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)

In PC12 cells, NGF and other ligands of tyrosine kinase receptors increased the activity of the Rous sarcoma virus (RSV) promoter. IGF-1 stimulated the RSV promoter in SH-SY5Y neuroblastoma cells. This promoter was also activated by oncogenic Ras and Raf in different cell types, and growth factor induction was inhibited by expression of dominant negative forms of ras and raf, showing that its effect is mediated by a Ras- and Raf-dependent mechanism. Therefore, the RSV promoter should not be used in the determination of transfection efficiency in the studies on regulation of gene expression by ligands of tyrosine kinase receptors, ras and raf.
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PMID:Growth factor ligands of tyrosine kinase receptors activate the Rous sarcoma virus promoter by a Ras- and Raf-dependent mechanism. 913 5

The low-affinity nerve growth factor receptor p75NTR belongs to a membrane receptor superfamily whose members, in certain cell types, are able to transduce an apoptotic signal. To investigate the effect of p75NTR expression in neuroblastoma cells, we transfected the p75NTR cDNA into SK-N-BE cells, a neuroblastoma cell line that lacks expression of both p75NTR and TrkA. Cell clones expressing elevated levels of p75NTR showed a high degree of cell death by apoptosis, even in serum-supplemented medium. Moreover, the level of apoptosis correlated directly with the expression level of the receptor, indicating that p75NTR could activate the cell death program by itself. Clones expressing p75NTR showed a dramatic increase of cell death when switched into serum-free medium; these cultures rapidly extinguished. This apoptotic effect was greatly inhibited by NGF treatment. Our results support the hypothesis that p75NTR, when it is not bound by NGF, may play a role in neuronal selection during embryonic development and suggest that neuroblastomas may arise from immature neuroblasts that escape programmed cell death. Therefore, the loss of p75NTR expression in developing neural crest cells might be a primary event in the genesis of neuroblastoma.
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PMID:Induction of apoptosis by p75 neurotrophin receptor in human neuroblastoma cells. 913 90

This paper presents evidence that a member of the L1 family of ankyrin-binding cell adhesion molecules is a substrate for protein tyrosine kinase(s) and phosphatase(s), identifies the highly conserved FIGQY tyrosine in the cytoplasmic domain as the principal site of phosphorylation, and demonstrates that phosphorylation of the FIGQY tyrosine abolishes ankyrin-binding activity. Neurofascin expressed in neuroblastoma cells is subject to tyrosine phosphorylation after activation of tyrosine kinases by NGF or bFGF or inactivation of tyrosine phosphatases with vanadate or dephostatin. Furthermore, both neurofascin and the related molecule Nr-CAM are tyrosine phosphorylated in a developmentally regulated pattern in rat brain. The FIGQY sequence is present in the cytoplasmic domains of all members of the L1 family of neural cell adhesion molecules. Phosphorylation of the FIGQY tyrosine abolishes ankyrin binding, as determined by coimmunoprecipitation of endogenous ankyrin and in vitro ankyrin-binding assays. Measurements of fluorescence recovery after photobleaching demonstrate that phosphorylation of the FIGQY tyrosine also increases lateral mobility of neurofascin expressed in neuroblastoma cells to the same extent as removal of the cytoplasmic domain. Ankyrin binding, therefore, appears to regulate the dynamic behavior of neurofascin and is the target for regulation by tyrosine phosphorylation in response to external signals. These findings suggest that tyrosine phosphorylation at the FIGQY site represents a highly conserved mechanism, used by the entire class of L1-related cell adhesion molecules, for regulation of ankyrin-dependent connections to the spectrin skeleton.
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PMID:Tyrosine phosphorylation at a site highly conserved in the L1 family of cell adhesion molecules abolishes ankyrin binding and increases lateral mobility of neurofascin. 915 75

