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 have previously reported that endothelin (RT) receptor activation increases intracellular calcium concentrations ([Ca2+]i) in NG108-15 cells, a hybrid of rat glioma C6-BU-1 and mouse neuroblastoma N18TG2 cells. This study was designed to further explore the origin of the ET receptor and [Ca2+]i mobilization in the parent cell lines hybridized to form the NG108-15 cells. [125I]ET-1 bound to a single class of high affinity sites in C6-BU-1 cells with a KD value of 108pM and Bmax of 12,400 sites/cell. ET-1, ET-2, ET-3 and big ET inhibited [125I]ET-1 binding to C6-BU-1 cells with KD values of 0.074, 0.167, 261 and 187 nM, respectively. All ETs produced a rapid increase in [Ca2+]i in C6-Bu-1 cells. EC50 values for ET-1, ET-2, ET-3 and big ET were 0.71, 1.14, 120 and 243 nM respectively. There was a significant correlation between the KD values obtained from competition binding experiments and the EC50 values from [Ca2+]i response curves in C6-BU-1 cells (r = 0.996, p less than 0.004). Ten nM ET-1 produced about 85% of the maximal [Ca2+]i increase in C6-BU-1 cells which was reduced by 96% in the absence of extracellular calcium. Furthermore, diltiazem (10 microM) and nifedipine (1 microM) failed to block ET-induced [Ca2+]i mobilization. None of the ETs elevated [Ca2+]i or displayed any specific [125I]ET-1 binding in N18TG2 cells. These data suggest that ET binds to a specific ET receptor in C6-BU-1 cells, and elevates [Ca2+]i through dihydropyridine-insensitive, receptor-mediated calcium influx. Further, the ability of ETs to elevate [Ca2+]i in NG108-15 hybrid cells is due to the ET receptor inherent to the C6-BU-1 glioma parent line.
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PMID:Comparison of endothelin binding and calcium mobilization in C6-BU-1 rat glioma and N18TG2 mouse neuroblastoma cells. 165 31

The effects of endothelin(ET)-1, ET-2, ET-3 and Big ET on intracellular level of Ca2+ ([Ca2+]i) were studied in neuroblastoma NG108-15 and NCB-20 cells. All ETs, except Big ET, induced an increase in [CA2+]i in NG108-15 cells in a dose-dependent manner, with EC50: 6.7, 11.2 and 71 nM, respectively. However, none of the ET increased [Ca2+]i in NCB-20 cells. Calcium channel blockers diltiazem or nicardipine had no effect on ET-induced increase in [CA2+]i, but extracellular Ca2(+)-depletion significantly reduced the response of NG108-15 cells to ETs. NG108-15 cells exhibited a homologous desensitization to sequential addition of ETs, but no heterologous desensitization among ET, bradykinin and PAF was observed. These data suggest that ET-induced receptor activation results in increased intracellular Ca2+ via a non voltage calcium channel mechanism and intracellular Ca2+ release.
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PMID:Effect of endothelins on cytosolic free calcium concentration in neuroblastoma NG108-15 and NCB-20 cells. 227 19

The mode of binding of [3H]BQ-123 (cyclo(-D-Trp-D-Asp-[prolyl-3,4 (n)-[3H]]Pro-D-Val-Leu)), an endothelin receptor antagonist radioligand, was evaluated in the human neuroblastoma cell line SK-N-MC at 37 degrees C. Scatchard analysis indicated the presence of a single class of [3H]BQ-123 binding sites with a high affinity of 3.2 nM. [3H]BQ-123 binding achieved steady state within 7 min and dissociated with a half-time of 1.4 min, while [125I] endothelin-1 binding barely reached a steady state even after 6 h and showed little dissociation. [3H]BQ-123 binding was sensitive to endothelin-1 and endothelin-2 (Ki values = 0.058 and 0.10 nM, respectively) and the endothelin ETA receptor-selective antagonist BQ-123 (Ki = 3.3 nM), while showing low affinity for endothelin-3 (Ki = 50 nM), the endothelin ETB receptor-selective agonist BQ-3020 (Ki = 970 nM) and other bioactive peptides. Thus, [3H]BQ-123 is a specific and reversible radioligand for endothelin ETA receptors. The rapid reversibility of [3H]BQ-123 binding should provide a tool for estimating the equilibrium inhibition constants (Ki values) of various compounds for endothelin ETA receptors.
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PMID:[3H]BQ-123, a highly specific and reversible radioligand for the endothelin ETA receptor subtype. 776 60

