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)

Spinal and bulbar muscular atrophy (SBMA) is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor that forms characteristic inclusions in affected neurons. In order to assess the role of ligand binding in androgen receptor aggregation, we examined the distribution of an androgen receptor with 51 glutamine residues in transfected mouse neuroblastoma cells treated with androgens and antiandrogens. Stimulation with testosterone of cells grown in depleted medium or exposed to tamoxifen, resulted in the aggregation of the expanded androgen receptor into characteristic cytoplasmic inclusions. By contrast, very few aggregates were obtained after treatment with cyproterone acetate and none after treatment with flutamide. Furthermore, aggregation was not correlated with an overt change in accumulation of smaller androgen receptor species. Differential modulation of polyglutamine-expanded androgen receptor aggregation by ligands in neuronal cells may partly explain the absence of an overt disease phenotype in female carriers of the SBMA mutation and define conditions to explore further the role of androgen receptor aggregation in the pathogenesis of SBMA.
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PMID:Ligand-dependent aggregation of polyglutamine-expanded androgen receptor in neuronal cells. 1243 37

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder similar to Huntington's disease, with clinical manifestations including chorea, incoordination, ataxia, and dementia. It is caused by an expansion of a CAG trinucleotide repeat encoding polyglutamine in the atrophin-1 gene. Both patients and DRPLA transgenic mice have nuclear accumulation of atrophin-1, especially an approximately 120-kDa fragment, which appears to represent a cleavage product. We now show that this is an N-terminal fragment that does not correspond to the previously described caspase-3 fragment, or any other known caspase cleavage product. The atrophin-1 sequence contains a putative nuclear localization signal in the N terminus of the protein and a putative nuclear export signal in the C terminus. We have tested the hypothesis that endogenous localization signals are functional in atrophin-1, and that nuclear localization and proteolytic cleavage contribute to atrophin-1 cell toxicity. In transient cell transfection experiments using a neuroblastoma cell line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines localized to both nucleus and cytoplasm, with no significant difference in toxicity between the normal and mutant proteins. A construct with 65 glutamine repeats encoding an N-terminal fragment (which removes an NES) of atrophin-1 similar in size to the truncation product in DRPLA patient tissue, showed increased nuclear labeling, and an increase in cellular toxicity, compared with a similar fragment with 26 glutamines. Full-length atrophin-1 with 65 polyglutamine repeats and mutations inactivating the NES also yielded increased nuclear localization and increased toxicity. These data suggest that truncation enhances cellular toxicity of the mutant protein, and that the NES is a relevant region deleted during truncation. Furthermore, mutating the NLS in the truncated protein shifted atrophin-1 more to the cytoplasm and eliminated the increased toxicity, consistent with the idea that nuclear localization enhances toxicity. In none of the experiments were inclusions visible in the nucleus or cytoplasm suggesting that inclusion formation is unrelated to cell death. These data indicate that truncation of atrophin-1 may alter its ability to shuttle between the nucleus and cytoplasm, leading to abnormal nuclear interactions and cell toxicity.
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PMID:Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. 1246 7

Human neuroblastoma SH-SY5Y cell lines stably expressing mutant truncated huntingtin with 82 (mutant) glutamine repeats (N63-82Q) were briefly exposed to hyperosmotic conditions which decrease cell volume and therefore transiently increased the concentration of N63-82Q, as well as activating specific stress-induced pathways. Transient hyperosmotic treatment significantly increased the number of cells with aggregates. When the N63-82Q cells were subsequently returned to iso-osmotic medium after the treatment, the number of cells with aggregates remained constant up to 12 h. However, between 12 and 24 h another significant increase in aggregate frequency was observed, with approximately 55% of the cells containing aggregates after 24 h. This may be due in part to the formation of microaggregates during hyperosmotic conditions that act as seeds for the aggregate formation. Further, treatment of cells with geldanamycin, which activates a heat shock response, significantly attenuated the hyperosmotic-induced increase in aggregate formation.
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PMID:Transient osmotic stress facilitates mutant huntingtin aggregation. 1249 64

