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)

Tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, is predominantly expressed in several cell groups within the brain, including the dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, and the noradrenergic neurons of the locus coeruleus. To investigate the regulation of cell type-specific TH expression, we cloned and sequenced a 5.5kb fragment of human genomic DNA immediately 5(') of the TH coding region. This 5(')-flanking region does not contain either a CAAT box or a GC-rich region, but does contain a TATA box and consensus binding sequences for basal (TATA and CRE), and DA neuron-specific (NBRE, Gli, and BBE) transcription factors. Sequence analysis showed low overall homology with the rat and mouse TH promoter regions, with the exception of two high-homology domains, which encompassed -2384 to -2323 and -123 to -65, respectively. Interestingly, these distal and proximal domains contained NBRE, BBE, CRE, and TATA boxes, which are known to play important roles in DA neurogenesis. To further localize the TH promoter region responsible for transcriptional activity, we fused a 3301-bp human TH promoter fragment (-3174 to +127) to a luciferase reporter gene, and used this to assess promoter activity in neuronal and non-neuronal cell lines. Consistent with endogenous TH expression, this promoter construct was active in SH-SY5Y human neuroblastoma cells but not F3 human neural stem cells (NSCs). Deletion analysis of TH promoter/luciferase constructs revealed the presence of the repressor element in -1232 to -1210 upstream of transcription initiation site. While this region repressed 85% of promoter activity when transfected into F3 cells, it was not active in SH-SY5Y cells. These data suggest that the repressor element may play an important role in neuron cell-specific expression of the TH gene. Our results may provide insight into neuronal cell-specific expression of the human TH gene and allow a better understanding of catecholaminergic neuron disorders such as Parkinson's disease and schizophrenia.
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PMID:Cloning and cell type-specific regulation of the human tyrosine hydroxylase gene promoter. 1465 89

Recently evidence has been presented that adenosine A2A and dopamine D2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk- cells. These A2A/D2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D2 or A2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A2A/D2 receptor heteromer represents the molecular basis for the antagonistic A2A/D2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.
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PMID:Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease. 1466 2

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.
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PMID:Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. 1513 Jul 72

Growing evidence has implicated the possible involvement of neurotrophins in the pathogenesis of functional psychoses such as schizophrenia and bipolar disorder. Previous studies reported a significant association of a dinucleotide repeat polymorphism of the neurotrophin-3 (NTF3) gene with schizophrenia. The aims of the present study were to examine whether this polymorphism is associated with bipolar disorder and whether the polymorphic region has an enhancer/silencer effect on transcriptional activity in an allele-dependent manner. In an association analysis between the polymorphism and bipolar disorder in a Japanese sample of 88 patients and 98 controls matched for age, sex, and ethnicity, the distribution of alleles did not differ significantly between the two groups. pGL3-promoter luciferase reporter vectors containing the polymorphic region increased luciferase activity relative to empty pGL3-promoter vector in HeLa, IMR-32 (neuroblastoma) and Hs683 (glioma) cell lines; however, no significant difference was detected between alleles for either cell line. Our results suggest that the examined polymorphism has no major role in giving susceptibility to bipolar disorder. Although the polymorphic region may have an enhancer-like effect on transcriptional activity, we obtained no evidence for allele-dependent differential effects.
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PMID:Analysis of enhancer activity of a dinucleotide repeat polymorphism in the neurotrophin-3 gene and its association with bipolar disorder. 1536 16

In view of prior reports suggesting associations between polymorphisms of the tumor necrosis factor gene (TNF) and schizophrenia, we sequenced all exons, introns and 7 kb flanking sequence at TNF in DNA pooled from 125 Caucasian schizophrenia cases and 200 controls. We identified 18 SNPs of which we selected and genotyped 8 among 244 cases and 276 controls. We detected no significant genotype or haplotype associations in the entire sample or in subgroups defined by gender or exposure to HSV1, HSV2, CMV, or Toxoplasma gondii. We used a dual-luciferase expression assay to quantify TNF expression driven by each common promoter haplotype in a neuroblastoma cell line. Three haplotypes drove significantly lower levels of TNF expression than the most common haplotype, including a haplotype with -308A, the allele reported to increase risk for schizophrenia (in contrast to earlier reports). We find no evidence to implicate TNF gene polymorphisms for schizophrenia risk in our sample.
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PMID:A comprehensive genetic association and functional study of TNF in schizophrenia risk. 1650

Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in a number of functional processes, including cognition, learning and memory, and alterations in their expression and/or activity have been implicated in various neurological disorders such as Alzheimer's disease (AD), Parkinson's disease and schizophrenia. Epidemiological studies have shown that exposure to electromagnetic fields (EMF) may contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Given the role of nAChRs in physiological and pathological conditions, we wondered whether an extremely low-frequency electromagnetic field (ELF-EMF) may affect the expression of the molecules involved in neurodegenerative processes. In order to investigate this possibility, we studied the expression of alpha3, alpha5 and alpha7 nicotinic subunits upon exposure of the SH-SY5Y human neuroblastoma cell line to a 50 Hz power-line magnetic field in a "blind trial" system; various magnetic flux densities and exposure times were applied. Our studies show that the expression of some relevant components of the cholinergic nicotinic system, which is one of the most affected neurotransmission systems in AD, did not undergo any change at molecular level by environmental exposure to ELF-EMF.
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PMID:Extremely low-frequency electromagnetic field (ELF-EMF) does not affect the expression of alpha3, alpha5 and alpha7 nicotinic receptor subunit genes in SH-SY5Y neuroblastoma cell line. 1651 98