Familial predisposition to neuroblastoma, a common embryonal cancer of childhood, segregates as an autosomal dominant trait with high penetrance. It is therefore likely that neuroblastoma susceptibility is due to germ line mutations in a tumor suppressor gene. Cytogenetic, functional, and molecular studies have implicated chromosome band 1p36 as the most likely region to contain a suppressor gene involved in sporadic neuroblastoma tumorigenesis. We now demonstrate that neuroblastoma predisposition does not map to any of eight polymorphic markers spanning 1p36 by linkage analysis in three families. In addition, there is no loss of heterozygosity at any of these markers in tumors from affected members of these kindreds. Furthermore, there is strong evidence against linkage to two Hirschsprung disease (a condition that can cosegregate with neuroblastoma) susceptibility genes, RET and EDNRB. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 tumor suppressor and the currently identified Hirschsprung disease susceptibility genes.
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PMID:Familial predisposition to neuroblastoma does not map to chromosome band 1p36. 875 5

Neuroblastoma has several clinical and molecular genetic parallels with the other paediatric embryonal tumours, such as retinoblastoma, including a hereditary form of the disease. We hypothesised that neuroblastoma susceptibility is due to germline mutations in a tumour suppressor gene and that this predisposition gene may be involved in sporadic neuroblastoma tumorigenesis as well. We therefore aimed to localise the familial neuroblastoma predisposition gene by linkage analysis in neuroblastoma kindreds. Eighteen families segregating for neuroblastoma were ascertained for candidate locus linkage analysis. Although many of the 49 affected individuals in these families were diagnosed as infants with multifocal primary tumours, there was marked clinical heterogeneity. We originally hypothesised that familial neuroblastoma predisposition would map to the telomeric portion of chromosome band 1p36, a genomic region likely to contain a sporadic neuroblastoma suppressor gene. However, neuroblastoma predisposition did not map to any of eight polymorphic markers spanning 1p36.2-.3 in three large kindreds. In addition, there was strong evidence against linkage to two Hirschsprung disease susceptibility genes (RET and EDNRB), a condition that can cosegregate with neuroblastoma as in one of the kindreds tested here. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 neuroblastoma suppressor and two of the currently identified Hirschsprung disease susceptibility genes.
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PMID:Molecular genetic analysis of familial neuroblastoma. 951 25

Despite significant advances in understanding the genetic background in Hirschsprung's disease (HD), the majority of cases are believed to be multigenic and multifactorial. Conditions associated with an increased risk of HD suggest some common inherited factor and include Down's syndrome, Waardenburg syndrome (WS), dominant sensorineural deafness, neurofibromatosis, neuroblastoma, phaechromocytoma, the MEN type 2B syndrome, and other abnormalities. The reported incidence of Down's syndrome in HD is approximately 2%, but the range varies from 2% to 15%. WS, on the other hand, is one of a number of uncommon human conditions in which pigmentary disturbances are associated with sensorineural deafness. HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans. Mutations of known genes appear to account for only a relatively small number of HD cases (20% in the case of RET). GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET). The genetic aspects of HD occurring in association with trisomy 21 and WS are reviewed. Clinical presentation, diagnosis, treatment and long-term outcome in this patient group are evaluated. Additional data are presented on 12 children with Down's syndrome out of 408 surgically treated HD patients. The role of associated anomalies is evaluated, and an increased susceptibility to severe enterocolitis associated with a high mortality rate is reported. Surgical correction can be achieved, but patients may require some form of ongoing help to facilitate acceptable bowel function. The decision as to the nature and timing of the surgical correction must be individualized.
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PMID:Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. 971 53

We sought to examine the effects of endothelin-1 on the intracellular free Ca(2+) concentration ([Ca(2+)](i)) and mitogenic response in the neuroblastoma cell line, B103 (B103 cells). The results obtained from an [125I] endothelin-1 binding assay demonstrated that B103 cells express the endothelin receptor. The B(max) and K(d) values for [125I]endothelin-1 binding were 70+/-36 fmol/mg protein and 52+/-13 pM, respectively. Endothelin-1 failed to stimulate cAMP formation, but it did inhibit forskolin-induced cAMP formation. Endothelin-1 also stimulated the accumulation of [3H]inositol phosphates. These results indicate that the endothelin receptor in B103 cells couples with G(i) and G(q) but not with G(s). Monitoring of [Ca(2+)](i) showed that endothelin-1 evoked a transient increase in [Ca(2+)](i); this remained even in the absence of extracellular Ca(2+). However, no sustained, endothelin-1-induced increase in [Ca(2+)](i) due to extracellular Ca(2+) influx was detected. The endothelin B receptor-selective antagonist, 2,6-Dimethylpiperidinecarbonyl-gamma-Methyl-Leu-N(in)-[Methoxycarbonyl]-D-Trp-D-Nle (BQ 788), abolished the endothelin-1-induced increase in [Ca(2+)](i), while the endothelin ET(A) receptor-selective antagonist, cyclo-D-Asp-Pro-D-Val-Leu-D-Trp (BQ 123), failed to inhibit it. These results indicate that B103 cells express endothelin ET(B) receptor or an endothelin ET(B)-like receptor predominantly and have no Ca(2+) channels activated by endothelin-1. Endothelin-1 activated mitogen-activated protein kinase in B103 cells. However, based on the data for 3-(4,5-dimethy-2-thiazolyl)-2,5-diphenyl tetrazolium bromide, [3H]thymidine incorporation, and apoptosis screening assays, endothelin-1 induces neither mitogenesis nor apoptosis. These results suggest that endothelin-1 has no role in the mitogenic response in B103 cells, and this is consistent with the notion that an endothelin-1-induced sustained increase in [Ca(2+)](i) plays a role in endothelin-1-induced cell proliferation.
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PMID:B103 neuroblastoma cells predominantly express endothelin ET(B) receptor; effects of extracellular Ca(2+) influx on endothelin-1-induced mitogenesis. 1151 35

