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)

The actions of basic fibroblast growth factor (bFGF) and ciliary neurotrophic factor (CNTF) on tyrosine hydroxylase (TH) gene expression were studied using IMR-32 neuroblastoma cells. Treatment of these cells with bFGF for 3 days induced the expression of detectable levels of immunoreactive TH protein and TH mRNA. In contrast, CNTF did not affect TH expression unless bFGF was present. In the presence of saturating amounts of bFGF, CNTF increased TH protein and mRNA levels of TH two-to threefold over those found in bFGF-treated cultures. The effects of CNTF on TH expression diminished with increasing culture time, and after 6 days of incubation CNTF no longer enhanced TH levels. The requirement for bFGF as cofactor in the effects of CNTF on TH was specific, as CNTF did not affect TH when it was coadministered with 8-(4-chlorophenylthio)-cyclic AMP, another agent that stimulates TH development in this cell line, and bFGF was not required for CNTF to stimulate the development of choline acetyltransferase. Moreover, cotreatment with bFGF reduced the ability of CNTF to enhance choline acetyltransferase. These results demonstrate that bFGF and CNTF can enhance expression of TH and that bFGF can modify the effects of CNTF on neurotransmitter phenotype.
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PMID:Regulation of tyrosine hydroxylase gene expression in IMR-32 neuroblastoma cells by basic fibroblast growth factor and ciliary neurotrophic factor. 776 21

Prosaposin, recently identified as a neurotrophic factor (1), is the precursor of saposins A, B, C, and D. The neurotrophic activity of prosaposin resides in the saposin C domain. We have pinpointed the active sequence to a linear 12-mer located in the NH2-terminal sequence of saposin C (LIDNNKTEKEIL). Nanomolar concentrations of a 22-mer peptide encompassing this region stimulated neurite outgrowth and choline acetyltransferase activity, and prevented cell death in neuroblastoma cells. In primary cerebellar granule cells, the 22-mer also stimulated neurite outgroth. Studies of the neuroblastoma line NS20Y using a radiolabeled 18-mer from the neurotrophic region identified a high-affinity (Kd = 70 pM) binding site indicative of receptor-ligand interaction. The 22-mer stimulated protein phosphorylation of several proteins, some of which were tyrosine-phosphorylated after brief exposure similar to saposin C. Circular dichroism studies demonstrated that the 22-mer was converted from a random to a helical structure by addition of ganglioside GM1. The results are consistent with receptor-ligand binding by the peptide initiating a signal transduction cascade and resulting in neuronal differentiation.
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PMID:Identification of the neurotrophic factor sequence of prosaposin. 776 61

Neuroblastoma (clones NS-20Y, N1E-115, and Neuro2A) and neuroblastoma x glioma hybrid (NG108-15) cells were transfected with mouse choline acetyltransferase (ChAT) complementary DNA (cDNA) or vector DNA alone and stably transformed cell lines were established to examine their ability to secrete acetylcholine (ACh). Membrane potentials were recorded from either presynaptic neuroblastoma and hybrid cells or postsynaptic myotubes in co-culture. After transformation with ChAT, synapses were formed and miniature end-plate potentials (MEPPs) were recorded in myotubes co-cultured with Neuro2A and N1E-115 cells, while parental and mock-transfected control cells totally lacked this ability. The rate of synapse formation and/or MEPP frequency was higher in transformed NG108-15 hybrid and NS-20Y cells than that in the control cells. Action potentials of NS-20Y, Neuro2A or NG108-15 cells overexpressing ChAT were able to evoke end-plate potentials in myotubes, though the average quantum content of these cells was 0.04-0.14, which is as low as the control value. The results show that increased concentrations of ACh by ChAT cDNA transfection reveal a masked property in vesicular ACh release from Neuro2A and N1E-115 cells with no endogenous ChAT activity, or modify their secretory capacity upwardly from NG108-15 and NS-20Y cells with endogenous activity.
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PMID:Discrete acetylcholine release from neuroblastoma or hybrid cells overexpressing choline acetyltransferase into the neuromuscular synaptic cleft. 779 84

