrations of Ca2+, diacylglycerol (DG), and cyclic GMP and decreasing the concentration of cyclic AMP. These second messengers modulated bradykinin-dependent IP3 release to varying degrees. A23187, a Ca2+ ionophore, produced a 37% decrease in IP3 concentration. 12-O-Tetradecanoylphorbol-13-acetate, which mimics the effects of DG and activates protein kinase C, inhibited IP3 release by 80%. Dibutyryl cyclic GMP produced little or no inhibition of IP3. [D-Ala2,D-Leu5]Enkephalin (DADLE), an opioid peptide that decreases cyclic AMP concentrations, likewise had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of bradykinin-induced inositol trisphosphate release in a novel neuroblastoma x dorsal root ganglion sensory neuron cell line (F-11). 349 4

The nuclear protein kinase NI (NI kinase) was purified from NB-15 mouse neuroblastoma cells by phosphocellulose column and casein affinity column chromatography. The purified NI kinase exhibited (i) an apparent subunit molecular weight of about 37,000, (ii) autophosphorylation, and (iii) insensitivity to inhibition by heparin. When NI kinase was added to heat-treated neuroblastoma nuclei in the presence of [gamma-32P] ATP, two proteins with apparent subunit molecular weights of 11,000 and 10,000 were prominently phosphorylated. Other protein kinases tested including the nuclear protein kinase NII, Type I cAMP-dependent protein kinase, and protein kinase C did not catalyze the phosphorylation of these two proteins. The NI kinase-catalyzed phosphorylation of these two proteins was completely inhibited by 1 mM spermine. In contrast, 10 mM putrescine, 2 mM spermidine, 5 mM arginine, and 10 mM NH4Cl, had no inhibitory effect on this phosphorylation reaction. Our study also indicated that the phosphorylation of the 11,000- and 10,000-dalton proteins occurred in the nuclear matrix fraction but not in heterogeneous nuclear ribonucleoproteins, high mobility group proteins, or histone fractions. We have previously reported that spermine specifically inhibits the endogenous phosphorylation of an 11,000-dalton nuclear protein in various mammalian cell lines (Chen, K. Y., and Verma, R. (1984) Biochem. Biophys. Res. Commun. 118, 710-716). The present study suggests that the 11,000- and 10,000-dalton nuclear proteins may be native substrates of nuclear protein kinase NI and that their phosphorylation can be affected by physiological concentrations of spermine.
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PMID:Spermine inhibits the phosphorylation of the 11,000- and 10,000-dalton nuclear proteins catalyzed by nuclear protein kinase NI in NB-15 mouse neuroblastoma cells. 394 52

Neuronal nicotinic acetylcholine receptors are expressed on a variety of cells in the nervous system where they play key roles in synaptic transmission and information transfer. Little is known, however, about the molecular mechanisms that control their expression, distribution, and function during nervous system development. We have investigated the control of expression during differentiation of one class of acetylcholine receptors that bind alpha-bungarotoxin of human neuroblastoma cells. We report that induction of differentiation of SH-SY5Y, SK-n-SH or IMR-32 cells by the phorbol ester 12-O-tetradecanoyl phorbol 13-myristate (10 nM, TPA) or by retinoic acid resulted in as much as a 70% decline in alpha-bungarotoxin receptors on the cells. The response to the phorbol ester was blocked by the protein kinase C inhibitors staurosporine and bisindolylmaleimide. The decrease in receptors induced by 10 microM retinoic acid was not affected by either agent. However, responses to lower (10 nM) concentrations of retinoic acid were blocked by staurosporine but not bisindolylmaleimide, suggesting a dual mechanism of action for retinoic acid in regulating acetylcholine receptors. It appears that acetylcholine receptors on neuroblastoma cells are regulated during differentiation by both protein kinase C-dependent and -independent mechanisms.
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PMID:Regulation of nicotinic acetylcholine receptors on human neuroblastoma cells during differentiation. 750 70

Phorbolester-triggered differentiation of SH-SY5Y neuroblastoma cells requires serum and a prolonged activation of protein kinase C (PKC). Under serum-free conditions development of a mature phenotype requires phorbolester in combination with a member of either the insulin-like growth factor (IGF) or the platelet-derived growth factor family. Here we report that basic and acidic fibroblast growth factor (FGF) and epidermal growth factor, but not nerve growth factor, synergistically potentiate phorbolester-induced differentiation. Alone these factors induced a mitogenic response which varied in magnitude, with basic FGF and IGF-I being the two most potent mitogens. However, a combination of basic FGF and IGF-I induced differentiation as judged by morphology and the increase in growth associated protein (GAP-43) and neuropeptide tyrosine mRNA levels. In contrast to the phenotype obtained in the presence of phorbolester, bFGF and IGF-I-treated SH-SY5Y cells retained their capacity to proliferate. Finally, in these cells, the phosphorylation of the endogenous PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS), was slightly increased during several days, suggesting an involvement of PKC in the bFGF and IGF-I-induced differentiation.
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PMID:Basic FGF and IGF-I promote differentiation of human SH-SY5Y neuroblastoma cells in culture. 751 11

