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)

Human neuroblastoma cells SK-N-SH express significant numbers of IL-1R type I on their surface, as detected by saturation binding and RT-PCR, and are responsive to IL-1beta activation by producing inflammatory cytokines IL-6 and IL-8. IL-1beta can also have an indirect effect on nervous cell functions, since it is able to modulate the stimulus-induced increase of intracellular Ca++ levels, one of the first steps of the cell activation mechanism. In fact, on SK-N-SH neuroblastoma cells, IL-1beta can inhibit the Ca++ increase induced by stimulation of acetylcholine receptors with carbachol. In parallel to IL-1beta, the neurotrophic factor CNTF also shows an inhibitory effect on carbachol-stimulated Ca++ increase in CNTFRalpha-expressing SK-N-SH cells. However, when simultaneously present, the two cytokines cross-inhibit, thus allowing full cell activation in response to the cholinoceptor agonist. The inhibitory effect of CNTF on IL-1beta activities on nervous cells was confirmed in the IL-6 production assay. In fact, while CNTF could not induce IL-6 production, it could strongly inhibit cytokine production in response to IL-1beta in SK-N-SH cells. The down-modulation of IL-1 effects by CNTF could be one of the mechanisms controlling the extent of the inflammatory reaction at the nervous system level.
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PMID:Interaction between interleukin-1 and ciliary neurotrophic factor in the regulation of neuroblastoma cell functions. 945 16

Functional nerve growth factor (NGF) responsiveness was investigated in human neuroblastoma (NB) cell lines in vitro and retinoic acid (RA) was found to transcriptionally enhance expression of the trkA, but not the trkB gene in GOTO cells, while the reverse was found in HTLA230 NB cells. Ciliary neurotrophic factor (CNTF) specifically induced trkA gene transcription in both cell lines. Transcriptional activation of the trkA gene increased total trkA protein and surface bound receptor, which was tyrosine phosphorylated upon NGF stimulation inducing immediate early response gene transcription (i.e. c-fos, Egr-1). Newly synthesized trkA protein had a molecular weight of 110 kDa and was post-translationally modified. Rapid down regulation of the receptor protein occurred upon NGF stimulation, despite the presence of high levels of trkA mRNA, due to an increased rate of receptor degradation. Transient DNA synthesis and cell proliferation upon NGF treatment occurred in GOTO cells with elevated trkA expression. In contrast, NGF induced neuronal differentiation in HTLA230 cells expressing the endogenous trkA receptor gene, despite the lack of p75 expression. Hence, transcriptional activation of trkA gene expression can be achieved by different signal pathways in human NB cells, but NGF can act either as mitogen or inducer of cell differentiation, depending on the tumor from which cells are derived.
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PMID:Regulation of NGF responsiveness in human neuroblastoma. 981 68

Erythropoietin (Epo) is a hematopoietic factor that facilitates erythroid progenitor cell proliferation and differentiation. Recently, trophic effects of Epo have been observed in central cholinergic neurons. We have confirmed the neurotrophic factor activity of Epo and moreover, demonstrated sprouting and signaling by Epo in neural cells. Further, we have identified a 17-mer peptide sequence (epopeptide AB) in Epo (AEHCSLNENITVPDTKV) with activity similar to that of the holoprotein. This peptide induces differentiation and prevents cell death in both murine NS20Y and human SK-N-MC neuroblastoma cell lines. However, epopeptide AB does not promote the proliferation of erythropoietic cell lines or mouse primary spleen cells. The biological activities in neural cells were blocked by the addition of an antibody to the extracellular domain of the Epo receptor, indicating that the bioactive effects of epo-peptide AB in neural cells are Epo receptor mediated. Both epopeptide AB and Epo stimulated phosphorylation of ERKs in PC12 cells. When epopeptide AB or Epo was locally injected into mice, the frequency of motor end plate sprouting in adjacent muscles increased in a manner similar to that induced by CNTF. These findings indicate that neural cells and not hematological cells respond to a peptide sequence within erythropoietin and suggests that Epo may have separate domains for neurotrophic and hematotrophic function.
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PMID:Identification of a neurotrophic sequence in erythropoietin. 985 25

