UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have utilised SH-SY5Y human neuroblastoma cells and primary cultures of rat neonatal cerebellar granule cells, both expressing M3 muscarinic receptors, to examine agonist driven polyphosphoinositide hydrolysis and alterations in intracellular calcium. 2. Stimulation of SH-SY5Y cells leads to a biphasic increase in intracellular calcium, the initial peak being due to the release of calcium from an intracellular store and the second maintained phase being due to calcium entry across the plasma membrane. The channel involved does not appear to be voltage sensitive, to involve a pertussis toxin sensitive G protein, or be opened by inositol polyphosphates. 3. Muscarinic receptor stimulation also leads to increased inositol polyphosphate formation in SH-SY5Y cells. Ins(1,4,5)P3 mass formation was biphasic in profile whereas Ins(1,3,4,5)P4 mass formation was slower and monophasic in profile. These data are consistent with substantial activity of 5-phosphatase (dephosphorylating Ins(1,4,5)P3 to Ins(1,4)P2) and 3-kinase (phosphorylating Ins(1,4,5)P3 to Ins(1,3,4,5)P4) in SH-SY5Y cells. 4. In order to better understand the role of Ins(1,4,5)P3 and its metabolites in calcium homeostasis we have examined the ability of a variety of natural and synthetic analogues to release intracellular sequestered calcium. The Ins(1,4,5)P3 calcium mobilizing receptor displays a remarkable degree of stereo- and positional selectivity with the most potent agonist to date being Ins(1,4,5)P3 (EC50 = 0.09 microM). 5. As an alternative to the continuous SH-SY5Y neuroblastoma (tumour derived) cell line we have used the primary cultured cerebellar granule cell. These cells also display a biphasic increase in Ins(1,4,5)P3 mass and a subsequent release of intracellular stored calcium. In our hands carbachol appears to increase calcium influx, a response which is only visible in the absence of magnesium.
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PMID:Muscarinic receptors, phosphoinositide metabolism and intracellular calcium in neuronal cells. 131 42

Calcineurin is a calcium/calmodulin-regulated protein phosphatase. By using enzyme-immunoassay and immunocytochemistry with an affinity-purified specific antibody to this protein, we have found that calcineurin is expressed in the central and peripheral neuroendocrine cells, also termed amine precursor uptake and decarboxylation cells. In addition, calcineurin immunoreactivity was found in the central neuroendocrine neoplasms such as pineocytoma, olfactory neuroblastoma and paraganglioma. The present findings indicate that the activity of phosphatase regulated by calcium and calmodulin is involved in neuroendocrine functions, and that the enzyme can be useful for the identification and characterization of neuroendocrine cell tumors.
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PMID:Calcineurin, a calcium/calmodulin-regulated protein phosphatase, in mammalian neuroendocrine cells and neoplasms. 133 5

The effects of chlorpromazine and related compounds upon soluble and particulate Ins(1,4,5)P3-5-phosphatase were investigated in rat GH3 pituitary and in human IMR-32 neuroblastoma cells. Chlorpromazine inhibited both soluble and particulate activities with an IC50 of 1 mM after a preincubation time of 10 min at 37 degrees C. The inhibition was time-dependent and could not be reversed by washing the membranes. Inhibition of soluble activity was found at mM concentrations with a number of phenothiazine derivatives with an apparent requirement for a-Cl, an-SCH3 or a-CF3 (compared with an-H or a-COCH3) substituent at the ring position 2. Such a requirement was also seen in other tricyclic compounds, although clozapine was not active and methixene was active. No such requirement was seen for the particulate enzyme.
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PMID:Inhibition of inositol-1,4,5-trisphosphate-5-phosphatase by chlorpromazine and related compounds. 133 63

A non-radioactive chromosomal in situ hybridization technique utilizing a biotin-streptavidin-polyalkaline-phosphatase complex was successfully applied to three neuroblastoma cell lines for detection of MYCN amplification. These cell lines, designated PER-106, PER-107, and PER-108, were derived from consecutive bone marrow samples taken from a patient with stage IV neuroblastoma. The cell line derived at diagnosis (PER-106) exhibited MYCN amplification in the form of variable numbers of double-minute chromosomes, small fragments, and rings of varying sizes. This observed variability of MYCN amplification may explain the reported heterogeneity of both MYCN mRNA and protein expression among individual cells of some neuroblastomas. The cell lines derived from subsequent samples (PER-107 and PER-108) contained amplified MYCN as two consistent homogeneously staining regions in every cell. These were located on the short arms of chromosomes 6 and 14. Thus, amplified MYCN was identified in each cell line and demonstrated the concurrent evolution of amplification with cytogenetic abnormalities.
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PMID:Detection of MYCN amplification in three neuroblastoma cell lines by non-radioactive chromosomal in situ hybridization. 158 79

