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

Phosphatidylinositol (PI) breakdown represents a powerful system participating in the transduction mechanism of some neurotransmitters and growth factors and producing two second messengers, diacylglycerol and inositol trisphosphate. The transformation of PC12 neuroblastoma cells into neuron-like cells induced by nerve growth factor (NGF) is preceded by a rapid stimulation of PI breakdown; however, it was not known whether PI breakdown mediates actions of other members of the neurotrophin family. The present study analyzed the effects of NGF, brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) on PI breakdown in primary cultures of embryonic rat brain cells. Cultures were grown for 7 days; PI was then labeled by incubating cultures with myo-[3H]inositol, which then were exposed acutely to growth factors. BDNF and NT-3, but not NGF, elevated the levels of labeled inositol phosphates within 10-15 min after addition to the cultures in a dose-dependent manner. ED50 values for BDNF and NT-3 were 12.4 and 64.5 ng/ml, respectively. Comparable effects were found in cultures of cortical, striatal, and septal cells. The actions of BDNF and NT-3 probably reflect actions on neurons, because no effects were seen in cultures of nonneuronal cells. In contrast, basic fibroblast growth factor induced a marked stimulation of PI breakdown in cultures of nonneuronal cells. K252b, which selectively blocks neurotrophin actions by inhibiting trk-type receptor proteins, prevented the PI breakdown mediated by BDNF and NT-3. The findings suggest that rapid and specific induction of PI breakdown is involved in the signal transduction of BDNF and NT-3, and they provide evidence that cortical neurons are functionally responsive to BDNF and NT-3 during development.
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PMID:Stimulation of phosphatidylinositol hydrolysis by brain-derived neurotrophic factor and neurotrophin-3 in rat cerebral cortical neurons developing in culture. 143 96

A large number of poor prognosis neuroblastoma (NB) tumors constitutively express brain-derived neurotrophic factor (BDNF) and variably express the gene for its tyrosine kinase (Trk) receptor TrkB. Good prognosis NB tumors typically express high levels of TrkA mRNA, which encodes the signal transducing receptor for nerve growth factor, p140TrkA. These neurotrophins are necessary for neural cell survival and differentiation. This study evaluates the effects of activation of the BDNF-TrkB signal transduction pathway on the growth, survival, morphology, and invasive capacity of NB cells. We find that the addition of BDNF to SY5Y cells induced to express p145TrkB by retinoic acid treatment does not significantly affect cell proliferation yet will support cell survival. Activation of the BDNF-TrkB signal transduction pathway stimulates disaggregation of cells and extension of neuritic processes which can be blocked by a BDNF-neutralizing antibody. Treatment of cells with K252a, an inhibitor of Trk, reverses the cellular disaggregation. An evaluation of the effects of BDNF and nerve growth factor on the ability of NB cells to penetrate basement membrane proteins indicated that BDNF stimulated a 2-fold increase while nerve growth factor inhibited RA-SY5Y cell invasion. Thus, activation of the p145TrkB signal transduction pathway stimulates NB cell survival, disaggregation, and invasion; all characteristics of metastatic cells. Furthermore, these studies indicate that activation of different Trk signal transduction pathways in NB cells results in distinct differences in tumor cell biology and these may be relevant to the clinical course of the patients.
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PMID:Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. 771 90

Prosaposin was identified as a neurotrophic factor stimulating neurite outgrowth in murine neuroblastoma (NS20Y) cells and choline acetyltransferase (ChAT) activity in human neuroblastoma (SK-N-MC) cells. The four naturally occurring saposins, which are derived by proteolytic processing of prosaposin, were tested for activity. Saposin C was found to be active, whereas saposins A, B, and D were inactive as neurotrophic factors. Dose-response curves demonstrated that nanomolar concentrations of prosaposin and saposin C stimulated neurite outgrowth and increased ChAT activity. Prosaposin and saposin C exerted activity by a mechanism independent of nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3. Binding assays utilizing saposin C as a ligand gave two saturable binding constants, a high-affinity (Kd = 19 pM) and a low-affinity (Kd = 1 nM) constant, with 2000 and 15,000 sites per NS20Y cell, respectively. Phosphorylation stimulation experiments demonstrated that brief treatment with prosaposin or saposin C enhanced phosphorylation of a variety of proteins, some of which contained phosphorylated tyrosine(s). Since both cell lines were also stimulated by ciliary neurotrophic factor (CNTF) as well as prosaposin, inhibition was tested by utilizing an anti-gp130 monoclonal antibody, which specifically inhibited CNTF stimulation; this antibody did not inhibit prosaposin or saposin C stimulation. These results indicate that prosaposin and saposin C are neurotrophic factors which initiate signal transduction by binding to a high-affinity receptor that induces protein phosphorylation.
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PMID:Identification of prosaposin as a neurotrophic factor. 793 12

