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)

Pituitary adenylyl cyclase activating polypeptide (PACAP-27), forskoline and carbachol increased type A atrial natriuretic peptide receptor (NPR-A) density, as well as NPR-A mRNA level, in the human neuroblastoma NB-OK-1 cell line. TPA did not have any effect per se, but blunted the effect of PACAP-27 on both NPR-A density and NPR-A mRNA. The half-life of the NPR-A mRNA was not modified by any of the agents tested. Our data support an original transcriptional upregulation of human NPR-A in response to cAMP-induced agents, and in response to carbachol.
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PMID:Human A-type ANP receptor upregulation by PACAP and carbachol in neuroblastoma cells. 1041 13

Retinoids are involved in the regulation of development and differentiation in many tissues, including the nervous system, where they have been associated with some neurotransmitter systems. In the present study, we evaluated the effects of all-trans retinoic acid (RA) on the biosynthesis and secretion of neuropeptide Y (NPY), a widely expressed neuroregulatory peptide. The SH-SY5Y human neuroblastoma cell line has been used as the in vitro model system. Treatment with 10 microM RA induced a marked decrease in NPY gene expression after as little as 3-6 h of incubation and resulted in its almost complete suppression at 12-24 h and after a 6-day differentiating treatment. The NPY content in cell extracts and the NPY secreted and accumulated in the culture medium were also reduced by exposure to 10 microM RA at 12 and 24 h and at 6 days. Moreover, RA treatment for 6 days, but not for 24 h, resulted in a marked stimulation of proNPY processing to mature NPY. The presence of negative retinoic acid-response elements in the human NPY promoter (up to -1078 bp) was excluded by a computer search. When SH-SY5Y cells were treated simultaneously with 20 nM TPA and 10 microM RA for 24 h, the marked stimulatory effect of TPA alone was completely suppressed. These observations suggest that the expression of NPY in SH-SY5Y human neuroblastoma cells is negatively regulated by RA at the level of gene expression, probably by mechanisms involving the interaction of activated RARs with transcription factors (such as AP-1).
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PMID:Retinoic acid negatively regulates neuropeptide Y expression in human neuroblastoma cells. 1085 7

Regulation of phospholipase D (PLD) activity participating in signal transduction involves complex interactions with small G-proteins (ARF, Rho) and protein kinase C isoforms (PKCalpha). In SK-N-MC human neuroblastoma cells, phorbol ester (TPA) activation of PLD was enhanced by overexpressing myristoylated alanine-rich C kinase substrate (MARCKS). To study MARCKS interactions with PLD, we investigated PLD isoform expression and activation by TPA and GTPgammaS in intact and digitonin-permeabilized clones transfected with MARCKS (M22). PLD2 was in both cytosol and membrane fractions while PLD1 was primarily membrane-associated in both vector control and M22 cells; location or quantities were unaltered by TPA treatment. TPA-stimulated PLD activity was higher in both intact and digitonin-permeabilized M22 cells than in vector controls. In contrast, GTPgammaS-stimulated PLD activity was independent of MARCKS expression but was additive with MARCKS-PKC-dependent activation in permeabilized cells. Combinations of PKC inhibition and down-regulation in intact and permeabilized (with GTPgammaS present) cells indicated that a PKC-mediated phosphorylation event was necessary in intact cells without access to GTPgammaS, stimulation of PLD mediated by GTPgammaS was independent of PKC, and PLD activation by PKC in permeabilized cells was kinase-independent. Western blot analysis showed that MARCKS, PKCalpha, PLD1 and PLD2 were present in a detergent-insoluble fraction (DIF); GTPgammaS increased recovery of PLD2 in DIF. Disruption of cholesterol-rich DIFs with digitonin, cyclodextrin or filipin potentiated activation of PLD by TPA. Our studies suggest that activation of PLD by PKC requires MARCKS and can involve both phosphorylation-independent and -dependent processes. As PLD activation by GTPgammaS is PKC-MARCKS-independent, MARCKS may provide a fine tuning component in conjunction with G-protein-mediated mechanisms for regulation of PLD.
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PMID:Activation of phospholipase D by PKC and GTPgammaS in human neuroblastoma cells overexpressing MARCKS. 1101 70

