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)

There is considerable interest in the role of the TRK family of neuotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.
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PMID:Expression and function of TRK-B and BDNF in human neuroblastomas. 826 43

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

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

The function of truncated trkB receptors during nervous system plasticity and regeneration is currently unknown. The extensive nonneuronal localization of truncated trkB-T1 receptors, coupled with their up-regulation by CNS glial cells in response to injury, has led to the speculation that these receptors may sequester BDNF and NT-4/5 to reduce their local availability and, thus, limit axonal sprouting. Conversely, trkB-T1 receptors could bind and present neurotrophins to injured axons and facilitate their regeneration in a manor analogous to that proposed for p75(NTR) receptors on Schwann cells. To address this issue, we used an in vitro coculture paradigm in which wild-type 3T3 NIH fibroblasts or two different 3T3 cell clones stably expressing trkB-T1 receptors served as monolayer substrates upon which to evaluate the effect of trkB-T1 receptors on nonneuronal cells to influence neurotrophin (NGF, BDNF, NT-3, and NT-4/5)-induced neurite outgrowth from retinoic acid (RA)-treated SY5Y neuroblastoma cells. In these experiments, BDNF and NT-4/5 produce a strong phosphorylation of trk receptors on the RA-SY5Y cells and induce differentiation of the SY5Y cells (as measured by the development of neurofilament-positive neuritic processes). This ability of the trkB ligands to stimulate neurite outgrowth is dose dependent since increasing concentrations of BDNF (5, 25, and 100 ng/ml) result in an increased percentage of SY5Y cells developing neurites and in progressively longer neurites from SY5Y cells on the control 3T3 monolayers. In these experiments, BDNF and NT-4/5 induce the strongest neurite outgrowth, followed by NT-3 and then NGF. When trkB-T1 receptors are present on the 3T3 cell substratum both BDNF- and NT-4/5-induced neurite extension from the SY5Y cells are strongly inhibited. In contrast, NGF-induced neurite growth is unaffected and NT-3-associated growth is somewhat reduced. These results suggest that the inhibitory effect of the trkB-T1 receptors on the nonneuronal cell substrates is selective for neurite outgrowth that is mediated via the trkB-kinase receptors on the neuroblastoma cells. This ability of trkB-T1 receptors on the nonneuronal substratum to inhibit BDNF-induced neurite outgrowth can be overcome by the addition of high concentrations of BDNF (1 microg/ml). Binding assays using 125I-BDNF suggest that this inhibitory effect could be mediated via binding and internalization of BDNF by the trkB-T1 receptors on the 3T3 cells. These results provide strong support for the hypothesis that the up-regulation of trkB-T1 receptors on astrocytes following CNS lesions enhances the sequestration of the trkB ligands, BDNF and NT- 4/5, at the site of reactive gliosis and, thus, contributes to the inhibition of CNS axonal regeneration from neurons expressing trkB-kinase receptors by removing their ligands from the extracellular environment.
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PMID:Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro. 941 37

Retinoic acid (RA) induces the differentiation of many cell lines, including those derived from neuroblastoma. RA treatment of SH-SY5Y cells induces the appearance of functional Trk B and Trk C receptors. Acute stimulation of RA-predifferentiated SH-SY5Y cells with brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), or neurotrophin 4/5 (NT-4/5), but not nerve growth factor (NGF), induces Trk autophosphorylation, followed by phosphorylation of Akt and the extracellular signal-regulated kinases (ERKs) 1 and 2. In addition, BDNF, NT-3, or NT-4/5, but not NGF, promotes cell survival and neurite outgrowth in serum-free medium. The mitogen-activated protein kinase and ERK kinase (MEK) inhibitor PD98059 blocks BDNF-induced neurite outgrowth and growth-associated protein-43 expression but has no effects on cell survival. On the other hand, the phosphatidylinositol 3-kinase inhibitor LY249002 reverses the survival response elicited by BDNF, leading to a cell death with morphological features of apoptosis.
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PMID:Extracellular-regulated kinases and phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor-mediated survival and neuritogenesis of the neuroblastoma cell line SH-SY5Y. 1050 Nov 84

