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)

The addition of the peroxovanadium (pV) derivatives potassium bisperoxo(1,10-phenanthroline)oxovanadate(v) (bpV[phen]) or potassium bisperoxo(pyridine-2-carboxylato) oxovanadate(v) (bpV[pic]), both of which are potent inhibitors of protein tyrosine phosphatases (PTPs) [Posner et al. (1994): J Biol Chem 269:4596-4604], to the culture medium of neuroblastoma NB 41 and glioma C6 cells resulted in a marked decrease in their proliferation rates and a progressive accumulation at the G2/M transition of the cell cycle. The effect was dependent on dose, cell type, and a pV compound employed. Mean values of the RNA-to-DNA and RNA-to-protein ratios in NB cells treated for 48 h with increased doses of bpV[phen] showed that general synthetic functions were not altered, nor did we observe oxidative damage to DNA using a sensitive DNA-nick detection assay. No changes in the expression and localization of vimentin, a component of the intermediate filament cytoskeleton, were observed by indirect immunofluorescence, showing that treatment did not disturb the cytoskeleton network. Measurements of BrdU incorporation into newly synthesized DNA showed that cells treated were not totally arrested. Furthermore, cells arrested G2/M were able to reenter the cycle rapidly after the release of inhibition. This progressive accumulation of G2/M coincided with the detection of tyrosine-phosphorylated p34cdc2 and a dramatic reduction in its kinase activity toward histone H1 by 48 h of culture. Both compounds were equally potent in inhibiting the catalytic activity of a yeast and the structurally distant mouse cdc25B in vitro, suggesting that augmented tyrosine phosphorylation of p34cdc2 derived from the in vivo inhibition of cdc25. Their equal in vitro potency contrasted with the considerably greater potency of bpV[phen] in vivo, in vivo suggesting that factors regulating the intracellular access of these compounds to cdc25 might be critical in determining in vivo specificity. In conclusion the final consequence of long-term exposure to potent and structurally defined PTP inhibitors on two highly proliferative nerve cell lines is to restrict cell growth. The corresponding hyperphosphorylation and reduced activity of p34cdc2 likely reflects the unusual sensitivity of cdc25 as an in vivo target for peroxovanadium compounds.
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PMID:Arrest at the G2/M transition of the cell cycle by protein-tyrosine phosphatase inhibition: studies on a neuronal and a glial cell line. 856 56

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.
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PMID:5-HT3 receptor-independent inhibition of the depolarization-induced 86Rb efflux from human neuroblastoma cells, TE671, by ondansetron. 856 32

Xenopus oocytes were injected with RNAs for the two inward-rectifier potassium channel subunits Kir3.1 (GIRK1) and Kir3.4 (rcKATP or CIR) in addition to RNA from the neuroblastoma cell line KAN-TS. Potassium currents were evoked by neuropeptide Y in oocytes injected with polyadenylated RNA or with cRNA from pools of a neuroblastoma (KAN-TS) cDNA library, and progressive subdivision of responding pools yielded a single cDNA. The encoded protein contains 381 amino acids, has the seven hydrophobic domains characteristic of G protein-coupled receptors, and is 31% identical to the Y1 receptor: potassium currents were induced by neuropeptide Y (EC50=60pm) and Y2-selective analogues. Coexpression with potassium channel subunits will be a generally useful method for the cloning of G protein-coupled receptors.
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PMID:Coexpression with potassium channel subunits used to clone the Y2 receptor for neuropeptide Y. 864 76

The D2-like dopamine (DA) receptor family has continued to expand and now includes the D2-short (D2S) and D2-long (D2L) receptor isoforms and the D3 and D4 receptors. The D2 receptor isoforms differ in length by 29 amino acids within the third cytoplasmic loop, a region of the receptor believed to be important for G protein coupling. This observation has led to the hypothesis that the two isoforms of the D2 receptor may utilize different signal transduction pathways when present in the same cell. The D2 and D3 receptors, although mostly different, show some common amino acid sequences within the third cytoplasmic loop. Thus, it is possible that the D2 and D3 receptors may employ similar signal transduction pathways. To test these hypotheses directly, NG108-15 neuroblastoma-glioma hybrid cells were stably transfected to express either the D2S, D2L, or D3 DA receptors. All transfected but not untransfected NG108-15 cells demonstrated a dose-dependent reduction in the peak whole-cell potassium (K+) current in response to receptor activation by DA or the DA receptor agonists quinpirole (QUIN) and apomorphine (APO). The modulation of K+ current by D2S receptor stimulation was prevented by pretreatment of the cells with cholera toxin (20 micrograms/ml for 18 h), whereas pertussis toxin pretreatment (500 ng/ml for 4 h) completely blocked the effects of D2L and D3 receptor activation. These observations suggest that the signal transduction mechanisms involved in coupling the two isoforms of the D2 receptor to the K+ current are different, whereas the D2L and D3 receptor coupling mechanisms may be similar. In direct support of this hypothesis, it was observed that the intracellular application of a polyclonal antibody that is specific for the GO alpha subunit completely blocked the ability of D2L and D3 receptors to modulate outward K+ currents. In contrast, the D2S-mediated modulation of K+ currents was blocked by intracellular application of an antibody recognizing GS alpha but not GO alpha. These findings demonstrate that D2S and D2L receptors are able to couple to a common effector in a cell via two G protein pathways.
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PMID:D2L, D2S, and D3 dopamine receptors stably transfected into NG108-15 cells couple to a voltage-dependent potassium current via distinct G protein mechanisms. 889 Apr 57