The ciliary neurotrophic factor (CNTF) can regulate survival and differentiation of many types of developing and adult neurons; in metastatic SK-N-BE neuroblastoma cells, it promotes differentiation and neurite outgrowth. The expression of Gelatinase A (MMP-2) and its specific tissue inhibitor (TIMP-2), a degradative system whose balance is involved in matrix invasion and metastasis, was investigated in SK-N-BE cells cultured with and without CNTF or NGF. Zymographic analysis of conditioned media revealed that the cells constitutively secrete two gelatinases, mainly pro-MMP-2 but also traces of pro-MMP-9. In a time-course experiment in the presence of 25 ng/ml of CNTF, the MMP-2 mRNA expression showed no significant modulation, while TIMP-2 mRNA up-regulated to > 2-fold after 48 h and then fell dramatically. At the same concentrations, NGF showed no effect. TIMP-2 mRNA expression showed a dose-dependent increase of up to 8-fold from 1 to 250 ng/ml of CNTF and increased secretion of TIMP-2 was confirmed by Western blotting. MMP-2 was only slightly over-expressed under the same conditions, at either mRNA or protein level, with no correlation with neurocytokine concentration. These results suggest that boosting the expression of TIMP-2 by CNTF could restrain both matrix degradation following nervous system injury and neuroblastoma aggressiveness.
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PMID:CNTF up-regulation of TIMP-2 in neuroblastoma cells. 937 46

During development in vivo and in vitro, estrogens: a) increase brain excitability, particularly in limbic structures; b) are responsible for the maturation and cyclicity of limbic-hypothalamic interrelations; c) enhance myelinogenesis; and d) may act with NGF to stimulate neurite formation. In senescence, estrogen administration would improve memory in postmenopausal women. The absence or low levels of estrogens after menopause would increase prevalence of Alzheimer's dementia (AD) more in women than men, irrespective of age or ethnicity. In the present study, addition of 17-beta estradiol to cultured human neuroblastoma cells affected growth slightly, but stimulated cell maturation as shown by increased tyrosine hydroxylase activity. The extracellular deposition in brain tissue and around blood vessels of the amyloid beta-peptide (A beta), a 4.3 kD fragment of the larger integral membrane protein, beta-amyloid precursor protein (beta-APP), is considered an important characteristic of AD. We investigated whether 17-beta estradiol may influence the formation of the A beta (thus the abnormal accumulation of amyloid proteins) in neuroblastoma cells and in a beta-APP transfected human kidney 293 cell line. Two doses of 17 beta-estradiol were added to the cultures of both cell lines. Cells were grown until confluence, metabolically labeled with 35S-methionine, immunoprecipitated with the rabbit antiserum R1282, gel electrophoresed and autoradiographed in order to compare levels of A beta under the different estradiol concentrations. While in neuroblastoma cells, levels of A beta were only slightly reduced after estradiol and a dose-effect relationship with the hormone could not be demonstrated, in the 293 cells, A beta band intensity decreased as concentration of estradiol increased. These data support the role of estrogen in normal and abnormal brain metabolism and suggest potential hormonal interventions which may reduce or prevent the formation of amyloid deposits occur in AD.
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PMID:Estrogens influence growth, maturation, and amyloid beta-peptide production in neuroblastoma cells and in a beta-APP transfected kidney 293 cell line. 941 80

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

Apolipoprotein E (apoE) is associated with the two hallmarks of Alzheimer's disease: A beta deposits and neurofibrillary tangles. ApoE synthesis was detected in astrocytes by in situ hybridization but was not detected in neurons. Nevertheless, different studies on apoE immunoreactivity reported the presence of apoE in neurons of Alzheimer, control, and necrosis pontisubicular brains. In this study, we addressed the question of potential synthesis of apoE in neurons and its possible involvement in or in response to pathological conditions. To this purpose, we have studied human neuronal cell lines (SY 5Y and Kelly cells) originating from neuroblastoma. Using monoclonal and polyclonal antibodies, a 32-kDa band was detected in SY 5Y and Kelly cells, before and after NGF differentiation. Two-dimensional gel electrophoresis analysis showed a typical profile of apoE spots resolved to the exact isoelectric points. By reverse transcription-polymerase chain reaction experiments, we demonstrated the presence of apoE mRNA in these cell lines. SY 5Y cells synthesized the apoE3 variant, whereas Kelly cells expressed both apoE3 and apoE4 isoforms, corroborating the two-dimensional gel results. These results suggested that apoE synthesis could occur in human neuronal cell lines under certain conditions.
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PMID:ApoE synthesis in human neuroblastoma cells. 944 Jan 24