Okadaic acid, a specific and potent inhibitor of protein phosphatases 2A and 1, was tested for its effect on the morphology of a number of cell types: freshly isolated rat hepatocytes in suspension or in primary culture, the human mammary carcinoma cell line MCF-7, the human neuroblastoma cell line SK-N-SH, rat pituitary adenoma GH3 cells, and rat promyelocytic IPC-81 cells. All the cell types reacted within a few hours to okadaic acid in the concentration range 0.1 to 1 microM with profound morphological alterations. Among the changes noted were: condensation of chromatin, shedding of cell contents via surface bleb formation, redistribution and compacting of cytoplasmic organelles, formation of cytoplasmic vacuoles, and hyperconvolution of the nuclear membrane. In some cells nuclear fragmentation was noted. In addition, cells growing as monolayers rounded up and detached from the substratum. The treated cells had no swollen mitochondria and retained the ability to exclude trypan blue until the final stage of dissolution, supporting the hypothesis that the changes were apoptotic rather than necrotic. In hepatocytes the action of okadaic acid was mimicked by another phosphatase inhibitor, microcystin, and was accompanied by shrinkage of the cell volume, as judged by Coulter counter analysis. The action of phosphatase inhibitor was not abolished by protein synthesis inhibitors, Ca(2+)-depleted medium, or phorbol ester. Although hepatocyte DNA replication was very sensitive to inhibition by okadaic acid, DNA fragmentation was less pronounced in response to okadaic acid than other agents inducing the morphological appearance of apoptosis.
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PMID:The protein phosphatase inhibitor okadaic acid induces morphological changes typical of apoptosis in mammalian cells. 164 24

To assess the usefulness of immunocytochemical analysis of bone marrow in patients with neuroblastoma, marrow smears from 33 staging procedures in 12 patients were examined using an indirect immunoalkaline phosphatase technique with monoclonal antibodies raised against human neural tissue. Marrow aspirate and trephine collagenase digest specimens from individual sites were each tested with the monoclonal antibody UJ13A and with a pool of three related antibodies. The results were compared with morphological assessment of conventionally stained aspirates and trephine specimens taken at the same time. Immunostaining suggested the presence of tumour in seven of 18 staging procedures in which conventional techniques had shown infiltration. Tumour infiltration was also suggested in four of 10 staging procedures with suspicious trephine specimens, but in none of three with relatively innocent histological and cytological features. Immunological investigation provides no additional information about the presence of infiltration if conventional microscopy has shown definite tumour. When histological appearances are suspicious, immunostaining of stored aspirate smears or collagenase digest specimens may provide evidence of infiltration. There are insufficient data to comment on the value of immunostaining when conventional techniques reveal "normal" marrow, but the impression gained from this study is that immunostaining has a limited role in the detection of metastatic neuroblastoma, which yet remains to be defined.
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PMID:Immunocytochemical examination of bone marrow in disseminated neuroblastoma. 169 Feb 23

The ability of D-6-deoxy-myo-inositol 1,4,5-trisphosphate [6-deoxy-Ins(1,4,5)P3], a synthetic analogue of the second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], to mobilise intracellular Ca2+ stores in permeabilised SH-SY5Y neuroblastoma cells was investigated. 6-Deoxy-Ins(1,4,5)P3 was a full agonist (EC50 = 6.4 microM), but was some 70-fold less potent than Ins (1,4,5)P3 (EC50 = 0.09 microM), indicating that the 6-hydroxyl group of Ins(1,4,5)P3 is important for receptor binding and stimulation of Ca2+ release, but is not an essential structural feature. 6-Deoxy-Ins(1,4,5)P3 was not a substrate for Ins (1,4,5)P3 5-phosphatase, but inhibited both the hydrolysis of 5-[32P]+ Ins (1,4,5)P3 (Ki 76 microM) and the phosphorylation of [3H]Ins(1,4,5)P3 (apparent Ki 5.7 microM). 6-Deoxy-Ins (1,4,5)P3 mobilized Ca2+ with different kinetics to Ins(1,4,5)P3, indicating that it is probably a substrate for Ins (1,4,5)P3 3-kinase.
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PMID:Interaction of synthetic D-6-deoxy-myo-inositol 1,4,5-trisphosphate with the Ca2(+)-releasing D-myo-inositol 1,4,5-trisphosphate receptor, and the metabolic enzymes 5-phosphatase and 3-kinase. 184 23