Cross-regulation from the stimulatory phospholipase C to the adenylyl cyclase pathways was explored in neuroblastoma-glioma NG-108-15 cells in culture. Activation of protein kinase C by phorbol myristic acid resulted in a markedly attenuated activation of the inhibitory adenylyl cyclase response to delta-opiate agonists and epinephrine but not to the muscarinic agonist carbachol. The ability of okadaic acid to mimic the effects of phorbol myristic acid on the inhibitory response suggested a role for protein phosphorylation. Adenylyl cyclase activity from cells in which protein kinase C had been activated demonstrated a loss in the inhibitory adenylyl cyclase response at the level of the G-protein. Activation of protein kinase C prompted a 2-4-fold increase in phosphorylation of G1 alpha 2 in cells metabolically labeled with [32P]orthophosphate. The phosphate content of Gi alpha 2 was determined to be approximately 0.5 mol/mol subunit in the unstimulated cells and approximately 1.5 mol/mol subunit for cells in which protein kinase C was activated. The effects of okadaic acid, 4-alpha-phorbol, and calphostin C on inhibition of adenylyl cyclase in cells treated with phorbol myristic acid correlate with the effects of these agents on phosphorylation of Gi alpha 2. The time courses for attenuation of inhibitory adenylyl cyclase and that for phosphorylation of Gi alpha 2 were similar in cells challenged with phorbol myristic acid. These data argue for cross-regulation from the stimulatory protein kinase C to inhibitory adenylyl cyclase pathways at the level of Gi alpha 2 via protein phosphorylation.
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PMID:Phosphorylation of Gi alpha 2 attenuates inhibitory adenylyl cyclase in neuroblastoma/glioma hybrid (NG-108-15) cells. 751 3

LAN-1 is a human neuroblastoma cell line that, in the undifferentiated state, does not respond to membrane depolarization with an elevation of [Ca2+]i, monitored by fura-2 single-cell microfluorimetry. The exposure of LAN-1 cells to the differentiating agent retinoic acid induced the appearance of [Ca2+]i elevation elicited by 55 mM K+. Maitotoxin, a putative activator of voltage-sensitive Ca2+ channels, did not evoke an elevation of [Ca2+]i in undifferentiated LAN-1 cells, but produced a marked and sustained increase in [Ca2+]i when superfused in retinoic acid-treated cells. Both high K(+)- and maitotoxin-induced [Ca2+]i elevation in retinoic acid-differentiated LAN-1 cells was reversed by the lanthanide Gd3+, an inorganic Ca(2+)-entry blocker, and by the snail toxin omega-conotoxin GVIA, which interacts with the N subtype of voltage-sensitive Ca2+ channels. In contrast, both Bay K 8644 and nimodipine, dihydropyridines that selectively activate or block, respectively, the L-channel subtype, were completely ineffective. The tumor promoter phorbol 12-myristate 13-acetate (100 nM), a protein kinase C activator, inhibited the elevation of [Ca2+]i due to Ca2+ influx elicited by membrane depolarization. K(+)-induced [Ca2+]i elevation appeared 24 h after the addition of retinoic acid and reached the highest magnitude after 72 h. Furthermore, 8 days after the removal of the differentiating agent from the culture medium, the high K(+)-induced increase of [Ca2+]i was still present.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Appearance of depolarization- and maitotoxin-induced [Ca2+]i elevation in single LAN-1 human neuroblastoma cells on exposure to retinoic acid. 752 2

In this study, we investigated the vasoactive intestinal polypeptide (VIP)-stimulated cAMP production and its interaction with protein kinase C activation and elevation of intracellular Ca2+ in N1E-115 neuroblastoma cells. VIP treatment caused a 55-fold increase in cAMP accumulation. Addition of 4 beta-phorbol 12-myristate 13-acetate reduced VIP- but not forskolin-stimulated cAMP response. In comparison, ionomycin potentiated both VIP- and forskolin-induced cAMP accumulation. Our results indicate that VIP stimulates cAMP accumulation in N1E-115 cells, and that although activation of protein kinase C inhibits the VIP-stimulated cAMP response, elevation of intracellular Ca2+ potentiates this signaling pathway.
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PMID:Vasoactive intestinal polypeptide stimulates cyclic AMP production in mouse N1E-115 neuroblastoma cells: modulation by a protein kinase C activator and ionomycin. 753 23

The effects of phorbol esters on Ca2+ channel currents in human neuroblastoma SH-SY5Y cells were studied using whole-cell patch-clamp recordings. Bath application of 12-O-tetradecanoylphorbol-13-acetate (TPA) or phorbol 12,13-dibutyrate (PDBu; 100 nM to 1 microM), known activators of protein kinase C (PKC), enhanced Ca2+ channel currents in a voltage-dependent manner similar to that of Bay K 8644. TPA also enhanced Ca2+ channel currents during cell dialysis with the PKC pseudosubstrate, PKC(19-36), and in cells which had been pre-incubated with 500 nM staurosporine, and which were exposed to staurosporine during recordings. Application of 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD; 100 nM), which does not activate PKC, caused current enhancement similar to the effects of TPA. However, intracellular dialysis of TPA was without effect on Ca2+ channel currents. Residual Ca2+ channel currents recorded after exposure to 1 microM omega-conotoxin GVIA were still enhanced by TPA, but in the presence of either Bay K 8644 (5 microM) or nifedipine (5 microM), TPA was without effect. When cells were pre-incubated for 10 min at 37 degrees C with 100 nM TPA, currents subsequently recorded in its absence were enhanced as compared to untreated cells; 5 microM nifedipine still inhibited currents to the same degree. This enhancement was not mimicked by 4 alpha-PDD, and was inhibited by staurosporine. Our results indicate that acute applications of phorbol esters (at concentrations commonly used to activate PKC) enhance L-type Ca2+ channel currents in SH-SY5Y cells via a PKC-independent mechanism which appears similar to that induced by Bay K 8644. By contrast, pre-incubation with TPA enhances both L- and N-type currents via activation of PKC.
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PMID:Enhancement of Ca2+ channel currents in human neuroblastoma (SH-SY5Y) cells by phorbol esters with and without activation of protein kinase C. 754 Jul 48


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