The role of glutamine and alanine transport in the recycling of neurotransmitter glutamate was investigated in Guinea pig brain cortical tissue slices and prisms, and in cultured neuroblastoma and astrocyte cell lines. The ability of exogenous (2 mm) glutamine to displace 13C label supplied as [3-13C]pyruvate, [2-13C]acetate, l-[3-13C]lactate, or d-[1-13C]glucose was investigated using NMR spectroscopy. Glutamine transport was inhibited in slices under quiescent or depolarising conditions using histidine, which shares most transport routes with glutamine, or 2-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of the neuronal system A. Glutamine mainly entered a large, slow turnover pool, probably located in neurons, which did not interact with the glutamate/glutamine neurotransmitter cycle. This uptake was inhibited by MeAIB. When [1-13C]glucose was used as substrate, glutamate/glutamine cycle turnover was inhibited by histidine but not MeAIB, suggesting that neuronal system A may not play a prominent role in neurotransmitter cycling. When transport was blocked by histidine under depolarising conditions, neurotransmitter pools were depleted, showing that glutamine transport is essential for maintenance of glutamate, GABA and alanine pools. Alanine labelling and release were decreased by histidine, showing that alanine was released from neurons and returned to astrocytes. The resultant implications for metabolic compartmentation and regulation of metabolism by transport processes are discussed.
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PMID:Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation. 1267 27

The alpha-ketoisocaproic acid (KIC) is a short branched-chain monocarboxylate, which accumulates in neural cells. It plays an important role in maintaining nitrogen balance in the brain, a process of a great importance for shuttling of glutamine and glutamate between astrocytes and neurons. Higher accumulation of KIC in isolated cerebral cortex neurons at lower external pH, as well as sensitivity of this process to alpha-cyano-4-hydroxycinnamate indicate an involvement of a transporter, belonging to the family of monocarboxylate transporters (MCT).The expression of MCT1 and MCT2 isoforms in the brain cells was studied using reverse transcriptase-polymerase chain reaction (RT-PCR) method. The mRNA coding MCT1 was detected in astrocytes, brain endothelial cells, tumour cells (neuroblastoma and glioma) and in cortex neurons of newborn rats, but not in adult ones. MCT2, which is less abundant isoform than MCT1, was expressed in astrocytes, in brain endothelial cells and at low level in newborn rats' neurons, being absent in neurons from adult brain.The observed sensitivity of KIC accumulation towards SH-groups reagents did not fit to the known characteristics of MCT1 and MCT2. Therefore, the change of MCT expression during brain development, as well as lack of MCT1 and MCT2 in neurons of adults, point to another MCT isoform being involved in alpha-ketoisocaproic acid accumulation. This could be either one of other known MCT isoforms or a new member of family MCT, specific towards branched chain alpha-ketoacids.
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PMID:Expression of monocarboxylic acid transporters (MCT) in brain cells. Implication for branched chain alpha-ketoacids transport in neurons. 1274 73

Spinal and bulbar muscular atrophy is a motor neuronopathy caused by a polyglutamine expansion in the androgen receptor (AR). Only males are affected as the development of pathology requires high levels of circulating androgens. Androgens promote aggregation of the AR into characteristic intracellular inclusions. As a potential factor contributing to the protection of female carriers, we assessed the effects of estrogens on AR aggregation in transfected neuronal cells using a filter retardation assay. Pre-treatment of mouse neuroblastoma Neuro2a cells expressing an AR with 51 glutamine residues with 10 microM 17beta- or 17alpha-estradiol prevented induction of AR aggregation by testosterone. Western blot analysis showed that the protective effects of estrogens occurred in the absence of a change in AR processing. We conclude that estrogens protect polyglutamine-expanded AR from aggregation through a non-genomic mechanism possibly involving estrogen binding to the AR.
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PMID:Protective effects of estrogens on polyglutamine-expanded androgen receptor aggregation in mice. 1296 12

The pathogenesis of X-linked spinal and bulbar muscular atrophy (SBMA) has been traced to an expansion of repeated glutamine (Gln) residues within the amino terminus of the human androgen receptor (AR). To examine the mechanisms by which these expanded repeat ARs (Exp-ARs) are toxic to neurons, we have established and characterized a cell culture model by stably transfecting SH-SY 5Y neuroblastoma cells with cDNAs containing either normal AR (81 series; 23 Glns) or Exp-AR (902 series; 56 Glns). At a low passage number, no differences in cell morphology, growth properties, or susceptibility to toxic insults were observed between clones expressing normal AR or Exp-AR. Initially, both types of cultures were found to express similar levels of specific hormone binding in monolayer binding assays. Immunohistochemical studies demonstrated the vast majority of both the normal AR and Exp-AR were localized to the nucleus in the absence and presence of androgen. As the 902 series of clones were propagated, the Exp-AR content in the cells appeared to decline progressively. However, this decrease actually reflects a gradual disappearance of the Exp-AR cell population. No such selection occurred during the propagation of cells expressing the normal AR. This selection against cells expressing physiological levels of Exp-AR occurs in the absence of intracellular aggregates and suggests that mechanisms other than those involving the formation of aggregates underlie the observed toxicity of Exp-ARs.
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PMID:Androgen receptors containing expanded polyglutamine tracts exhibit progressive toxicity when stably expressed in the neuroblastoma cell line, SH-SY 5Y. 1296 71

