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)

Ethanol has deleterious effects on neuronal cells both in vivo and in vitro, but the mechanisms are unknown. Here, treatment with increasing doses of ethanol (from 20 up to 600mM) decreased the viability of a mouse hippocampal neuroblastoma cell line, HT22. The glutathione concentration decreased and intracellular reactive oxygen species (ROS) increased in a dose-and time-dependent manner, suggesting that the neurotoxicity was due to oxidative stress. Expression of heme oxygenase (HO)-1, a redox regulator and heat shock protein, increased with time after ethanol treatment, but HO-2 was expressed constitutively. The addition of 5microM zinc protoporphyrin IX (ZnPP IX), a competitive HO inhibitor, with the ethanol further reduced cell viability and increased intracellular ROS, but these effects were reversed by co-treatment with 50nM bilirubin, a well-known antioxidant and a product of HO catalysis. These results suggest that HO has a protective role in hippocampal neurons as an intrinsic factor against ethanol-induced oxidative stress and the protection depends on the degree of oxidative stress.
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PMID:Heme oxygenase protects hippocampal neurons from ethanol-induced neurotoxicity. 1685 15

Cellular levels of G protein-coupled receptor kinase (GRK)3 determine the sensitivity of the alpha(2A/B)-adrenoceptor (alpha(2)-AR) to agonist-induced down-regulation. Using human neuroblastoma BE(2)-C cells, this study examines how cellular GRK3 levels are affected by several mechanisms reported to influence stability and degradation of other GRKs. We first examined the interaction between the 90-kDa heat shock protein (Hsp90) and GRK3; Hsp90 reportedly affects the maturation and stability of GRK2. In unstimulated cells, GRK3 coimmunoprecipitates with Hsp90, suggesting a physical interaction. Moreover, when GRK3 protein expression was increased by 24-h epinephrine (EPI) treatment, Hsp90 protein expression increased with a similar but slightly delayed time course. To investigate the influence of Hsp90 on GRK3 protein stability, we determined the effect of the Hsp90 inhibitor geldanamycin (GA) on cellular GRK3 levels. GA eliminated the interaction between Hsp90 with GRK3 and produced a rapid, proteasome-mediated, 70% decrease in GRK3 levels within 24 h. To investigate the influence of Hsp90 on up-regulation of GRK3 expression, we examined the effect of GA on EPI-induced up-regulation. GA reduced the absolute increase in GRK3; however, the percentage of increase in GRK3 by EPI was not significantly different in the absence versus presence of GA (141 +/- 41 versus 94 +/- 12%). Finally, we examined the influence of Ca(2+)-activated proteases on cellular GRK3. Treatment with the calcium ionophore ionomycin produced a rapid decrease in GRK3 levels that was inhibited by the calpain inhibitor calpeptin. In conclusion, several mechanisms influence the degradation of GRK3 and therefore have the potential to affect GPCR signaling by regulating GRK3 levels in neurons.
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PMID:Role of 90-kDa heat shock protein (Hsp 90) and protein degradation in regulating neuronal levels of G protein-coupled receptor kinase 3. 1717 67

Geldanamycin (GA) is a specific inhibitor of the 90 kDs heat shock protein (Hsp90) in the cytoplasm of mammalian cells, which binds directly to Hsp90 and promotes proteolytic degradation of its client proteins. As an antitumor drug, GA antagonizes the protecting effects of Hsp90 on cell survival, while its mechanisms remain unclear. Here, we show that GA induces apoptosis in a human neuroblastoma cell line, SH-SY5Y. Treatment of the cells with all trans retinoic acid (RA) generates a neuron-like, morphological change of differentiation, and results in the activation of ERK and Akt pathways, an inhibition of the nuclear translocation of p53 induced by GA, and induces higher resistance to the GA-induced apoptosis. These results provide the first evidence for the requirement of p53 nucleation in SH-SY5Y cells to counteract GA in neuron survival.
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PMID:Resistance to geldanamycin-induced apoptosis in differentiated neuroblastoma SH-SY5Y cells. 1729 44