The cytoskeletal protein non-erythroid alpha-spectrin is well documented as an endogenous calpain substrate, especially under pathophysiological conditions. In cell necrosis (e.g. maitotoxin-treated neuroblastoma SH-SY5Y cells), alpha-spectrin breakdown products (SBDPs) of 150 kDa and 145 kDa were produced by cellular calpains. In contrast, in neuronal cells undergoing apoptosis (cerebellar granule neurons subjected to low potassium and SH-SY5Y cells treated with staurosporine), an additional SBDP of 120 kDa was also observed. The formation of the 120 kDa SBDP was insensitive to calpain inhibitors but was completely blocked by an interleukin 1 beta-converting-enzyme (ICE)-like protease inhibitor, Z-Asp-CH2OC(O)-2,6-dichlorobenzene. Autolytic activation of both calpain and the ICE homologue CPP32 was also observed in apoptotic cells. alpha-Spectrin can also be cleaved in vitro by purified calpains to produce the SBDP doublet of 150/145 kDa and by ICE and ICE homologues [ICH-1, ICH-2 and CPP32(beta)] to produce a 150 kDa SBDP. In addition, CPP32 and ICE also produced a 120 kDa SBDP. Furthermore inhibition of either ICE-like protease(s) or calpain protects both granule neurons and SH-SY5Y cells against apoptosis. Our results suggest that both protease families participate in the expression of neuronal apoptosis.
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PMID:Non-erythroid alpha-spectrin breakdown by calpain and interleukin 1 beta-converting-enzyme-like protease(s) in apoptotic cells: contributory roles of both protease families in neuronal apoptosis. 892 Sep 67

Opiates and opioid peptides carry out their regulatory effects mainly by inhibiting neuronal activity. At the cellular level, opioids block voltage-dependent calcium channels, activate potassium channels and inhibit adenylate cyclase, thus reducing neurotransmitter release. An increasing body of evidence indicates an additional opposite, stimulatory activity of opioids. The present review summarizes the potentiating effects of opioids on transmitter release and the possible cellular events underlying this potentiation: elevation of cytosolic calcium level (by either activating Ca2+ influx or mobilizing intracellular stores), blockage of K+ channels and stimulation of adenylate cyclase. Biochemical, pharmacological and molecular biology studies suggest several molecular mechanisms of the bimodal activity of opioids, including the coupling of opioid receptors to various GTP-binding proteins, the involvement of different subunits of these proteins, and the activation of several intracellular signal transduction pathways. Among the many experimental preparations used to study the bimodal opioid activity, the SK-N-SH neuroblastoma cell line is presented here as a suitable model for studying the complete chain of events leading from binding to receptors down to regulation of transmitter release, and for elucidating the molecular mechanism involved in the stimulatory effects of opioid agonists.
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PMID:Stimulatory effects of opioids on transmitter release and possible cellular mechanisms: overview and original results. 894 25

An expression profile of active genes in a human neuroblastoma cell line CHP134 was obtained by collecting 1222 partial sequences from a 3'-directed cDNA library representing a non-biased mRNA population. By comparing this expression profile with the compiled profiles of multiple tissues, several novel gene transcripts that appeared only in the profile of the neuroblastoma cell line were identified. Further analyses by Northern blotting revealed two specific cDNA clones that are expressed in most of the human neuroblastomas examined, and three that are in some of the human neuroblastoma cell lines as well as in the adult human brain. Full-size cDNAs were cloned using these five partial cDNA sequences as probes and sequenced. A database search revealed that they are all novel and unique sequences: one sharing some amino acid sequence similarities with a cytoskeletal protein, two clones likely to be transcriptional factors, a clone that has characteristic potassium channel properties, and a clone that is non-homologous to any one of the known proteins. Thus, we argue that the collection of 3'-directed cDNA sequences in combination with the compiled expression profiles of active genes in multiple tissues is a powerful tool for discovering novel genes that are specifically expressed in a given cell or tissue, in this case neuroblastomas and/or nerve tissue.
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PMID:Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles. 903 1