The agonist stimulation of a variety of cells results in the induction of specific lipid metabolism in nuclear membranes, supporting the hypothesis of an important role of the lipids in nuclear signal transduction. While the existence of a phosphatidylinositol cycle has been reported in cellular nuclei, little attention has been given to the metabolism of phosphatidylcholine in nuclear signaling. In the present study the metabolism of phosphatidylcholine in the nuclei of neuroblastoma cells LA-N-1 was investigated. The incubation of LA-N-1 nuclei with radioactive choline, phosphocholine or CDP-choline led to the production of labelled phosphatidylcholine. The incorporation of choline and phosphocholine but not CDP-choline was enhanced in nuclei of TPA treated cells. Moreover the presence of choline kinase, phosphocholine cytidylyltransferase and phosphocholine transferase activities were detected in the nuclei and the TPA treatment of the cells stimulated the activity of the phosphocholine cytidylyltransferase. When cells prelabelled with [3H]palmitic acid were stimulated with TPA in the presence of ethanol, an increase of labelled diacylglycerol and phosphatidylethanol in the nuclei was observed. Similarly, an increase of labelled diacylglycerol and phosphatidic acid but not of phosphatidylethanol occurred in [3H]palmitic acid prelabelled nuclei stimulated with TPA in the presence of ethanol. However the production of phosphatidylethanol was observed when the nuclei were treated with TPA in the presence of ATP and GTPgammaS. The stimulation of [3H]choline prelabelled nuclei with TPA also generated the release of free choline and phosphocholine. The results indicate the presence of PLD and probably PLC activities in LA-N-1 nuclei and the involvement of phosphatidylcholine in the production of nuclear lipid second messengers upon TPA stimulation of LA-N-1 cells. The correlation of the disappearance of phosphatidylcholine, the production of diacylglycerol and phosphatidic acid with the stimulation of phosphatidylcholine synthesis in nuclei of TPA treated LA-N-1 suggests the existence of a phosphatidylcholine cycle in these nuclei.
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PMID:Phosphatidylcholine metabolism in nuclei of phorbol ester-activated LA-N-1 neuroblastoma cells. 1105 44

The aim of this study was to obtain further understanding of the mechanism by which activation of muscarinic M(1) receptors inhibits K(+)-evoked noradrenaline (NA) release in the human neuroblastoma SH-SY5Y. Previous studies have found that muscarinic M(1) and M(3) receptors couple to the activation of phospholipase C in SH-SY5Y cells leading to an increase in (a) intracellular calcium ([Ca(2+)](i)) and (b) activation of protein kinase C (PKC). This study used specific inhibitors of PKC and conditions which deplete Ca(2+)(i) stores to examine the role of protein kinase C and changes in [Ca(2+)](i) in mediating the inhibition of K(+)-evoked NA release by muscarine. Our data show that pretreatment of SH-SY5Y cell layers with bisindolylmaleimide I (BIM-I) (i) failed to reverse inhibition of K(+)-evoked NA release by muscarine but (ii) did overcome the attenuation of muscarine inhibition following pretreatment with TPA. Furthermore pretreating cell layers with Ca(2+)-free Hepes buffered saline in the presence of thapsigargin, conditions which prevented muscarine induced increases in [Ca(2+)](i), failed to prevent inhibition of K(+)-evoked NA release by muscarine. The effect of muscarine on K(+)-evoked uptake of Ca(2+)(e) was examined in SH-SY5Y cells loaded with Fura-2. Muscarine inhibited Ca(2+)(e)-uptake by decreasing the rate at which Ca(2+) entered SH-SY5Y cells via voltage sensitive Ca(2+)-channels. Thus this study shows that muscarine inhibits depolarisation-evoked NA release by a mechanism which is not dependent on activation of PKC or release of Ca(2+) from internal stores.
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PMID:Inhibition of depolarisation-evoked [(3)H]noradrenaline release from SH-SYFY human neuroblastoma cells by muscarinic (M1) receptors is not mediated by changes in [Ca(2+)]. 1122 62

SH-SY5Y neuroblastoma cells are a well-characterized model for studying the induction of neuronal differentiation. TPA treatment of these cells induces cytoskeletal rearrangements that ultimately result in neurite extension. However, the signaling pathways that precede these changes are poorly understood. Other investigators have shown that TPA treatment of SH-SY5Y cells results in increased tyrosine phosphorylation of cytoskeletal-associated proteins, including the adapter protein Cas. In this report, we examine the events upstream and downstream of Cas phosphorylation. We show that TPA treatment induces the PKC-dependent association of tyrosine-phosphorylated Cas with Crk. The activity of two protein tyrosine kinases, Src and FAK, was shown to be necessary and sufficient for TPA-induced Cas phosphorylation. We propose that the PKC-dependent phosphorylation of Cas by Src and FAK promotes the establishment of Cas-Crk complexes and that these interactions may play an important role in regulating the actin cytoskeleton during neuronal differentiation.
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PMID:PKC-dependent activation of FAK and src induces tyrosine phosphorylation of Cas and formation of Cas-Crk complexes. 1126 86