Human neuroblastoma cells (IMR32) respond to treatment with either dibutyryl-cAMP or nerve factor by acquiring a neuronal phenotype which is accompanied by a marked increase in the density of neuronal (N-type) VDCC currents. Using IMR32 cells as a model for neuronal differentiation, we were interested in examining possible changes in the level of expression of the alpha1B subunit of N-type calcium channels as well as beta subunit isoforms. Upon differentiation with dibutyryl-cAMP and 5-bromo-2-deoxyuridine for 16 days, we observed a dramatic increase in alpha1B protein which initiated between day 8 and 10. Day 10 evidenced maximal expression of alpha1B protein, which was followed by an interval of relatively constant expression of alpha1B (day 12 to day 16). Monitoring beta subunit expression using a pan specific anti-beta antibody (Ab CW20), we observed an increase in expression of a single 82 kDa beta subunit. The predominant 82 kDa beta subunit expressed throughout the course of differentiation was identified as the beta1b isoform using a panel of beta subunit specific antibodies. Of significance, neither the beta2 nor beta3 isoforms were detected in full differentiated IMR32 cells. Contrary to a previous report on the absence of neurotypic expression of VDCC beta subunits in a second model for in vitro differentiation, NGF-treated rat pheochromocytoma cells (PC12 cells) [1], we report the regulated expression of the beta1b protein in differentiated IMR32 cells suggesting a cell specific function for this beta subunit which parallels the acquisition of the neuronal phenotype. The restrictive expression of the beta1b in IMR32 cells may reflect a cell-type specific function that extends beyond its role as an auxiliary subunit of VDCC complexes.
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PMID:Beta1B subunit of voltage-dependent Ca2+ channels is predominant isoform expressed in human neuroblastoma cell line IMR32. 945 May 53

The association of molecular characteristics with prognosis has been reported, but not their relationship with each other and their impact in the context of known clinical risk factors. In this study, data of 1249 consecutive intent-to-treat-neuroblastoma patients with more than 1 year follow-up were examined by multivariate analysis using loglinear and Cox proportional hazard regression models on a stage-related basis (stages 1-3: 600, 4S: 116, 4: 533). In a first step, risk factors were identified from 18 selected clinical variables, and risk groups defined. The second step investigated whether molecular characteristics (MYCN, LOH 1p, del 1p, CD44, N-ras, NGF-R, bcl-2, APO-1 (CD95)) contributed additional prognostic information to the model. The loglinear model demonstrated several interactions between clinical factors. By the Cox regression model, seven independent clinical risk factors were found for stages 1-3, seven for stage 4 and two for stage 4S. By subsequent introduction of all molecular variables, MYCN amplification only added significant prognostic information to the clinical factors in localised and stage 4 neuroblastoma. The models allowed the definition of risk groups for stages 1-3 patients by age (e beta = 5.09) and MYCN (e beta = 4.26), for stage 4 by MYCN (e beta = 2.78) and number of symptoms (e beta = 2.44) and for stage 4S by platelet count (e beta = 3.91) and general condition (e beta = 2.99). Molecular factors and in particular MYCN contribute significantly to risk estimation. In conjunction with clinical factors, they are powerful tools to define risk groups in neuroblastoma.
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PMID:The current contribution of molecular factors to risk estimation in neuroblastoma patients. 951 60

Tau and other microtubule-associated proteins promote the assembly and stabilization of neuronal microtubules. While each microtubule-associated protein has distinct properties, their in vivo roles remain largely unknown. Tau is important in neurite outgrowth and axonal development. Recently, we showed that the amino-terminal region of tau, which is not involved in microtubule interactions, is important in NGF induced neurite outgrowth in PC12 cells. Here we report that a proline rich sequence in the amino terminus of tau interacts with the SH3 domains of fyn and src non-receptor tyrosine kinases. Tau and fyn were co-immunoprecipitated from human neuroblastoma cells and co-localization of tau and fyn was visualized in co-transfected NIH3T3 cells. Co-transfection of tau and fyn also resulted in an alteration in NIH3T3 cell morphology, consistent with an in vivo interaction. Fyn-dependent tyrosine phosphorylation of tau occurred in transfected cells and tyrosine phosphorylated tau was identified in human neuroblastoma cells as well. Our data suggest that tau is involved in signal transduction pathways. An interaction between tau and fyn may serve as a mechanism by which extracellular signals influence the spatial distribution of microtubules. The tyrosine phosphorylation of tau by fyn may also have a role in neuropathogenesis, as fyn is upregulated in Alzheimer's disease.
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PMID:Tau interacts with src-family non-receptor tyrosine kinases. 976 11


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