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)

We previously showed that ethanol regulates dopamine beta-hydroxylase (DBH) mRNA and protein levels in human neuroblastoma cells (Thibault, C., Lai, C., Wilke, N., Duong, B., Olive, M. F., Rahman, S., Dong, H., Hodge, C. W., Lockhart, D. J., and Miles, M. F. (2000) Mol. Pharmacol. 58, 1593-1600). DBH catalyzes norepinephrine synthesis, and several studies have suggested a role for norepinephrine in ethanol-mediated behaviors. Here, we performed a detailed analysis of mechanism(s) underlying ethanol regulation of DBH expression in SH-SY5Y cells. Transient transfection analysis showed that ethanol (25-200 mM) caused concentration- and time-dependent increases in DBH gene transcription. Progressive deletions identified ethanol-responsive sequences in the -262 to -142 bp region of the DBH gene promoter. Mutagenesis of cAMP-response element (CRE) sequences in this region abolished ethanol responsiveness while maintaining responsiveness to phorbol esters. Coexpression of dominant-negative CRE-binding protein greatly reduced ethanol induction of DBH. Inhibitors of protein kinase A, casein kinase II, and MAPK reduced ethanol induction of DBH promoter activity. Pharmacogenomic studies with microarrays showed that protein kinase A, MEK, and casein kinase II inhibitors blocked induction of DBH and a large subset of ethanol-responsive genes. These genes had diverse functional groupings, including multiple members of the MAPK and phosphatidylinositol signaling cascades. Real-time PCR analysis validated select microarray results. Taken together, these results suggest that ethanol regulation of DBH requires a functional CRE and its binding protein and may require interaction of multiple kinase pathways. This mechanism may also mediate ethanol responsiveness of a complex subset of genes in neural cells. These studies may have implications for behavioral responses to ethanol or mechanisms underlying ethanol-related neurological disease.
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PMID:Pharmacogenomic analysis of mechanisms mediating ethanol regulation of dopamine beta-hydroxylase. 1284 74

The cholinergic differentiation factor ciliary neurotrophic factor (CNTF) suppresses noradrenergic properties while inducing cholinergic and peptidergic properties in sympathetic neurons. In the rat, this includes suppression of the noradrenergic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase. Lower enzyme levels result in part from suppression of gene transcription, but the mechanisms are unknown. We found that ciliary neurotrophic factor decreased the transcriptional activator Phox2a in neuroblastoma cells and cultured sympathetic neurons, suggesting that the loss of Phox2a is part of the mechanism by which CNTF suppresses tyrosine hydroxylase and dopamine beta-hydroxylase. Consistent with this model, Phox2a is suppressed in rat cholinergic sympathetic neurons where noradrenergic enzymes decrease, but is not altered in mouse cholinergic neurons where these enzymes remain high.
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PMID:Ciliary neurotrophic factor suppresses Phox2a in sympathetic neurons. 1510 27

The gene expression profiles of human postmortem parietal and prefrontal cortex samples of normal controls and patients with bipolar disease, or human neuroblastoma flat (NBFL) cells treated with the mood-stabilizing drug, valproate, were used to compare the performance of Affymetrix oligonucleotide U133A GeneChips and Agilent Human 1 cDNA microarrays. Among those genes represented on both platforms, the oligo array identified 26-53% more differentially expressed genes compared to the cDNA array in the three experiments, when identical fold change and t-test criteria were applied. The increased sensitivity was primarily the result of more robust fold changes measured by the oligonucleotide system. Essentially all gene changes overlapping between the two platforms were co-directional, and ranged from 4 to 19% depending upon the amount of biological variability within and between the comparison groups. Q-PCR validation rates were virtually identical for the two platforms, with 23-24% validation in the prefrontal cortex experiment, and 56% for both platforms in the cell culture experiment. Validated genes included dopa decarboxylase, dopamine beta-hydroxylase, and dihydropyrimidinase-related protein 3, which were decreased in NBFL cells exposed to valproate, and spinocerebellar ataxia 7, which was increased in bipolar disease. The modest overlap but similar validation rates show that each microarray system identifies a unique set of differentially expressed genes, and thus the greatest information is obtained from the use of both platforms.
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PMID:Comparison of microarray-based mRNA profiling technologies for identification of psychiatric disease and drug signatures. 1532 26