Both ice-like protease and calpain have been shown to be involved in apoptosis in non-neuronal cells. Cultured rat cerebellar granule neurons undergo apoptosis when exposed to low potassium-containing medium. Calpain inhibitors 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD150606) and N-acetyl-Leu-Leu-Met-CHO (calpain inhibitor II) as well as interleukin-beta 1 converting enzyme (ICE)-like protease inhibitor Z-Asp-CH2OC(O)-2,6-dichlorobenzene (Z-D-DCB) protect against such apoptotic death. They also reduce DNA laddering and the number of apoptotic nuclei. Staurosporine treatment also evokes apoptosis in human neuroblastoma SH-SY5Y. While Z-D-DCB is again anti-apoptotic, calpain inhibitors only provide modest effects in this model. Our results suggest that ICE-like protease plays a critical role in neuronal apoptosis whereas the contributions of calpain are more cell-type dependent.
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PMID:Effects of ICE-like protease and calpain inhibitors on neuronal apoptosis. 905 90

The relative permeability sequences of the rat connexin 43 (rCx43) gap junction channel to seven cations and chloride were examined by double whole cell patch clamp recording of single gap junction channel currents in rCx43 transfected neuroblastoma 2A (N2A) cell pairs. The measured maximal single channel slope conductances (gammaj, in pS) of the junctional current-voltage relationships in 115 mM XCI were RbC1 (103) > or = CsC1 (102) > KC1 (97) > NaC1 (79) > or = LiC1 (78) > TMAC1 (65) > TEAC1 (53) and for 115 mM KY were KBr (105) > KC1 (97) > Kacetate (77) > Kglutamate (61). The single channel conductance- aqueous mobility relationships for the test cations and anions were linear. However, the predicted minimum anionic and cationic conductances of these plots did not accurately predict the rCx43 channel conductance in 115 mM KC1. Instead, the conductance of the rCx43 channel in 115 mM KC1 was accurately predicted from cationic and anionic conductance-mobility plots by applying a mobility scaling factor Dx/Do, which depends upon the relative radii of the permeant ions to an estimated pore radius. Relative permeabilities were determined for all of the monovalent catious and anions tested from asymmetric salt reversal potential measurements and the Goldman-Hodgkin-Katz voltage equation. These experiments estimate the relative chloride to potassium permeability to be 0.13. The relationship between the relative cation permeability and hydrated radius was modeled using the hydrodynamic equation assuming a pore radius of 6.3 +/- 0.4 A. Our data quantitatively demonstrate that the rCx43 gap junction channel is permeable to monovalent atomic and organic cations and anions and the relative permeability sequences are consistent with an Eisenman sequence II or I, respectively. These predictions about the rCx43 channel pore provide a useful basis for future investigations into the structural determinants of the conductance and permeability properties of the connexin channel pore.
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PMID:Monovalent ion selectivity sequences of the rat connexin43 gap junction channel. 910 7

The unitary conductances and permeability sequences of the rat connexin40 (rCx40) gap junction channels to seven monovalent cations and anions were studied in rCx40-transfected neuroblastoma 2A (N2A) cell pairs using the dual whole cell recording technique. Chloride salt cation substitutions (115 mM principal salt) resulted in the following junctional maximal single channel current-voltage relationship slope conductances (gamma 1 in pS): CsC1 (153), RbC1 (148), KC1 (142), NaC1 (115), LiC1 (86), TMAC1 (71), TEAC1 (63). Reversible block of the rCx40 channel was observed with TBA. Potassium anion salt gamma j are: Kglutamate (160), Kacetate (160), Kaspartate (158), KNO3 (157), KF (148), KC1 (142), and KBr (132). Ion selectivity was verified by measuring reversal potentials for current in rCx40 gap junction channels with asymmetric salt solutions in the two electrodes and using the Goldman-Hodgkin-Katz equation to calculate relative permeabilities. The permeabilities relative to Li+ are: Cs+ (1.38), Rb+ (1.32), K+ (1.31), Na+ (1.16), TMA+ (0.53), TEA+ (0.45), TBA+ (0.03), Cl- (0.19), glutamate+ (0.04), and NO(3)- (0.14), assuming that the monovalent anions permeate the channel by forming ion pairs with permeant monovalent cations within the pore thereby causing proportionate decreases in the channel conductance. This hypothesis can account for why the predicted increasing conductances with increasing ion mobilities in an essentially aqueous channel were not observed for anions in the rCx40 channel. The rCx40 effective channel radius is estimated to be 6.6 A from a theoretical fit of the relationship of relative permeability and cation radius.
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PMID:Monovalent cation permeation through the connexin40 gap junction channel. Cs, Rb, K, Na, Li, TEA, TMA, TBA, and effects of anions Br, Cl, F, acetate, aspartate, glutamate, and NO3. 910 8


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