Schizophrenia is associated with a number of pathological changes, including alterations in levels of specific proteins. Calprotectin is a novel 36 kDa calcium-binding protein of the S100 family and appears to be a nonspecific marker of inflammation. Calprotectin has not previously been investigated in brain tissue. Samples of post-mortem brain tissue from Brodmann area 9 were obtained from prefrontal cortex from subjects with schizophrenia, bipolar affective disorder, major depression, and from controls. Calprotectin levels were determined by ELISA. To determine cellular localization, immunocytochemical and fluorescent double-labelling analyses were performed. Exogenous calprotectin was added to retinoic acid-differentiated human SH-SY5Y neuroblastoma cell cultures in order to investigate mechanisms of action of calprotectin. Calprotectin was detectable in all samples, and mean levels were noted to be highest in schizophrenic brains (P < 0.05) and lowest in controls. Levels were intermediate in bipolar affective disorder and major depression. Exogenous calprotectin appeared to induce dendritic extension in SH-SY5Y cell culture in a dose-dependent manner. Calprotectin was found to be localized to microglia. These findings suggest that increased levels of calprotecitn in the brain may reflect inflammatory processes, which play a role in the pathogenesis of major psychiatric disorders. Furthermore, calprotectin may influence dendritic plasticity.
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PMID:Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? 1722 4

Protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and members of the Wnt signal transduction pathway were recently found to be altered in schizophrenia and targeted by antipsychotic drugs. In the current study, selected Wnt signalling proteins were investigated to determine if they are altered by the antipsychotics clozapine or haloperidol in the rat prefrontal cortex. Pheochromocytoma (PC12) and neuroblastoma (SH-SY5Y) cells were also used to elucidate how antipsychotics generated the pattern of changes observed in vivo. Western blotting (WB) revealed that treatment with haloperidol or clozapine caused an up-regulation of Wnt-5a, dishevelled-3, Axin, total and phosphorylated GSK-3 and beta-catenin protein levels. Treatment of PC12 and SH-SY5Y cells with a variety of pharmacological agents as well as the over-expression of several Wnt related proteins failed to mimic the pattern observed in vivo following antipsychotic treatment. However, the over-expression of dishevelled-3 nearly perfectly duplicated the changes observed in vivo. Immunoprecipitations (IP) conducted using protein isolated from the rat prefrontal cortex indicated that dishevelled-3 is associated with the D2 dopamine receptor thereby suggesting that antipsychotics may act on dishevelled-3 via D2 dopamine receptors to initiate a cascade of downstream changes involving Axin, GSK-3 and beta-catenin that may help to alleviate psychosis in schizophrenic patients.
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PMID:Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. 1747 3

Until now reduced estrogen level has been considered to affect some psychiatric symptoms, because there are sex differences in onset of Schizophrenia and Alzheimer's disease. Estrogen is associated with cognitive functions, and it has been reported to protect oxidative damage of DNA related to base excision repair (BER). Some patients with Xeroderma Pigmentosum, who have normal BER and impaired nucleotide excision repair (NER), are known to be suffering from mental retardation. Therefore we hypothesized that impaired NER was partly associated with pathology of mental disorder and investigated the effects of estrogen on NER for ultraviolet-induced DNA damage. The N2a neuroblastoma cell line was used as a representative of neuronal cells and 17p-estradiol was selected as one of the most active estrogen derivatives. There were no significant effects of 17p-estradiol on prevention of DNA damage, promotion of DNA repair, or cell survival at the concentration of 0-0.1 microM 17p-estradiol (below cytotoxicity level). These results described that estrogen might not directly affect NER except through another DNA repair system.
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PMID:[Effect of estrogen on nucleotide excision repair of N2a neuroblastoma cells]. 1751 14

Abnormalities of striatal dopaminergic neurotransmission play a significant role in the pathophysiology of central nervous system disorders such as movement disorders, addictions and schizophrenia. The striatum appears to be exposed to intrinsically high levels of oxidative stress (OS). Little is known, however, on the effect of OS on the regulation of the dopamine D2 receptor (DRD2), a key component of striatal dopaminergic neurotransmission. We report here on the effects of H2O2 (a canonical oxidant and non conventional messenger) and polyinosinic-polycytidylic acid (poly(IC) which elicits schizophrenia-like behaviors in newborn rodents and disrupts dopaminergic system development), on DRD2 levels in retinoic acid differentiated SH-SY5Y neuroblastoma. H2O2 elicited a significant increase in DRD2 mRNA and protein levels. Conversely, poly(IC) did not regulate DRD2 levels, although SH-SY5Y cells were confirmed to express TLR3 receptors. Under our conditions, H2O2, but not poly(IC), increased NFkappaB activation (as assessed by p65 nuclear translocation), which paralleled their effects on DRD2 levels regulation.
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PMID:Subacute H2O2, but not poly(IC), upregulates dopamine D2 receptors in retinoic acid differentiated SH-SY5Y neuroblastoma. 1796 Jul 67


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