Neurotrophins are responsible for the differentiation and survival of neurons in the developing and in the adult nervous system. They bind to specific membrane receptors with tyrosine kinase activity whose prototype is the product of the trkA proto-oncogene. TrkB, a member of this family, is the receptor for the neurotrophins brain derived growth factor (BDNF) and neurotrophins-3, -4/5. In this study, we show that stable expression of the c-erbA proto-oncogene, which encodes the alpha 1-isoform of the nuclear receptor for thyroid hormone (Tr alpha 1) induces the expression of trkB mRNA with a concomitant decrease to undetectable levels of trkA and trkC mRNAs in the mouse neuroblastoma N2a cell line. trkB induction by c-erbA is ligand independent, since addition of T3 had no effect. The induced trkB transcript encodes a functional gp145trkB protein, which is phosphorylated on tyrosine in response to BDNF. Furthermore, induction of trkB mRNA is also caused by transient expression of either TR alpha 1 or beta 1 isoforms. Our results are compatible with the idea that there are certain pathways which are under control of unliganded thyroid hormone receptor, and that one of these pathways results in regulation of trk expression.
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PMID:Unliganded c-erbA/thyroid hormone receptor induces trkB expression in neuroblastoma cells. 813 11

Retinoic acid (RA) induces the neuronal differentiation of many human neuroblastoma cell lines. In this study, we show that RA treatment of neuroblastoma cells induces the expression of TrkB, the receptor for the neurotrophins BDNF, NT-3, and NT-4/5. BDNF addition to RA-treated SH-SY5Y neuroblastoma cells stimulated the tyrosine phosphorylation of TrkB and neuronal differentiation. RA treatment of KCNR neuroblastoma cells, which constitutively express BDNF mRNA, resulted in the expression of TrkB and differentiation in the absence of added BDNF. Finally, in 15N neuroblastoma cells, which express BDNF mRNA but do not differentiate in response to RA, RA induced only a truncated form of TrkB. 15N cells transfected with full-length TrkB differentiated in the absence of RA. These results indicate that RA induces the neuronal differentiation of neuroblastoma cells by modulating the expression of neurotrophin receptors.
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PMID:Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. 839 22

We have used the human neuroblastoma cell line SH-SY5Y as a model system to investigate the expression and regulation of the receptors for brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) family of neurotrophins. We demonstrate that SH-SY5Y cells express transcripts encoding the low-affinity NGF receptor (LNGFR) and trkB, the signal transducing receptor unit for BDNF. Interaction of BDNF with SH-SY5Y cells increased the transcription of the c-fos gene, showing that these molecules encode functional BDNF receptors. Our findings that differentiating agents such as retinoids and cAMP analogs increased the expression of LNGFR, but decreased trkB mRNA levels, suggest that LNGFR and trkB have different roles during neuronal differentiation.
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PMID:Expression of low-affinity NGF receptor and trkB mRNA in human SH-SY5Y neuroblastoma cells. 839 2

We have previously reported that ciliary neurotrophic factor (CNTF) mRNA is upregulated in the rat striatum following trauma and that its peak is coincident with a peak in the number of GFAP-positive astrocytes. CNTF, or other neurotrophic factors present in the traumatized striatum, may be involved in the dopaminergic fiber sprouting seen following cavitation or graft implantation in animal models of Parkinson's disease. This study was undertaken in order to further characterize the neurotrophic activity present following trauma through the use of bioassays. Adult rats underwent stereotaxic biopsy of the right striatum, and gelatin sponge [gelfoam (GF)] was placed in the resultant cavity. GF was collected from 1 to 30 days following trauma and homogenized. GF extracts (with equal protein concentrations) were assayed using dorsal root ganglion (DRG) explants, dissociated ciliary ganglia (CG), and human dopaminergic neuroblastoma cell (SH-SY5Y) cultures. The GF extracts had significant neurite-promoting activity (NPA) for DRG, CG, and SH-SY5Y cells, with the maximum effect seen 7 days after trauma. NPA was not blocked by anti-nerve growth factor (NGF) Ab, but anti-brain-derived neurotrophic factor (BDNF) Ab significantly blocked the activity for DRG. The GF extracts protected the SH-SY5Y cells from the neurotoxins 6-OHDA and MPP+, as did NGF and BDNF. This neuroprotective effect of GF was not blocked by anti-NGF Ab. This study suggests that the neurotrophic activity in GF extracts has CNTF-like and BDNF-like components as well as another, undefined component.
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PMID:Traumatized rat striatum produces neurite-promoting and neurotrophic activities in vitro. 865 21