Immortalized hybrid cells were generated by somatic cell fusion of 18-d-old embryonic corpus striatum of the mouse strain C57BL/6J with the N18TG2 neuroblastoma. One of the cell populations obtained was treated with a combination of 1 mM n-butyric acid and 10 microM SKF 38393 (a specific D1 agonist), and a surviving cell population (E1X) was subcloned. Twenty-seven monoclonal cell lines were obtained and screened for the expression of striatal-specific characteristics including gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), acetylcholine (ACh), mRNA for specific dopamine receptors, and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein, M(r) 32,000 (DARPP-32), and functional D1 and D2 dopamine receptors. Neither the parent hybrid cell population (E1X) nor any of the monoclonal cell lines examined expressed GABA levels significantly different than that of the N18TG2 parent neuroblastoma cells (1.36 +/- 0.07 micrograms/mg protein). The range of ChAT activity in the monoclonal hybrid cell lines was 5.5 +/- 0.3 to 921.3 +/- 97.4 pmol/min/mg protein. Two of the cell lines expressing ChAT activity (X52 and X58) contained ACh (49.64 +/- 4.23 and 1.78 +/- 0.07 ng/mg protein, respectively). The neuronal origin of four of the monoclonal hybrid lines was shown by their immunoreactivity, following differentiation with 10 microM forskolin, to neurofilament protein, a neuron-specific marker. The monoclonal hybrid cell lines, but not the N18TG2 neuroblastoma, were shown to express an array of D1, D2, and D5 receptor mRNA as well as DARPP-32 mRNA. Two monoclonal cell lines expressed D1 receptor binding sites (X57, 29.2 +/- 4.5 fmol/mg protein and X62, 43.8 +/- 6.8 fmol/mg protein) which mediated the stimulation of adenylate cyclase activity. One cell line, X58, expressed only D2 dopamine receptors (80.9 +/- 9.8 fmol/mg protein) which were negatively coupled to adenylate cyclase activity. These findings suggest that the immortalized monoclonal hybrid cell lines are of neuronal origin and have incorporated elements of the medium spiny and cholinergic neurons of the developing striatum.
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PMID:Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties. 782 71

The promoter regions of human choline acetyltransferase (ChAT) and aromatic L-amino acid decarboxylase (AADC) genes have been analyzed by transient transfection assays. AADC gene is transcribed from two alternative noncoding first exons, 1N and 1NN, expressed in pheochomocytoma and hepatoma cells, respectively. 5' flanking sequences of exon 1 N (from 9000 to 147 bp) display promoter activity in SK-N-BE neuroblastoma cells, but not in MC-I-XC cholinergic neuroepithelioma cells, and in AADC-rich non-neuronal cells. On the contrary, 5' flanking sequences of exon 1 NN (from 1117 to 119 bp) display high promoter activity in human hepatoma cells HepG2, but not in SK-N-BE cells, suggesting high degrees of specificity of promoters N and NN for AADC-expressing neuronal and non-neuronal cells, respectively. Preliminary evidence suggests that leukemia inhibitory factor suppresses the activity of the neuronal promoter in cultured sympathetic neurons. Two alternative first exons, R and M, have been localized in human ChAT gene, and the corresponding promoters characterized in cholinergic PC12 and NG-108-15 cells, and in non-cholinergic neuro2A cells. Several positively or negatively acting cis elements have been localized in the two promoters, as well as a cAMP-inducible, enhancer-like element in the second intron. Among the various cell lines studied, there was no correlation between promoter activities and the expression of the endogenous ChAT gene, suggesting that the fine-tuning of ChAT gene expression is controlled by silencer elements which remain to be localized.
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PMID:Multiple promoters of human choline acetyltransferase and aromatic L-amino acid decarboxylase genes. 787 82

In the human neuroblastoma cell line LA-N-2, recombinant rat ciliary neurotrophic factor (CNTF) induced neurite growth and cholinergic differentiation that were both half-maximally saturated at < 100 pM of the neurokine, but was not required for cell survival in serum-free conditions over a 13-day period. CNTF markedly stimulated choline acetyltransferase activity and acetylcholine synthesis, whereas high-affinity choline transport was only slightly enhanced and acetylcholinesterase activity was unchanged. Leukemia inhibitory factor had effects identical to CNTF on neurite growth and choline acetyltransferase activity, but interleukin 6 had no effect. Radioiodinated CNTF binding and affinity cross-linking studies were consistent with tripartite receptor activation as a mediator of the observed biological effects.
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PMID:Differentiation effects of ciliary neurotrophic factor on human neuroblastoma cells. 789 Oct 74

Retinoids are chemical compounds which play important roles in ontogenetic development and cranio-caudal differentiation in animals, but their effect on phenotypic expression of neurotransmitters are unknown. We studied the pharmacological and morphological effects of retinoic acid (RA) on two types of immature vertebrate neurons, the human derived neuroblastoma cells, NB69, and fetal rat mid brain neurons in culture. The pharmacological effects of RA on the cultures and their relation to catecholamine and acetylcholine neurotransmission were evaluated according the levels of catecholamines, tyrosine hydroxylase (TH) activity, TH immunostaining, and choline acetyltransferase (CAT) activity, respectively. RA reduces catecholamine levels and TH activity in NB69 cells and the number of dopamine neurons in cultures derived from rat fetal mid brain. The detrimental effect of RA on mid brain neurons is dose- dependent; limited to TH+ cells at low concentrations (100 to 500 nM) and toxic for all types of cells at high concentrations (1 to 2 microM). RA increases CAT activity in NB 69 cells and produces phenotypic differentiation of these to a more mature neuronal phenotype with more prolonged neurite extensions. Therefore, RA may play a trophic positive role in the differentiation of immature cells to cholinergic neurons; this contrasts with the detrimental effects of RA on catecholamine neurons.
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PMID:Effects of retinoic acid on NB 69 human neuroblastoma cells and fetal rat mid brain neurons. 789 79