The development of an infection in soybean [Glycine max L. cultivar (cv.) Peking] roots by incompatible (I) and compatible (C) populations of soybean cyst nematode (SCN) (Heterodera glycines) was assayed using an AffymetriX soybean GeneChip. This time-course microarray analysis, using 37,744 probe sets, measured transcript abundance during I and C. These analyses reveal that infection by individual I and C H. glycines populations influence the transcription of G. max genes differently. A substantial difference in gene expression is present between I and C at 12 h post infection. Thus, G. max can differentiate between I and C nematode populations even before they have begun to select their feeding sites. The microarray analysis identified genes induced earlier in infection during I than C. MA also identified amplitude differences in transcript abundance between I and C reactions. Some of the probe sets measuring increased transcript levels during I represented no apical meristem (NAM) and WRKY transcription factors as well as NBS-LRR kinases. Later during I, heat shock protein (HSPs) probe sets (i.e. HSP90, HSP70, ClpB/HSP101) measured increased transcript abundance. These results demonstrate that G. max roots respond very differently to the different H. glycines races even before their feeding site selection has occurred. The ability of G. max to engage an I reaction, thus, appears to be dependent on the ability of root cells to recognize the different races of H. glycines because these experiments were conducted in the identical G. max genetic background.
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PMID:A time-course comparative microarray analysis of an incompatible and compatible response by Glycine max (soybean) to Heterodera glycines (soybean cyst nematode) infection. 1765 70

Neuroblastoma (NB) and Ewing's sarcoma (ES) cell lines were analysed by two-dimensional gel electrophoresis (2-DE) searching for new diagnostic/prognostic markers. Protein expression profiles displayed a high degree of similarity with the exception of marked heat shock protein (HSP) 27 and less marked HSP60 and HSP70 family up-modulations in NB cells. HSP27, which showed peculiar variability in different NB cell preparations, responded to all trans-retinoic acid treatment in NB cells but not in ES cells at gene and protein expression levels. Immunohistochemistry studies showed different behaviours of HSP27 and HSP70 expression in NB and ES biopsies. HSP27 was less expressed, whereas HSP70 was more expressed in the immature areas of NB. HSP27 expression showed positive and statistically significant correlation with favourable prognosis, and HSP27 expression also negatively correlated with increasing aggressiveness of histological type. In ES, both chaperones were expressed without characteristic patterns. Our results suggest that HSP27, after further clinical validations, could be used as a marker of neuronal differentiation in vivo for the assessment of the biological behaviour of NB and for the risk stratification of patients.
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PMID:Proteomic identification of heat shock protein 27 as a differentiation and prognostic marker in neuroblastoma but not in Ewing's sarcoma. 1806 88

When human neuroblastoma cells (SH-SY5Y) were exposed to 0.5 - 5 mM acrylamide for 18 hr, the levels of heat shock proteins (HSPs) of 90, 70 and 27 kDa (Hsp90, Hsp70, and Hsp27, respectively) were elevated in the incubation media depending on the dose of acrylamide whereas only the Hsp70 level increased within cells. U0126, a specific inhibitor of extracellular signal-regulated protein kinase kinase and a potent suppressor of the cytotoxicity of acrylamide, suppressed the increase in the levels of all HSPs in the incubation media but not their expression within cells. Total protein concentrations in the incubation media increased depending on the dose of acrylamide, and this increase was associated with the increasing number of bands detected by silver staining after SDS-polyacrylamide gel electrophoresis. One of the clearest bands was identified as Hsp90 by peptide mass fingerprinting. Thus, acrylamide causes release of proteins, including that of HSPs, from SH-SY5Y cells. HSP in extracellular fluid may be a good indicator of cytotoxicity of acrylamide.
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PMID:Release of heat shock proteins from human neuroblastoma cells exposed to acrylamide. 1830 90