Fibroblast growth factor (FGF) has been shown to protect tissue damage in animal models of cerebral and myocardial ischemia. The cellular and molecular mechanisms of FGF effects have not been fully defined. In the present study, we have investigated the effect of FGF homologs on nitric oxide (NO)-mediated neuronal cell death. Addition of NO donor S-nitroso-N-acetylpenicillamine (SNAP) to cultures of human neuroblastoma SHSY-5Y cells resulted in a concentration-dependent cell death. TdT-mediated dUTP-X nick end labeling and oligonucleosome assays confirmed that NO-mediated cell death occurred through the apoptotic pathway. In the presence of 150 microM SNAP, about 40% of the cells in culture underwent apoptosis. Treatment with FGF-2 resulted in greater than 80% reduction in NO-induced cell death. FGF addition to cell cultures also enhanced cell survival without affecting cell proliferation. FGF-2 effectively inhibited NO-mediated apoptosis even when added 6 h after treatment with SNAP. Examination of other homologs of FGF on NO-mediated cell death showed that in SHSY-5Y cells, FGF-2 and FGF-4, but not other FGF homologs, inhibited NO-mediated apoptosis. These results show that FGF-2 was a potent cell survival factor and protected SHSY-5Y cells from NO-mediated apoptosis. These effects were limited to FGF-2 and FGF-4 homologs.
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PMID:Fibroblast growth factor protects nitric oxide-induced apoptosis in neuronal SHSY-5Y cells. 1108 21

Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of a number of neural cell types. Its receptor complex consists of a ligand-binding component, CNTF receptor (CNTFR), associated with two signaling receptor components, gp130 and leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second developmentally important ligand. We recently demonstrated that cardiotrophin-like cytokine (CLC) associates with the soluble orphan receptor cytokine-like factor-1 (CLF) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite CNTF receptor on their surface. In this present study we examined the membrane binding of the CLC/CLF composite cytokine and observed a preferential interaction of the cytokine with the CNTFR subunit. Signaling pathways recruited by the CLC/CLF complex in human neuroblastoma cell lines were also analyzed in detail. The results obtained showed an activation of Janus kinases (JAK1, JAK2, and TYK2) leading to a tyrosine phosphorylation of the gp130 and LIFR. The phosphorylated signaling receptors served in turn as docking proteins for signal transducing molecules such as STAT3 and SHP-2. In vitro analysis revealed that the gp130-LIFR pathway could also stimulate the phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathways. In contrast to that reported before for CNTF, soluble CNTFR failed to promote the action CLC/CLF, and an absolute requirement of the membrane form of CNTFR was required to generate a functional response to the composite cytokine. This study reinforces the functional similarity between CNTF and the CLC/CLF composite cytokine defining the second ligand for CNTFR.
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PMID:Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component. 1129 41

Neuroblastomas that overexpress N-Myc due to amplification of the MYCN oncogene are aggressive tumors that become very resistant to treatment by chemotherapy and irradiation. to identify tumor suppressor genes in this group of neuroblastomas we analyzed the expression and function of both apoptosis-related cell cycle regulatory genes in cell lines and patient tumor samples. We found that in a high percentage of neuroblastoma cell lines and patient samples with amplified MYCN, caspase-8 mRNA is not expressed. The caspase-8 gene, CASP8, was deleted or silenced by methylation in the neuroblastoma cell lines while methylation of its promoter region was the predominant mechanism for its inactivation in the patient tumor samples. Reintroduction of caspase-8 into the neuroblastoma cell lines resensitized these cells to drug-induced and survival factor dependent apoptosis. Subsequently others have also shown that caspase-8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors, and that the caspase-9 regulator Apaf-1 is silenced by methylation in melanoma cell lines and patient samples. We conclude that caspase-8 acts as a tumor suppressor gene in neuroblastomas, that its silencing provides a permissive environment for MYCN gene amplification once the tumors are treated with chemotherapeutic drugs/irradiation, and that expression of this gene in these tumor cells may be of clinical benefit. We also discuss the possible significance of the neural crest cell progenitor cell origin and the silencing of important apoptotic regulators via methylation in both neuroblastoma and melanoma tumors.
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PMID:Aggressive childhood neuroblastomas do not express caspase-8: an important component of programmed cell death. 1151 73

In most postmitotic neurons, expression or activation of proteins that stimulate cell cycle progression or DNA replication results in apoptosis. One potential exception to this generalization is neuroblastoma (NB), a tumor derived from the sympathoadrenal lineage. NBs often express high levels of N-myc, a proto-oncogene that can potently activate key components of the cell cycle machinery. Here, we show that in postmitotic sympathetic neurons, N-myc can induce S-phase entry while protecting neurons from death caused by aberrant cell cycle reentry. Specifically, these experiments demonstrate that expression of N-myc at levels similar to those in NBs caused sympathetic neurons to reenter S-phase, as monitored by 5-bromo-2-deoxyuridine incorporation and expression of cell cycle regulatory proteins, and rescued them from apoptosis induced by withdrawal of their obligate survival factor, nerve growth factor. The N-myc-induced cell cycle entry, but not enhanced survival, was inhibited by coexpression of a constitutively hypophosphorylated form of the retinoblastoma tumor suppressor protein, suggesting that these two effects of N-myc are mediated by separate pathways. In contrast, N-myc did not cause S-phase entry in postmitotic cortical neurons. Thus, N-myc both selectively causes sympathetic neurons to reenter the cell cycle and protects them from apoptosis, potentially contributing to their transformation to NBs.
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PMID:N-myc promotes survival and induces S-phase entry of postmitotic sympathetic neurons. 1182 11

