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)

A 23-kDa (p23k) rat brain protein was stereospecifically eluted from a 14 beta-bromoacetamidomorphine affinity column, purified to apparent homogeneity by reverse phase HPLC, and partially sequenced. Three degenerate oligodeoxynucleotide probes were synthesized based on this partial amino acid sequence. A rat brain cDNA library was screened using these probes, and a full-length cDNA was isolated. The deduced protein, 187 amino acids long, is rich in glutamic and aspartic acid residues, endowing p23k with a net negative charge at neutral pH. The protein lacks a signal sequence as well as any transmembrane domains. Based on predictions of secondary structure, p23k is a globular protein composed of 30% alpha-helices and 18% beta-pleated sheets. Northern blot analysis revealed p23k transcripts in rat brain, liver, and the mouse x rat neuroblastoma-glioma NG108-14 cell line. Although not an opioid receptor itself, this protein may be associated with such a receptor or be related to a protein that has been shown to be cross-linked to the opioid peptide beta-endorphin.
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PMID:Purification, cloning, and tissue distribution of a 23-kDa rat protein isolated by morphine affinity chromatography. 197 48

Non-saturable penetration and the V and Km constants of saturable influx of leucine, lysine and glycine were always greater in cultured neuroblastoma (C1300) than in glioma (C6) cells. Aspartate uptake was detected only in glioma cells. Unstimulated efflux of the amino acids was initially fast in both cell types but soon slowed down. The efflux of glycine and aspartate exhibited no heteroexchange, the efflux of lysine was stimulated by extracellular leucine and that of leucine slightly by lysine and glycine but only in glioma cells.
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PMID:Transport of leucine, lysine, glycine and aspartate in neuroblastoma C1300 and glioma C6 cells. 312 24

Rubrophilin, a unique brain specific polypeptide, was purified to apparent homogeneity from microsomal fractions of bovine brains. The peptide stains pink with Coomassie Brilliant Blue R-250 (C.I. No. 42660) under specific conditions, has an apparent Mr of 53,000, and is acidic with an apparent pI of 4.9. The purification involves initial solubilization of delipidated microsomes in sodium dodecyl sulfate, followed by ammonium sulfate fractionation, reversed ammonium sulfate gradient elution from diatomaceous earth, gel filtration on polyacrylamide (Biogel P-200), gradient elution chromatography from hydroxylapatite, and reverse-phase chromatography from phenyl-Sepharose. A yield of about 5 mg of rubrophilin was obtained from 9 g of microsomal proteins. Amino acid analysis shows that rubrophilin contains only nine amino acids with residues/mol as follows: alanine (102), glutamic acid (97), lysine (65), proline (55), aspartic acid (48), glycine (44), serine (37), threonine (35), and valine (10). Cysteine, methionine, tryptophan, tyrosine, isoleucine, phenylalanine, histidine, and arginine could not be detected. Relative rubrophilin content of vertebrate brains was as follows: mammals greater than birds greater than reptiles greater than fishes. It is present in mouse retina and human neuroblastoma cell cultures but could not be detected in octopus optic lobe or in cultured C-6 rat glioma cells.
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PMID:Purification and properties of rubrophilin: a novel brain specific membrane polypeptide. 380 7