The hypothesis that the small portion of cellular phosphoinositide participating in signal transduction might be preferentially recycled within the plasma membrane was tested in rat glioma (C6) and murine neuroblastoma (N1E-115) cells. Percoll density gradient centrifugation was used to isolate a purified plasma membrane fraction and the subcellular distribution of all enzymes mediating phosphoinositide turnover was assessed. A small but significant proportion of PtdInsP2-specific phosphodiesterase was located in the plasma membrane but only two of the five enzymes required to replace PtdInsP2 (diacylglycerol kinase and PtdInsP kinase) also were present. CTP:phosphatidate cytidylyltransferase and CMP-phosphatidate:inositol phosphatidyltransferase were located exclusively in a microsomal fraction containing enriched levels of endoplasmic reticulum markers. Thus, diacylglycerol from agonist-stimulated cleavage of PtdInsP2, or phosphatidic acid formed from it, must be transferred to the endoplasmic reticulum for conversion to PtdIns. Plasma membrane also lacked PtdIns kinase. If the soluble PtdIns kinase has access to membrane-bound substrate, PtdIns may be phosphorylated to PtdInsP before or during transport to the plasma membrane. Phosphorylation by the predominantly plasma membrane PtdInsP kinase to form PtdInsP2 completes the cycle. PtdInsP phosphatase was present in all membrane fractions suggesting that PtdInsP can be returned to the PtdIns pool in plasma membrane and elsewhere. PtdInsP2 phosphatase was almost exclusively in the cytosol suggesting that reversible interchange between PtdInsP and PtdInsP2 in the plasma membrane may be modulated by the ability of this phosphatase to act on PtdInsP2 in the membrane. Thus, PtdIns resynthesis in the plasma membrane of these cells does not occur and is not required for phosphoinositide-mediated signal transduction.
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PMID:Phosphoinositide metabolism in cultured glioma and neuroblastoma cells: subcellular distribution of enzymes indicate incomplete turnover at the plasma membrane. 215 58

The contribution of polyphosphoinositides to muscarinic receptor-stimulated phosphoinositide turnover has been evaluated for intact and digitonin-permeabilized human SK-N-SH neuroblastoma cells. Addition of carbamoylcholine to [3H]inositol-prelabeled intact cells resulted in a rapid (5-10 sec) loss of phosphatidylinositol-4,5-bisphosphate and the concomitant appearance of radiolabeled inositol-1,4,5-trisphosphate, inositol-1,3,4-trisphosphate, and inositol tetrakisphosphate. In the presence of the agonist, production of these inositol polyphosphates remained enhanced for up to 45 min. Inositol mono- and bisphosphates steadily accumulated in response to receptor activation and in the presence of Li+ comprised greater than 95% of agonist-stimulated inositol phosphate formation at incubation times greater than 5 min. The major inositol bisphosphate isomer was the 1,4-species. Of the two inositol monophosphates produced, radioactivity recovered in inositol-4-monophosphate increased continuously, whereas that in the inositol-1-monophosphate/inositol-3-monophosphate fraction was delayed in appearance but thereafter progressively accumulated. Omission of Ca2+ reduced carbamoylcholine-stimulated inositol phosphate release by greater than 50% but did not significantly influence the ratio of inositol monophosphates formed. Upon addition of atropine to agonist-pretreated cells, radioactivity was lost from inositol phosphates in the following order: inositol-1,4,5-trisphosphate greater than inositol-1,3,4-trisphosphate greater than inositol-1,4-bisphosphate = inositol-4-monophosphate greater than inositol-1-monophosphate/inositol-3-monophosphate. Although carbamoylcholine addition to digitonin-permeabilized cells also resulted in a sustained release of inositol monophosphates, relatively more inositol-4-monophosphate was produced in these preparations. Omission of ATP from permeabilized cell incubations inhibited carbamoylcholine-stimulated 'inositol phosphate formation by greater than 70%. Whole homogenates of SK-N-SH cells metabolized added inositol-1,4,5-trisphosphate and inositol-1,4-bisphosphate exclusively to inositol-4-monophosphate, whereas inositol-1,3,4,5-tetrakisphosphate was degraded to inositol-1- or 3-monophosphate. Measurement of inositol trisphosphate 3'-kinase and 5'-phosphatase activities revealed that, following permeabilization, 3'-kinase activity was diminished, whereas that of 5'-phosphatase was enhanced. The results indicate that occupancy of muscarinic cholinergic receptors in SK-N-SH cells elicits a continuous Ca2(+)-dependent breakdown of the polyphosphoinositides rather than of phosphatidylinositol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Polyphosphoinositides are the major source of inositol phosphates in carbamoylcholine-stimulated SK-N-SH neuroblastoma cells. 216 31