Our laboratory has recently been involved in investigating factors which influence plasticity of neurotransmitter phenotypic expression both in vivo and in culture. Our previous studies have shown that precursor neuroblasts are pluripotential with respect to neurotransmitter phenotype and respond differentially to microenvironmental signals. In the present study, we examined phenotypic expression in neuroblastoma cells, P2 clone, using the activities of choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH) as neuronal markers for the cholinergic and catecholaminergic phenotypes, respectively. Cells were plated and grown for 4 days in culture, harvested and frozen for assay of ChAT and TH. Basal activity of ChAT was 2.47 +/- 0.22 nmoles Ach formed /h/mg protein and that of TH was 5.23 +/- 0.41 pmoles CO2 formed /h/mg protein in control cultures. When intracellular cAMP levels were increased by addition to the growth medium of 10 micrograms/ml prostaglandin E1 (PGE1; a receptor-mediated enhancer of adenylate cyclase activity) or 200 micrograms/ml RO20-1724 (an inhibitor of cyclic nucleotide phosphodiesterase) the activity of TH was increased 340- and 423-fold, respectively. In marked contrast, the activity of ChAT was not affected by either agent. Double staining immunocytochemical examination demonstrated that both ChAT and TH were colocalized in the same cell. The molecular mechanism whereby catecholaminergic expression exclusively is affected in this cell model is currently under investigation. We conclude that (1) P2 neuroblastoma is a pluripotential cell line, (2) phenotypic expression in a homogenous cell population, such as P2 neuroblastoma, is differentially regulated. Moreover, this cell line is a unique model for studying the molecular mechanisms of phenotypic expression and neuronal plasticity.
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PMID:Differential regulation of phenotypic expression in a pluripotential neuroblastoma cell line. 792 54

Prosaposin was identified as a neurotrophic factor stimulating neurite outgrowth in murine neuroblastoma (NS20Y) cells and choline acetyltransferase (ChAT) activity in human neuroblastoma (SK-N-MC) cells. The four naturally occurring saposins, which are derived by proteolytic processing of prosaposin, were tested for activity. Saposin C was found to be active, whereas saposins A, B, and D were inactive as neurotrophic factors. Dose-response curves demonstrated that nanomolar concentrations of prosaposin and saposin C stimulated neurite outgrowth and increased ChAT activity. Prosaposin and saposin C exerted activity by a mechanism independent of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Binding assays utilizing saposin C as a ligand gave two saturable binding constants, a high-affinity (Kd = 19 pM) and a low-affinity (Kd = 1 nM) constant, with 2000 and 15,000 sites per NS20Y cell, respectively. Phosphorylation stimulation experiments demonstrated that brief treatment with prosaposin or saposin C enhanced phosphorylation of a variety of proteins, some of which contained phosphorylated tyrosine(s). Since both cell lines were also stimulated by ciliary neurotrophic factor (CNTF) as well as prosaposin, inhibition was tested by utilizing an anti-gp130 monoclonal antibody, which specifically inhibited CNTF stimulation; this antibody did not inhibit prosaposin or saposin C stimulation. These results indicate that prosaposin and saposin C are neurotrophic factors which initiate signal transduction by binding to a high-affinity receptor that induces protein phosphorylation.
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PMID:Identification of prosaposin as a neurotrophic factor. 793 12

This study used reporter gene constructs containing regulatory regions of the c-fos, vasoactive intestinal peptide, and choline acetyltransferase genes to determine the role of p21ras and protein kinase C in the action of ciliary neurotrophic factor and leukemia inhibitory factor. Down-regulation of protein kinase C with phorbol ester did not affect the induction of either c-fos-beta-galactosidase or vasoactive intestinal peptide-luciferase by ciliary neurotrophic factor or leukemia inhibitory factor. In contrast, while leukemia inhibitory factor induction of choline acetyltransferase-luciferase expression was protein kinase C-independent, there appears to be both protein kinase C-dependent and -independent pathways for induction of choline acetyltransferase-luciferase by ciliary neurotrophic factor. Cotransfection of a dominant-negative mutant p21rasN17 blocked nerve growth factor-mediated induction of c-fos-beta-galactosidase, but did not affect induction of c-fos-beta-galactosidase, vasoactive intestinal peptide-luciferase, or choline acetyltransferase-luciferase by either ciliary neurotrophic factor or leukemia inhibitory factor. Thus, in contrast to the action of nerve growth factor, gene induction by ciliary neurotrophic factor, and leukemia inhibitory factor is ras-independent in IMR-32 neuroblastoma cells.
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PMID:Differential requirements for p21ras and protein kinase C in the regulation of neuronal gene expression by nerve growth factor and neurokines. 803 40


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