Neuropeptide Y (NPY) participates in the regulation of reproduction and food intake. The adipose-secreted hormone, leptin, has also been involved in these processes, and has been shown to exert its effects in part by controlling NPY synthesis and release at the hypothalamic level. In the present study, we utilized the SH-SY5Y human neuroblastoma cell line, to study the leptin-NPY interrelationships. SH-SY5Y cells were found to express leptin receptors (RT-PCR and Western blot analyses). A 24-h treatment with leptin at different concentrations did not affect NPY gene expression, but resulted in a stimulation of NPY release. This stimulated secretion was blocked by the combined treatment with leptin and the muscarinic agonist carbachol or the phorbol ester TPA. Leptin and carbachol also caused an increased intracellular content of NPY. In conclusion, the SH-SY5Y human neuroblastoma cell line appears to be a suitable in vitro model for studying the pharmacological effects of leptin on the biosynthesis and secretion of NPY.
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PMID:Control of the expression of human neuropeptide Y by leptin: in vitro studies. 1128 96

LMO4 is a transcription regulator interacting with proteins involved, among else, in tumorigenesis. Its function in the nervous system, and particularly in the adult nervous system, has however still to be elucidated. We decided to modify its expression in a neuronal model, human SH-SY5Y neuroblastoma cells, by permanent transfection of sense or anti-sense Lmo4 cDNAs. Generated clones overexpressing the Lmo4 transcript in sense orientation tended to aggregate. They showed significantly reduced average number of neurites per cell and average neuritic length per cell. The opposite was observed with clones overexpressing the anti-sense Lmo4 transcript. Furthermore, selected clones were subjected to 72 h long-term treatments with retinoic acid and phorbol ester (TPA), two biochemicals known to stimulate differentiation of non-transfected SH-SY5Y cells and other neuroblastoma cells. Neuritogenesis occurred after retinoic acid stimulation in all cases. The inhibitory effect of sense Lmo4 RNA overexpression on neuritic outgrowth was indeed prevented. The protein kinase C activator TPA could not induce neuritogenesis in SH-SY5Y cells overexpressing sense Lmo4 RNA. Thus, sense Lmo4 RNA overexpression, not Lmo4 endogenous transcription, overrides the stimulatory effect of TPA upon neuritic outgrowth. We also showed that Lmo4-dependent neuritic retraction and outgrowth correspond to altered phosphorylation of cytoskeletal proteins. Overall, Lmo4 RNA overexpression interferes with neuritic outgrowth, whereas anti-sense Lmo4 RNA expression favors neuritogenesis in SH-SY5Y cells. Consequently, changes in Lmo4 RNA expression levels might alter the rate of neuritic outgrowth in the developing and adult nervous system.
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PMID:Transcription regulator LMO4 interferes with neuritogenesis in human SH-SY5Y neuroblastoma cells. 1287 80

Human neuroblastoma SH-SY5Y cells stably transfected with both wild-type and exon-9 deleted (deltaE9) presenilin constructs were used to study the role of the presenilin proteins during differentiation. Cells transfected with either wild-type or deltaE9 PS1, of which the latter abolishes normal endoproteolytic cleavage of the protein, showed no obvious differences in their ability to differentiate to a neuronal-like phenotype upon treatment with retinoic acid (RA). A defined pattern of PS1 expression was observed during differentiation with both RA and the phorbol ester TPA. Full-length PS1 was shown to increase dramatically within 5-24 h of RA treatment. TPA gave an earlier and longer lasting increase in full-length PS1 levels. The intracellular distribution pattern of PS1 was markedly altered following RA treatment. Within 24h PS1 was highly up-regulated throughout the cell body around the nucleus. Between 2 and 4 weeks PS1 staining appeared punctate and also localised to the nucleus. Increases in PS1 expression upon treatment with RA and TPA were blocked by treatment with cycloheximide, indicating a role of de-novo protein synthesis in this effect. PS2 expression remained unchanged during differentiation. Levels of full-length PS1 were also seen to increase during neurogenesis and neuronal differentiation in the forebrain of first trimester human foetuses between 6.5 and 11 weeks. These combined observations support the idea that PS1 is involved in neuronal differentiation by a mechanism likely independent of endoproteolysis of the protein.
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PMID:Presenilin expression during induced differentiation of the human neuroblastoma SH-SY5Y cell line. 1520 17

Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.
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PMID:Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds. 1580 99


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