The homeodomain protein Arix/Phox2a plays a role in the development and maintenance of the noradrenergic cell type by regulating the transcription of genes involved in the biosynthesis and metabolism of noradrenaline. Previous work has shown that Arix/Phox2a is a phosphoprotein, and the phosphorylated form of Arix/Phox2a exhibits poorer DNA-binding activity than does the dephosphorylated form. Here, we demonstrate that Arix/Phox2a is phosphorylated by extracellular signal-related kinase (ERK)1/2 at two sites within the N-terminal transactivation domain. The phosphorylation level of Arix in cultured SH-SY5Y neuroblastoma cells is reduced when cells are treated with the mitogen activated protein kinase kinase 1 (MEK1) inhibitor UO126. Treatment of sympathetic neurons with the MEK1 inhibitor, PD98059, results in an elevation of mRNAs encoding noradrenergic proteins, dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET), but not tyrosine hydroyxlase (TH). Treatment of neuroblastoma cultures with PD98059 increases the interaction of Arix with DBH and NET genes, but not the TH gene. Together, these results suggest that phosphorylation of Arix by ERK1/2 inhibits its ability to interact with target genes, and that both specificity of expression and modulation by external stimuli are monitored through the same transcription factor.
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PMID:ERK1/2 is a negative regulator of homeodomain protein Arix/Phox2a. 1615 42

The noradrenergic cell type is characterized by the expression of proteins involved in the biosynthesis, transport, and secretion of noradrenaline and is dependent on the sequential and combinatorial expression of numerous transcription factors, including Phox2a, Phox2b, dHAND, GATA2, GATA3, and MASH1. Phox2a and Phox2b transactivate the promoter of the gene encoding the noradrenergic biosynthetic enzyme, dopamine beta-hydroxylase (DBH), and dHAND potentiates the activity of Phox2a. In this study, we use chromatin immunoprecipitation assays to identify target genes of the Phox2 proteins and dHAND. All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells. The interaction between Phox2a and dHAND is analyzed by fluorescent anisotropy, which demonstrates that dHAND causes an eightfold increase in the affinity of Phox2a for its recognition sites on the DBH promoter region. The Phox2 proteins are not found on the genes encoding other noradrenergic enzymatic or transport proteins but are reciprocally bound to each other's promoters in SH-SY5Y cells. Together with Phox2a and Phox2b, dHAND is bound to the PHOX2B promoter and is also associated with the GATA2 and eHAND genes in the absence of the Phox2 proteins. These results demonstrate the direct interactions of the Phox2 and dHAND transcription factors within a noradrenergic cell type. The Phox2 proteins were found to share all target genes, whereas dHAND binds to genes independently of Phox2a.
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PMID:Phox2 and dHAND transcription factors select shared and unique target genes in the noradrenergic cell type. 1628 May 98

Classically, upon hypothalamic stimulation, adrenocorticotropic hormone (ACTH) is released from the pituitary and acts on melanocortin 2 receptors (MC2R) in the adrenal cortex, stimulating glucocorticoid synthesis and release. Our earlier studies suggested that ACTH might have a direct effect on sympathetic ganglia. To analyze further the involvement of ACTH in regulation of gene expression of norepinephrine (NE) biosynthetic enzymes, we examined the effect of bilateral adrenalectomy (ADX) of Sprague-Dawley male rats. Fourteen days post-ADX, as expected, plasma ACTH was elevated, and levels of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and MC2R mRNAs in superior cervical ganglia (SCG), and TH mRNA in locus coeruleus (LC) were increased compared with sham-operated animals. To determine effect of pulsatile elevation of ACTH, corticosterone pellets were implanted to ADX rats. Similar to immobilization (IMO) stress ACTH injections to these animals caused a rise in ACTH in plasma and triggered elevation of TH and DBH mRNAs in SCG and in LC with single and repeated daily injections, and MC2R mRNA in SCG with single injections. To study the effect of ACTH in isolated cells, primary cultures of rat SCG were transfected with TH and DBH promoter constructs and treated with ACTH. In agreement with the in vivo data, ACTH elevated their promoter activities similar to levels triggered by cyclic AMP analog. ACTH in the human SK-N-SH neuroblastoma cells increased TH and DBH promoter activity and endogenous DBH mRNA levels. The results show that ACTH can have a direct effect on transcription and gene expression of NE biosynthetic enzymes even without contribution of adrenal hormones.
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PMID:Adrenocorticotropic hormone elevates gene expression for catecholamine biosynthesis in rat superior cervical ganglia and locus coeruleus by an adrenal independent mechanism. 1844 Jul 7