Neuronal differentiation of the NG108-15 neuroblastoma-glioma hybrid cells is accompanied by a marked attenuation in the heat shock induction of the Hsp70-firefly luciferase reporter gene activity. Analysis of the amount and activation of heat shock factor 1, induction of mRNA(hsp), and the synthesis and accumulation of heat shock proteins (HSPs) in the undifferentiated and differentiated cells suggest a transcriptional mechanism for this attenuation. Concomitant with a decreased induction of the 72-kDa Hsp70 protein in the differentiated cells, there is an increased abundance of the constitutive 73-kDa Hsc70, a protein known to function in vesicle trafficking. Assessment of sensitivity of the undifferentiated and differentiated cells against stress-induced cell death reveals a significantly greater vulnerability of the differentiated cells toward the cytotoxic effects of arsenite and glutamate/glycine. This study shows that changes in regulation of the HSP and HSC proteins are components of the neuronal cell differentiation program and that the attenuated induction of HSPs likely contributes to neuronal vulnerability whereas the increased expression of Hsc70 likely has a role in neural-specific functions.
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PMID:Changes in the regulation of heat shock gene expression in neuronal cell differentiation. 1834 44

The aim of this study was to assess the neurotoxicity of diazinon oxon (DZO), a major in vivo metabolite of the phosphorothionate insecticide diazinon (DZ), on differentiating mouse N2a neuroblastoma cells. When used at concentrations of 1, 5 and 10 microM, DZO did not cause cell death but it impaired the outgrowth of axon-like processes after 24 h. Densitometric scanning of Western blots of lysates of N2a cells revealed that exposure to 5 or 10 microM DZO for 24 h increased the expression of phosphorylated neurofilament heavy chain (NFH) compared to controls, while there was no significant change in total NFH. By contrast, treatment of N2a cells with 1-10 microM DZO resulted in marked reductions in the expression of the axon growth-associated protein GAP-43. DZO-treated cells also showed an increased expression of the heat shock protein HSP-70 compared to controls. The above biochemical changes were not temporally related to inhibition of acetylcholinesterase (AChE). These data suggest that biologically relevant, subcytotoxic levels of DZO may exert neurotoxic effects on differentiating cells and that the mechanisms involved are different from those attributed to its parent compound.
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PMID:Diazinon oxon affects the differentiation of mouse N2a neuroblastoma cells. 1863

Heat shock protein 90 (Hsp90) safeguards the structural integrity and function of many of the key growth regulatory proteins found in malignant cells. Consequently, among the new generation targeted therapeutics, heat shock protein inhibitors have the unique property of being able to target an expansive array of divergent molecular mechanisms involved in cancer growth and metastasis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) is one such agent that has been shown to bind to Hsp90 and thus reduce the stability and activity of many key growth regulatory molecules and pathways. A number of recent clinical trials have investigated the maximum tolerated dose, toxicity and pharmacokinetic profiles of 17-AAG in pediatric patients with recurrent tumors. In this study, we describe the effects of 17-AAG against a panel of neuroblastoma (NB) cell lines with respect to cytotoxicity, target modulation and inhibition of vascular endothelial growth factor (VEGF) expression. 17-AAG was found to inhibit the growth of all NB cell lines tested, though effective inhibitory concentrations varied among cell lines. 17-AAG also suppressed the expression of VEGF. The cytotoxic effect of 17-AAG on tumor cells was diminished when co-cultured with bone marrow stromal cells suggesting a potential role for the microenvironment in tumor drug interactions. Findings from target modulation analysis as well as drug combination assays provide a frame-work to formulate effective protocols for the treatment of NB.
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PMID:Effects of Hsp90 inhibition in neuroblastoma: analysis of drug sensitivity, target modulation and the influence of bone marrow microenvironment. 1906 27

Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone activity. Radiolabeled dopamine binding studies with recombinant human CRP40 protein demonstrated the ability of this protein to bind dopamine with low affinity and high capacity. The full-length human CRP40 nucleotide sequence was elucidated (accession #DQ480334) with RNA ligase-mediated rapid amplification of complementary DNA ends polymerase chain reaction, while Northern blot hybridization suggested that human CRP40 is an alternative splice variant of the 70-kDa mitochondrial heat shock protein, mortalin. Human SH-SY5Y neuroblastoma cells treated with the antipsychotic drug, haloperidol, exhibited a significant increase in CRP40 messenger RNA expression compared to untreated control cells, while other dopamine agonists/antagonists also altered CRP40 expression and immunolocalization. In conclusion, these results show that we have cloned a splice variant of mortalin with a novel catecholamine binding function and that this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders.
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PMID:Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders. 1928 Mar 69


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