Several neuropathologic findings in infants and children with human immunodeficiency virus type-1 (HIV-1) infection are different from those observed in adults, probably related to the fact that the retroviral infection occurs in the setting of neuro-development. This report describes the interaction and biologic activity of tat, the HIV-1 trans-activating protein on human neuroblasts. Two human neuroblastoma cell lines, LAN-5 and GI-CA-N, have been studied for their capability to adhere to tat (full recombinant protein) and to two different peptide residues of it. Both cells adhere to tat and tat46-60 basic domain, although not to tat65-80 residue, which contains the RGD (arginine-glycine-aspartic acid) motif. Adhesion to collagen I was inhibited by preincubating GI-CA-N cells with tat,46-60 although not with tat,65-80 indicating the capability of the basic residue to interfere with collagen I-induced cellular adhesion. The expression of 200-kD neurofilaments induced by collagen I was not induced by tat,46-60 indicating that neural differentiation along the same pathway is not mimicked by this peptide. Neuroblast cell proliferation was not affected by adhesion to tat46-60 nor to tat.65-80 GI-CA-N cells are not permissive to HIV-1 infection. However, proviral DNA was documented in the cell lysate for 14 consecutive in vitro passages, whereas HIV-1 transcription was never detectable. This would exclude the possibility that tat would be transduced by these cells. GI-CA-N stained negative for CD4, although positive for Gal-C, which may explain HIV-1 entry. Results show that immature human neural cells interact with tat protein and/or its basic residue in vitro. A mechanism similar to that herein described would possibly be active in vivo, which may help in clarifying the pathogenic mechanisms of neurologic dysfunction and destruction of the CNS observed in infants infected with HIV-1.
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PMID:Adhesion of human neuroblasts to HIV-1 tat. 855 50

Several attempts to investigate the bioactive conformation of neuropeptide Y have been made so far. As cyclic peptides are much more rigid than linear ones, we decided to synthesise cyclic analogues of the C-terminal dodekapeptide amide neuropeptide Y Ac-25-36. Cyclisation was performed by side chain lactamisation of ornithine or lysine and glutamic or aspartic acid. The affinity of the 19 peptides ranged from Ki 0.6 nM to greater than 10,000 nM. We found that the size, position, orientation, configuration. and the location of the cycle plays an important role for receptor recognition. Circular dichroic studies have been performed to characterise the secondary structure of each peptide. Receptor binding studies were carried out on human neuroblastoma cell lines SK-N-MC (Y1) and SMS-KAN (Y2), and on rabbit kidney membranes (Y2). The pharmacological and spectral data showed that the alpha-helix content was not the predominant factor for high Y2-receptor affinity. Instead, the location and the size of the hydrophobic lactam bridge, and the conserved C-terminal tetrapeptide (Arg-Glu-Arg-Tyr) seemed to be the main parameters. Using molecular dynamics, the structures of four cyclic peptides (i,i+4) have been investigated and compared with the previously published NMR structure of one of the cyclic peptide analogues. Significant differences have been found in the overall three-dimensional fold of the peptides. The distances between the N- and the C-terminus allow discrimination between peptides with high binding affinity and those with low binding affinity, because of the correlation that was found with the measured affinity. Thus, this study suggests that a turn-like structure and the orientation of the C-terminus towards the N-terminus play major roles for high affinity binding of cyclic dodecapeptides to the Y2-receptor. None of the cyclic segments exhibits significant affinity to the Y1-receptor. Thus, these results support the hypothesis of a discontinuous binding site of neuropeptide Y at the Y1-receptor.
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PMID:The bioactive conformation of neuropeptide Y analogues at the human Y2-receptor. 928 27

Serial passage of yellow fever 17D virus (YF5.2iv, derived from an infectious molecular clone) on mouse neuroblastoma (NB41A3) cells established a persistent noncytopathic infection associated with a variant virus. This virus (NB15a) was dramatically reduced in plaque formation and exhibited impaired replication kinetics on all cell lines examined compared to the parental virus. Nucleotide sequence analysis of NB15a revealed a substitution in domain III of the envelope (E) protein at residue 360, where an aspartic acid residue was replaced by glycine. Single mutations were also found within the NS2A and NS3 proteins. Engineering of YF5.2iv virus to contain the E(360) substitution yielded a virus (G360 mutant) whose plaque size and growth efficiency in cell culture resembled those of NB15a. Compared with YF5.2iv, both NB15a and G360 were markedly restricted for spread through Vero cell monolayers and mildly restricted in C6/36 cells. On NB41A3 cells, spread of the viruses was similar, but all three were generally inefficient compared with spread in other cell lines. Compared to YF5.2iv virus, NB15a was uniformly impaired in its ability to penetrate different cell lines, but a difference in cell surface binding was detected only on NB41A3 cells, where NB15a appeared less efficient. Despite its small plaque size, impaired growth, and decreased penetration efficiency, NB15a did not differ from YF5.2iv in mouse neurovirulence testing, based on mortality rates and average survival times after intracerebral inoculation of young adult mice. The data indicate that persistence of yellow fever virus in NB41A3 cells is associated with a mutation in the receptor binding domain of the E protein that impairs the virus entry process in cell culture. However, the phenotypic changes which occur in the virus as a result of the persistent infection in vitro do not correlate with attenuation during pathogenesis in the mouse central nervous system.
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PMID:Neuroblastoma cell-adapted yellow fever 17D virus: characterization of a viral variant associated with persistent infection and decreased virus spread. 1202 51