Little is known about the signal transduction pathways of TRK family receptors in neuroblastoma (NB) cells. In this study, an NB cell line, designated MP-N-TS, was established from an adrenal tumor taken from a 2-year-old boy. This cell line expressed both TRK-A and TRK-B receptors, which is rare in a single NB cell line. Therefore, the MP-N-TS cell line was used to determine whether the signal transduction through these constitutive receptors is functional. Three neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4 / 5 (NT-4 / 5), induced tyrosine phosphorylation of panTRK, and BDNF and NT-4 / 5 induced tyrosine phosphorylation of TRK-B. Tyrosine phosphorylation of panTRK and / or TRK-B by the neurotrophins was inhibited in the presence of a tyrosine kinase inhibitor K252a. Tyrosine phosphorylation of Src homologous and collagen (Shc), extracellular signal-regulated kinase (ERK)-1 and ERK-2, and phospholipase C-gamma1 (PLC-gamma1) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a. Activation of Ras, detected as the GTP-bound form of Ras, was induced by the three neurotrophins. The neurotrophins did not modulate the expressions of TRK-A or TRK-B mRNA, but they did induce the expression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, whereas exogenous BDNF and NT-4 / 5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4 / 5 increased the number of viable cells, while NGF did not. Our results demonstrate that the signal transduction pathways through TRK-A and TRK-B in MP-N-TS cells are functional and similar, and the main downstream signaling pathways from the three neurotrophins are mitogen-activated protein kinase (MAPK) cascades through Shc, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-gamma1. Further, BDNF and NT-4 / 5 increased cell viability. The MP-N-TS cell line should be useful for clarifying the TRK-A and TRK-B signaling pathways responsible for the different prognoses in patients with NB.
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PMID:Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells. 1122 44

Trophic molecules are key regulators of survival, growth and differentiation of neural cells. Neuronal cell type Neuro-2a is a good model to study development and molecules modulating this process, and retinoic acid (RA) and neurotrophins (NGF, BDNF, NT-3 and NT-4) have been shown to be active in this modulation. The purpose of the present study was the functional analysis of these trophic molecules in our short-term bioassay of Neuro-2a cells, an immortalised murine neuroblastoma cell line. Through cell counting, image process and arithmetic combination of digital parameters of treated and untreated cultures, we show that RA inhibits growth and induces morphological neuronal phenotype of treated cells. Through DNA labelling with BrdU we also show that NGF, BDNF, and NT-3 increase survival and proliferation of cells, grown in serum-deprived media. From these results we conclude that neurotrophins have manifest trophic effects on cells improving survival, growth and proliferation and we also confirm the growth arrest and differentiation properties of RA on Neuro-2a cells.
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PMID:Growth inhibition, morphological differentiation and stimulation of survival in neuronal cell type (Neuro-2a) treated with trophic molecules. 1151 98

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans and is characterized by neuronal loss, neurofibrillary tangles and beta-amyloid deposition. The interaction between neurotrophins and their tyrosine kinase (trk) receptors is important for cellular differentiation and survival. Interestingly, marked reductions in neurotrophins and receptors have been reported in AD. The cause of the decrease in these molecules remains unclear. However, the role of beta-amyloid (A beta) appears central in understanding the mechanisms controlling neurotrophin/trk expression. In this study we exposed SHSY5Y neuroblastoma cells to A beta or hydrogen peroxide and measured the expression of trk B/truncated trk B, and brain-derived neurotrophic factor (BDNF)/NT4 at the protein and molecular level. We show that A beta or hydrogen peroxide (H(2)O(2)) induces oxidative stress and cell cytotoxicity. The exposure of cells to A beta results in an increased trk B expression with a concurrent reduction in truncated trk B levels. H(2)O(2) exposure decreased both trk B and truncated trk B levels at the cell surface. At the molecular level trk B RNA increased in the presence of A beta and was unaffected by H(2)O(2). Similarly, BDNF and NT4 levels increased in the presence of A beta. Pre-treatment of cells with the anti-oxidant melatonin returns trk receptor expression, mRNA and BDNF/NT4 secretion to normal levels. These results are significant as they can help in the planning and implementation of AD treatment strategies involving neurotrophins.
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PMID:Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin. 1289 7

The Trk family consists of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-NGF, BDNF, NT3 and NT4. Neurotrophins mediate their multiple effects through a number of distinct intracellular signaling cascades regulating such diverse biological responses as cell survival, proliferation and differentiation in normal and neoplastic neuronal cells. Expression of Trk receptors also plays an important role in the biology and clinical behavior of neuroblastomas. High expression of TrkA is present in neuroblastomas with favorable biological features and highly correlated with patient survival, whereas TrkB is mainly expressed on unfavorable, aggressive neuroblastomas. This short review discusses recent data on the biological roles of TrkA and TrkB signaling in neuroblastoma.
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PMID:Biological effects of TrkA and TrkB receptor signaling in neuroblastoma. 1592 51


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