Neurons and glia are capable of both secreting and responding to a large variety of growth factors. However, information on multiple expression of growth factors and their receptors was usually obtained from uncorrelated observations, using cells from various animals of origin, developmental stages, growth phases, culture ages and culture conditions. Because of its specificity and extreme sensitivity, reverse transcription-polymerase chain reaction (RT-PCR) is uniquely suitable to study a large panel of growth factors and their receptors from a limited cell sample, free of these intervening variables. In this paper we evaluate the expression of mRNA of a total of 35 growth factor-related proteins by conducting RT-PCR on three neuronal cell lines: the PC12 rat pheochromocytoma line, the MAH rat sympathoadrenal progenitor line, and the N18 mouse neuroblastoma line. Three types of results are presented. The first confirms the existing knowledge such as the presence of Trk-A (NFG receptor) in PC12. The second consists of new information that expands and extends earlier observations, such as the presence of CNTF receptor complex in PC12, which explains our previous report that CNTF enhances the biological effects of NGF on these cells. The third consists of novel information that leads the way to further experimentation by the more conventional methods. These include the strong expression of Trk-B by MAH, predicting the biological responsiveness of MAH to BDNF and NT-4, and the expression of CNTF receptor in N18. Our results also suggest that CNTF is an autocrine factor for PC12 and MAH, since both lines express the growth factor as well as the receptor. Thus, RT-PCR is a valuable tool in growth factor research that can be used in complement to, and interactively with, other approaches such as bioassay, receptor binding, and immunochemical determination. It will be particularly useful for screening a large number of growth factors in minute areas of the brain in patients suffering from neurodegenerative diseases such as Parkinson's and Alzheimer's.
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PMID:Expression of mRNAs of multiple growth factors and receptors by neuronal cell lines: detection with RT-PCR. 878 8

A diphtheria toxin-neurotrophin-4/5 (NT-4/5) chimera (DAB389-NT4), in which the native receptor binding domain of diphtheria toxin was replaced with a synthetic gene encoding rat NT-4/5, was expressed, refolded, and purified. This fusion toxin has a deduced molecular mass of 60,163 and is formed by joining the first 389 amino acids of diptheria toxin to amino acids 1-130 of mature rat NT-4/5, using an NH2-terminal bridge of 33 additional amino acids including six consecutive histidines. Neural cell types expressing only p75LNGFR or p75LNGFR and full-length or truncated TrkB were used to evaluate the cytotoxic efficacy of DAB389-NT4. The fusion toxin produced a concentration-dependent killing of all cell populations, with LC50 values that largely reflected the known NT-4/5 binding affinities for these receptor proteins. Mean LC50 values ranged from 2,960 pM in p75LNGFR-expressing neuro-2a neuroblastoma cells to 1,075 and 70 pM, respectively, in hippocampal astrocytes (p75LNGFR+/truncated TrkB+) and cerebellar granule cells (p75LNGFR+/TrkB+). The LC50 for DAB389-NT4 in receptor-negative 3T3 fibroblasts was 20 nM. NT-4/5 and brain-derived neurotrophic factor but not ciliary neurotrophic factor added in excess neutralized DAB389-NT4 cytotoxicity. NT-4/5, however, did not reduce the cytotoxicity of intact diphtheria toxin.
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PMID:Synthesis and cytotoxic profile of a diphtheria toxin-neurotrophin-4 chimera. 900 40

Cell proliferation, the balance between mitosis and apoptosis is the result of the continuous integration of a number of different signal transduction pathways stimulated in a cell at any given point in its life. Neuroblastoma cells regulate the switch between mitosis and death, according both to intrinsic factors and extrinsic factors, such as growth factor withdrawal and action of the vitamin A derivative, retinoic acid. In this review, we describe the balance of some factors regulating growth and death of human neuroblastoma cells in vitro. These dynamic studies are necessarily-performed on cell lines, which offer controlled conditions enabling the disection of the complex stimuli mediating survival and growth (IGF, trk, BDNF) and death (transglutaminase, free radicals, Bcl-2). Although the conclusions drawn may therefore not be directly applicable to tumour cells in vivo, the results herein discussed are of sufficient significance to warrant in vivo relevance.
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PMID:Retinoids and the control of growth/death decisions in human neuroblastoma cell lines. 904 32


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