Electrically permeabilised [3H]inositol-labelled SH-SY5Y human neuroblastoma cells were employed to examine the effects of two synthetic, phosphatase-resistant analogues of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] on the metabolism of cell membrane-derived [3H]Ins(1,4,5)P3 or exogenous [5-32P]Ins(1,4,4)P3. Incubation of permeabilised SH-SY5Y cells for 5 min at 37 degrees C with carbachol and guanosine 5'-[gamma-thio]triphosphate caused a decrease in [3H]phosphoinositol phospholipid levels and an increase in [3H]inositol phosphate accumulation with inositol 4-phosphate, inositol 1,4-bisphosphate, Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate comprising approximately 79%, 16%, 3% and 2%, respectively, of the increase. Inositol 1-phosphate levels did not increase upon stimulation, nor was inositol 4-phosphate converted rapidly to inositol. In parallel incubations, the analogues, DL-inositol 1,4,5-trisphosphorothioate (DL-InsP3S3) and DL-inositol 1,4-bisphosphate 5-phosphorothioate (DL-InsP3S), and synthetic racemic Ins(1,4,5)P3 (DL-InsP3), altered the profile of the [3H]inositol phosphates recovered and led, at millimolar concentrations, to a 10-15-fold increase in [3H]Ins(1,4,5)P3. The extent of inhibition of [3H]Ins(1,4,5)P3 metabolism was, however, greatest in the presence of synthetic D-Ins(1,4,5)P3 (greater than or equal to 5 mM), when [3H]Ins(1,4,5)P3 comprised approximately 50% of the increase in total [3H]inositol phosphates. Thus, under these conditions, at least 50% of [3H]inositol phosphates were derived from [3H]phosphatidylinositol 4,5-bisphosphate. [32P]Pi release from exogenous [5-32P]Ins(1,4,5)P3 was also inhibited by DL-InsP3S3, DL-InsP3S and DL-InsP3, with half-maximal inhibition at approximately 50 microM, 160 microM and 240 microM respectively. These actions were approximately ten times more potent than the effects of these compounds on [3H]inositol phosphate accumulation, indicating that homogenous mixing of exogenous and cell-membrane-derived Ins(1,4,5)P3 does not occur. These findings indicate that DL-InsP3S3 and DL-InsP3S inhibit Ins(1,4,5)P3 5-phosphatase. In contrast, the effects of synthetic DL-InsP3 and D-Ins(1,4,5)P3 are due to isotopic dilution. Whilst DL-InsP3S3 was the most potent inhibitor of dephosphorylation of exogenous or cell-membrane-derived Ins(1,4,5)P3, it was the weakest inhibitor of 3-kinase-catalysed Ins(1,4,5)P3 phosphorylation. Similarly, although approximately 50 times less potent than DL-InsP3S3, 2,3-diphosphoglycerate inhibited Ins(1,4,5)P3 5-phosphatase activity and was apparently without effect of Ins(1,4,5)P3 3-kinase activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of inositol 1,4,5-trisphosphate metabolism in permeabilised SH-SY5Y human neuroblastoma cells by a phosphorothioate-containing analogue of inositol 1,4,5-trisphosphate. 220 1

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