TrkA is the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and stimulates NGF-dependent cell survival and differentiation in primary neurons and also differentiation of neuroblastomas and apoptosis of medulloblastomas. We have previously shown that aspartic acid and glutamic acid substitution (AspGlu and GluAsp) of the activation loop tyrosines in TrkA (Tyr(683) and Tyr(684)) supports NGF-independent neuritogenesis and cell survival in PC12 cell-derived nnr5 cells. In this study, the AspGlu and GluAsp mutant Trks have been analysed for their ability to support NGF-independent and NGF-dependent neuritogenesis, proliferation and cell signalling in the human neuroblastoma cell line, SY5Y. We find that the AspGlu and GluAsp mutant Trks support NGF-dependent, but not NGF-independent, autophosphorylation, neuritogenic responses and/or inhibit cell cycle progression. The NGF-dependent neuritogenic responses are lower for the mutant Trks (approximately 30-60% for AspGlu and 50-60% for GluAsp), relative to wild-type TrkA. While both the AspGlu and GluAsp mutant Trks support NGF-dependent transient phosphorylation of Shc, PLCgamma-1, AKT, FRS2, SH2B as well as prolonged MAP kinase activation, the GluAsp mutant induces stronger NGF-dependent tyrosine phosphorylation of FRS2 and SH2B, as well as a stronger reduction in bromodeoxyuridine (BrdU) incorporation. Collectively, these data suggest that neither absolute levels of receptor autophosphorylation, high levels of TrkA expression nor the activation of a specific signalling pathway is dominant and absolutely essential for neuritogenesis and cell cycle arrest of SY5Y cells.
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PMID:Acidic substitution of the activation loop tyrosines in TrkA supports nerve growth factor-dependent, but not nerve growth factor-independent, differentiation and cell cycle arrest in the human neuroblastoma cell line, SY5Y. 1464 72

Persistent infection of mouse neuroblastoma NB41A3 cells with yellow fever 17D virus generates viral variants which exhibit defective cell penetration, poor cell-to-cell spread, small plaque size and reduced growth efficiency, caused by substitution of glycine for aspartic acid or glutamic acid at positions 360 and 362 in the envelope protein. These positions occur within a charge cluster, Asp360-Asp361-Glu362, located in domain III, near its interface with domain I. To characterize further the molecular basis for the variant phenotype, a series of mutant viruses containing substitutions at position 360, 361 and 362, were studied for effects on the cell culture properties typical of the neuroblastoma-adapted variant. Most substitutions at position 360 gave rise to viruses that were very defective in cell penetration, growth efficiency and cell-to-cell spread, whereas substitution with glutamic acid yielded a virus indistinguishable from parental yellow fever 17D. Substitution with lysine was not tolerated and substitution with asparagine resulted in frequent wild-type revertants. A glycine residue was not tolerated at position 361, but substitution at 362 yielded a small plaque virus, similar to the effect of substitution at position 360. These data indicate that the yellow fever virus E protein contains a locus within domain III where a negative-charge cluster is important for optimal function of this domain in virus-cell interactions beyond the stage of virus attachment. Modelling predictions suggest that the mutations alter the local properties of the loop within domain III, and may compromise interactions of this domain with an adjacent region of domain I during conformational changes that occur in the E protein in association with virus entry.
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PMID:Neuroblastoma cell-adapted yellow fever virus: mutagenesis of the E protein locus involved in persistent infection and its effects on virus penetration and spread. 1565 61