We investigated the roles of endogenous glutathione on 6-hydroxydopamine (6-OHDA)-induced apoptosis in human neuroblastoma SK-N-SH cells using DNA fragmentation enzyme-immunoassay and the DNA dye Hoechst 33258 staining. We observed that exogenous reduced glutathione (GSH), but not oxidized glutathione (GSSG), protected 6-OHDA (25 micro M)-induced apoptosis in a dose-dependent manner. Preincubation (18 h) with the glutathione synthesis inhibitor DL-buthionine-(S,R)-sulfoximine (BSO) significantly potentiated the toxic effects of 6-OHDA (12.5 or 25 micro M). In contrast to BSO, N-acetylcysteine (NAC) blocked, and L-(-)-cystine, the glutathione precursor, significantly attenuated 6-OHDA (25 micro M)-induced apoptosis, respectively. No alterations in endogenous glutathione concentrations were detected at 5, 15, 30, 60 min, 1 hour, 3 hours, or 6 hours after 6-OHDA (25 micro M) treatment. However, we found a 3.5-fold increase of intracellular glutathione levels 24 hours later. On the contrary, higher concentration (100 micro M) of 6-OHDA treatment, which caused more severe cell death, showed no changes of glutathione levels. These results suggest that delayed induction of endogenous glutathione might play an important role in the neuroprotective mechanism against dopamine cell death. In addition, we found that NAC might work as a beneficial catecholaminergic neuron-survival factor more efficiently than exogenous glutathione or L-cystine.
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PMID:Roles of endogenous glutathione levels on 6-hydroxydopamine-induced apoptotic neuronal cell death in human neuroblastoma SK-N-SH cells. 1224 73

The effect of CNTF and BDNF on a proteolytic complement instrumental to invasion and on differentiation was studied in two murine neuroblastoma clones, N1 and N7. At the membrane level, gelatinase MMP-2--mainly the activated form--was restrained by CNTF and BDNF to a residual 34% with both factors; membrane-type 1 MMP was down-regulated to 50% (10 h) and 34% (24 h) with both factors; and urokinase-type plasminogen activator was restrained mainly by BDNF to 70%. In the medium, the two gelatinases MMP-2 and MMP-9 were mainly in zymogen form: only MMP-2 was restrained in N1 cells, while only MMP-9 was restrained in N7 cells by both factors, single or in combination. These effects were paralleled by the induction of neurite outgrowth, which was more stimulated in the less differentiated clone. These dose-dependent and transient effects make CNTF and BDNF ideal candidates for constraining the potentially invasive behavior of nervous system tumors.
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PMID:Modulation of proteolytic potential and differentiation by CNTF and BDNF in two mouse neuroblastoma clones: relation to invasion. 1255 77

Although glial cell-line derived neurotrophic factor (GDNF) acts as a potent survival factor for dopaminergic neurons, it is not known whether GDNF can directly alter dopamine synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine biosynthesis, and its activity is regulated by phosphorylation on three seryl residues: Ser-19, Ser-31, and Ser-40. Using a TH-expressing human neuroblastoma cell line and rat primary mesencephalic neuron cultures, the present study examined whether GDNF alters the phosphorylation of TH and whether these changes are accompanied by increased enzymatic activity. Exposure to GDNF did not alter the TH protein level in either neuroblastoma cells or in primary neurons. However, significant increases in the phosphorylation of Ser-31 and Ser-40 were detected within minutes of GDNF application in both cell types. Enhanced Ser-31 and Ser-40 phosphorylation was associated with increased TH activity but not dopamine synthesis in neuroblastoma cells, possibly because of the absence of l-aromatic amino acid decarboxylase activity in these cells. In contrast, increased phosphorylation of Ser-31 and Ser-40 was found to enhance dopamine synthesis in primary neurons. Pharmacological experiments show that Erk and protein kinase A phosphorylate Ser-31 and Ser-40, respectively, and that their inhibition blocked both TH phosphorylation and activity. Our results indicate that, in addition to its role as a survival factor for dopaminergic neurons, GDNF can directly increase dopamine synthesis.
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PMID:Enhancement of tyrosine hydroxylase phosphorylation and activity by glial cell line-derived neurotrophic factor. 1457 Aug 86


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