We describe characteristics of a selective endothelin (ET) ET(B) receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ-788 potently and competitively inhibited (125)I-labeled ET-1 binding to ET(B) receptors in human Girrardi heart cells (hGH) with an IC(50) of 1.2 nM, but only poorly inhibited the binding to ET A receptors in human neuroblastoma cell line SK-N-MC cells (IC(50), 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 showed no agonistic activity up to 10 microM and competitively inhibited the vasoconstriction induced by an ET(B)-selective agonist (pA(2), 8.4). BQ-788 also inhibited several bioactivities of ET-1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET-1. Thus, it is confirmed that BQ-788 is a potent, selective ET(B) receptor antagonist. In vivo, in conscious rats, BQ-788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET-1- or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)-induced ET(B) receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ET(B) receptor blockade in vivo. In Dahl salt-sensitive hypertensive (DS) rats, BQ-788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ-788 also inhibited ET-1-induced bronchoconstriction, tumor growth and lipopolysaccharide-induced organ failure. These data suggest that BQ-788 is a good tool for demonstrating the role of ET-1 and ET(B) receptor subtypes in physiological and/or pathophysiological conditions.
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PMID:BQ-788, a selective endothelin ET(B) receptor antagonist. 1207 May 34

Neuroblastoma is a neural crest-derived tumor of childhood with a serious prognosis; only 20% of patients with stage 4 disease survive 5 years from diagnosis. Mechanisms involved in neuroblastoma development are unclear, but the engagement of many neuroblastoma-related gene(s) is suggested by specific chromosomal alterations. Most prominent among these is the amplification of the MYCN oncogene and the deletion of the 1p36 region. Other genetic aberrations have been discovered over the years such as deletions of 11q and 14q and gain of 17q. Although tumor aggressiveness greatly depends on the most frequent genetic abnormalities, to date no neuroblastoma-related gene has been discovered. Neuroblastoma usually occurs sporadically, but 1.5% of all diagnosed cases show familial recurrence with an autosomal dominant inheritance and incomplete penetrance. A comparison between hereditary and sporadic neuroblastomas led Knudson and Strong to gather that the two-hit hypothesis, proposed for retinoblastoma, could be applied to neuroblastoma. To determine if the 1p36 region harbors a predisposition gene for familial neuroblastoma, we carried out linkage analysis at 1p36 loci in two families with recurrent neuroblastoma. Similarly, we analyzed loci of chromosome 16, where a predisposition locus was recently mapped. We also analyzed markers located close to several candidate genes (RET, NF1, GDNF, GFRA1, EDNRB, and EDN3) involved to a different extent in other neurocristopathies. Our findings indicate that the candidate chromosomal regions and genes analyzed are not in linkage with neuroblastoma.
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PMID:Linkage analysis in families with recurrent neuroblastoma. 1209 31

Tumours of the Ewing's sarcoma (ES) family and neuroblastoma (NBL) were examined by reverse transcriptase-PCR for expression of mRNA for endothelin (ET) receptors ET-A and ET-B, and the ligands ET-1, ET-2 and ET-3. The effect of ET-1, ET-3, an ET-1-neutralizing antibody and ET-A receptor antagonist BQ-123 on cell proliferation was examined using an ELISA. Loss of ET-B receptor mRNA occurred in 57% of ES and 42% of NBL tumours. This appeared to be associated with the presence of metastatic disease and disease progression. ET-A receptor mRNA was expressed in all ES and 85% of NBL tumours, and in all ES and NBL cell lines examined. All ET ligands were detected in NBL cell lines, but only ET-1 and ET-2 were expressed in ES cell lines. Treatment of ES and NBL cells with ET-1 increased proliferation, but ET-3 had no effect. Incubation of ES and NBL cells with an ET-1-neutralizing antibody or BQ-123 decreased proliferation. The ET-3 ligand and ET-B receptor may be associated with migration and metastasis of ES and NBL, whereas ET-1 (acting through the ET-A receptor) may regulate their proliferation.
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PMID:Endothelins may modulate invasion and proliferation of Ewing's sarcoma and neuroblastoma. 1219 14


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