In eukaryotic cells IQGAP1 binds to and alters the function of several proteins, including actin, E-cadherin, beta-catenin, Cdc42, and Rac1. Yeast IQGAP1 homologues have an important role in cytoskeletal organization, suggesting that modulation of the cytoskeleton is a fundamental role of IQGAP1. Phosphorylation is a common mechanism by which cells regulate protein function. Here we demonstrate that endogenous IQGAP1 is highly phosphorylated in MCF-7 human breast epithelial cells. Moreover, incubation of cells with phorbol 12-myristate 13-acetate (PMA) stimulated phosphate incorporation into IQGAP1. By using mass spectrometry, Ser-1443 was identified as the major site phosphorylated on IQGAP1 in intact cells treated with PMA. Ser-1441 was also phosphorylated but to a lesser extent. In vitro analysis with purified proteins documented that IQGAP1 is a substrate for protein kinase Cepsilon, which catalyzes phosphorylation on Ser-1443. Consistent with these findings, inhibition of cellular protein kinase C via bisindolymaleimide abrogated Ser-1443 phosphorylation in response to PMA. To elucidate the biological sequelae of phosphorylation, Ser-1441 and Ser-1443 were converted either to alanine, to create a nonphosphorylatable construct, or to glutamic acid and aspartic acid, respectively, to generate a phosphomimetic IQGAP1. Although overexpression of wild type IQGAP1 promoted neurite outgrowth in N1E-115 neuroblastoma cells, the nonphosphorylatable IQGAP1 S1441A/S1443A had no effect. In contrast, the S1441E/S1443D mutation markedly enhanced the ability of IQGAP1 to induce neurite outgrowth. Our data disclose that IQGAP1 is phosphorylated at multiple sites in intact cells and that phosphorylation of IQGAP1 will alter its ability to regulate the cytoskeleton of neuronal cells.
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PMID:IQGAP1 promotes neurite outgrowth in a phosphorylation-dependent manner. 1569 13

IGF binding proteins (IGFBPs) modulate IGF cellular bioavailability and may directly regulate tumor growth and invasion. We have previously shown that IGFBP-2 binds and localizes IGF-I to the pericellular matrix and have provided some evidence suggesting that the heparin binding domain (HBD) or the arginine-glycine-aspartic acid (RGD) integrin binding motif may be involved in these interactions. However, the precise mechanisms involved remain to be elucidated. We therefore mutated the HBD or RGD sequence of IGFBP-2 and investigated consequent effects on extracellular matrix (ECM) binding, IGF-induced proliferation, and migration of neuroblastoma cells. IGFBP-2 and its arginine-glycine-glutamic acid (RGE) mutant similarly bound ECM components, whereas binding of mutant HBD-IGFBP-2 to each of the ECM substrates was markedly reduced by 70-80% (P < 0.05). IGF-I (100 ng/ml) increased incorporation of 3H-thymidine in neuroblastoma SK-N-SHEP cells by approximately 30%, an effect blunted by exogenously added native or either mutant IGFBP-2. Overexpression of IGFBP-2 and its RGE mutant potently promoted SHEP cell proliferation (5-fold), whereas SHEP cell proliferation was negligible when HBD-IGFBP-2 was overexpressed. Addition or overexpression of IGFBP-2 and its RGE mutant potently (P < 0.05) enhanced SHEP cell migration/invasion through the ECM. However, overexpression of the HBD-IGFBP-2 mutant potently inhibited (50-60%) SHEP cell invasion through ECM. Thus, IGFBP-2, which binds to the ECM, enhances proliferation and metastatic behavior of neuroblastoma cells, functions that directly or indirectly use the HBD but not the integrin binding sequence. Our novel findings thus point to a key role for the HBD of IGFBP-2 in the control and regulation of neuroblastoma growth and invasion.
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PMID:Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. 1599 46


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