N-Acetylaspartylglutamate (NAAG) is a neuropeptide that is thought to modulate neurotransmitter release through pre-synaptic mGluR3 receptors. Despite years of research into NAAG biochemistry, almost nothing is known about NAAG biosynthesis. To date, NAAG biosynthesis has only been demonstrated conclusively in explanted animal neural tissues, including frog retina, rat dorsal root ganglia and crayfish nerve cord, but not in human cells or tissues. We show here that a human neuroblastoma cell line, SH-SY5Y, provides a good model system for the study of NAAG biosynthesis. Radiolabled NAAG synthesis occurred using both L-[3H]glutamic acid and L-[3H]glutamine as precursors, with glutamine being the preferred substrate. Differentiation of SH-SY5Y cells with retinoic acid resulted in decreased radiolabel incorporation into NAAG, whereas differentiation with nerve growth factor did not affect radiolabel incorporation.
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PMID:SH-SY5Y neuroblastoma cells: a model system for studying biosynthesis of NAAG. 1512 67

Olanzapine has previously been shown to stimulate the growth of neuronal cells in culture. A major goal of the present studies was to determine if olanzapine also provided neuroprotection to pheochromocytoma (PC12) cells, SH-SY5Y neuroblastoma cells, and primary cultures of rat cortical neurons. Olanzapine was mitogenic and enhanced the survival of PC12 cells, SH-SY5Y cells and 3T3 preadipocytes, but not L6 myoblasts or myeloma cells. It protected neuronal cells from death induced by serum and glutamine deprivation, amyloid beta peptide (25-35), and fluphenazine. Molecular mechanisms of the neuroprotection by olanzapine were explored, specifically the activation of various protein kinase signaling pathways including Akt/protein kinase B (PKB), extracellular-regulated kinase (ERK), ERK1/2, and mitogen-activated protein kinase (MAPK), p38. Olanzapine treatment led to rapid phosphorylation of kinases from all three pathways in PC12 cells. Phosphorylation of Akt was blocked with selective inhibitors (wortmannin and LY294002), which implicates phosphoinositide 3-kinase (PI3K) in the signaling cascade. Short-term mitogenic effects of olanzapine were abolished with a selective inhibitor of Akt, but not by inhibition of the ERK pathway. Other antipsychotic drugs stimulated phosphorylation of a subset of the kinase panel, but not all three kinases. The present findings demonstrate that olanzapine has both mitogenic and neuroprotective effects in neuronal cells.
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PMID:Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. 1514 Jun 44

Both amino acid transport and glutathione play a key role in regulating cancer cell growth. Glutamine can serve as an important ATP source for cancer cells, and it can supply glutamate, a precursor for the synthesis of glutathione, by the hydrolysis of glutamine. We examined the effects of glutamine concentrations [2 mM (control), 400 microM, 200 microM, and 0 microM] on cell growth, amino acid transport, and glutathione levels in a human neuroblastoma cell line, SK-N-SH, by using cell culture technique. Cell growth rates were dependent on glutamine concentrations in culture media. Glutamate transport significantly increased in glutamine-deprived groups, and this increase was remarkable in lower glutamine groups (200 microM and 0 microM glutamine). Glutamine deprivation resulted in a significant decrease in glutathione levels by 20% compared with control, but glutathione in 0 microM glutamine was maintained with the same levels found in 400 microM and 200 microM glutamine. DNA and protein synthesis correlated directly with glutamine concentrations in culture media. Our results suggest that glutamine mediates neuroblastoma cell proliferation by regulating amino acid transport and glutathione synthesis, both when sufficient nutrients are present and when key nutrients such as glutamine are in limited supply.
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PMID:Glutamine regulates amino acid transport and glutathione levels in a human neuroblastoma cell line. 1537 87


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