Activin A is a multifunctional homo-dimeric protein that belongs to the transforming growth factor (TGF)-beta superfamily. In neurons, activin has neuroprotective effects both in vitro and in vivo, but it inhibits neuronal differentiation in some cell lines. Here we report that activin A can promote neuronal differentiation in particular cases. We examined activin A-induced neuronal differentiation and survival in a selected subpopulation of a human neuroblastoma cell line, SK-N-SH, grown in low-serum (differentiation-inducing) conditions. Activin A caused dramatic neurite outgrowth, and increased the expression of neuronal markers and the transactivation of dopamine beta-hydroxylase. We demonstrated that the activin A signal is transduced through the activin A type 1 receptor, ALK4, and transactivates several TGF-beta target genes in a SMAD-independent manner. That is, activin A did not induce the phosphorylation of SMAD2/3, the interaction of SMAD2/3 with SMAD4, the binding of SMAD2/3 to the promoter of TGF-beta target genes, or the accumulation of SMAD2/3 in the nucleus. These results suggest that, in particular cases, activin A can induce neuronal differentiation and support neuronal survival in vitro. These findings may reflect previously unknown functions of activin A in neuronal cells in vivo.
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PMID:Activin A induces neuronal differentiation and survival via ALK4 in a SMAD-independent manner in a subpopulation of human neuroblastomas. 2022 72

BL191, a newly developed phosphodiesterase inhibitor, markedly potentiated a differentiation of neuroblastoma cell clones (Neuro2a, NS-20Y, and N1E115) induced by dibutyryl cyclic adensoine 3?:5?-monophosphate(dibutyryl cAMP) and prostaglandin E(1) (PGE(1)). BL191 (1 mM) inhibited DNA synthesis more strongly when used together with PGE(1) (0.5 ?g/ml) and dibutyryl cAMP (0.5 mM) than papaverine (1.6 ?g/ml) alone did. The inhibition rates of DNA synthesis were 72.5% for N1E-115, 75.3% for Neuro2a, and 82.5% for NS-20Y. After the treatment with BL191. PGE(1), and dibutyryl cAMP for 48 h all of three cell lines became enlarged and flattened, and extended long processes. The specific activities of choline acetyl transferase (EC 2.3.1.9) of NS-20Y and dopamine ?-hydroxylase (EC 1.14.17.1) of N1E-115 increased about 3-fold as compared to the controls. The tumorigenicities of Neuro2a and N1E-115 cells were decreased, but not of NS-20Y. These data suggest the heterogenous responsiveness in neuroblastoma cells to drug treatment.
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PMID:Potentiation by BL191 of differentiation of neuroblastoma cells induced by dibutyryl cAMP and prostaglandin E(1). 2048 96

Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies. However, little is known about any effects of these drugs on the central nervous system. The aim of the present study was to analyze the effects of trichostatin A (TSA)--a broad-spectrum histone deacetylase inhibitor--on the transcriptional regulation of several genes involved in dopamine- and serotonergic neurotransmission. To this end, short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with TSA either alone or in combination with hypoxia, and mRNA levels of dopamine receptor D3 (DRD3) and D4 (DRD4), dopamine transporter (DAT), dopamine hydroxylase (DBH), dopamine receptor regulating factor (DRRF), catechol-O-methyltransferase (COMT), serotonin receptor 1A (HTR1A), monoamino oxidase A (MAO-A), serotonin transporter (SLC6A4) and tryptophan hydroxylase 2 (TPH2) were determined by quantitative PCR. We found that TSA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes, implying that induction of these genes is not mediated directly by hypoxia inducible factor-1alpha. On the other hand, TSA dramatically upregulated the expression of DAT and SLC6A4 (45-fold and 15-fold, respectively), while transcript levels of MAO-A and COMT were significantly reduced (by 70% and by more than 90%, respectively). Induction of DAT protein expression was detected by western blotting. These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons.
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PMID:Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells. 2178 40


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