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)

We investigated the agonistic activities of N(4)-(7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl)-N(1),N(1)-diethyl-pentane-1,4-diamine (XIB4035), at the glial cell line-derived neurotrophic factor (GDNF) family receptoralpha-1(GFRalpha-1) in Neuro-2A cells, a mouse neuroblastoma cell line which is a suitable model for investigating functions mediated through GFRalpha-1. XIB4035 concentration-dependently inhibited [(125)I]GDNF binding in Neuro-2A cells with an IC(50) of 10.4 microM. GDNF induced autophosphorylation of Ret protein, and promoted neurite outgrowth in Neuro-2A cells. XIB4035, like GDNF, induced Ret autophosphorylation in the Neuro-2A cells. Moreover, XIB4035 promoted neurite outgrowth in a concentration-dependent manner. These results show that XIB4035 may act as an agonist at GFRalpha-1 receptor complex, and mimic neurotrophic effects of GDNF in Neuro-2A cells. This is an interesting finding showing that a nonpeptidyl small molecule is capable of inducing activation of a receptor that normally bind a relatively large protein ligand such as GDNF.
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PMID:XIB4035, a novel nonpeptidyl small molecule agonist for GFRalpha-1. 1244 Nov 71

We show that the glial cell line-derived neurotrophic factor (GDNF) activates the PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional Ret-receptor complexes. Consistent with this finding we show PI3K-dependent Bad-inactivation by binding to 14-3-3 proteins in response to GDNF. Using differential display techniques we detected several cDNA clones differentially expressed after treatment with GDNF or 6-OHDA.
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PMID:Signaling pathways mediate the neuroprotective effects of GDNF. 1248 36

Glial cell line-derived neurotrophic factor (GDNF), a potent survival and trophic factor for various neuronal cells, has been measured by assaying its bioactivity based on neurite outgrowth or cell proliferation. We describe herein a sensitive and simple non-radioactive quantitative bioassay for GDNF family proteins based on their ability to induce tyrosine hydroxylase (TH) gene expression. Human neuroblastoma SK-N-MC cells were stably transfected with expression constructs of c-ret and with a luciferase reporter gene driven by 2 kb of the rat TH gene promoter region. In the presence of GDNF, luciferase activity increased with 20 h of incubation. A dose-dependent increase in luciferase activity was observed in the presence of GDNF between 1 and 300 ng/ml. This assay was also applicable for the quantification of the bioactivity of neurturin, another member of the GDNF family showing an even more sensitive profile of dose dependency than GDNF. Typical culture media were applicable in this assay. This method can be easily applied to numerous samples of conditioned medium in a short time.
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PMID:A rapid assay for glial cell line-derived neurotrophic factor and neurturin based on transfection of cells with tyrosine hydroxylase promoter-luciferase construct. 1273 7

Glial cell line-derived neurotrophic factor (GDNF) activates c-Ret tyrosine kinase and several downstream intracellular pathways; the biological effects caused by the activation of each of these pathways, however, remain to be elucidated. Here we report the ability of GDNF to induce proliferation, rather than differentiation, of neuroblastoma cells (SH-SY5Y) by targeting the signaling pathway responsible for mediating this proliferative effect. GDNF induces the phosphorylation of Akt and p70S6 kinase (p70S6K) in SH-SY5Y cells in which Ret protein expression is relatively low. Interestingly, treating SH-SY5Y cells with retinoic acid greatly increases Ret protein levels and GDNF-induced Ret tyrosine phosphorylation, but does not affect the mitogenic action of GDNF and the activation of the Akt/p70S6K pathway. In contrast, the activation of the ERK pathway and the resulting induction of immediate-early genes parallel the increases in Ret protein levels. Rapamycin, a specific inhibitor of p70S6K activation by the mammalian target of rapamycin, completely prevents GDNF-induced proliferation and activation of p70S6K. These results suggest that GDNF promotes cell proliferation via the activation of p70S6K, independent of the ERK signaling pathway, and that GDNF activates the Akt/p70S6K pathway more efficiently than the ERK pathway in the cells in which Ret expression is low.
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PMID:Mitogenic effect of glial cell line-derived neurotrophic factor is dependent on the activation of p70S6 kinase, but independent of the activation of ERK and up-regulation of Ret in SH-SY5Y cells. 1291 61

Glial cell line-derived neurotrophic factor (GDNF) signals through multisubunit receptor complex consisting of RET tyrosine kinase and a glycosylphosphatidylinositol-anchored coreceptor called GDNF family receptor alpha1 (GFRalpha1). In the current study, we cloned a human SEP1 gene as a GDNF-inducible gene using human neuroblastoma cells that express RET and GFRalpha1. The induction of the SEP1 gene showed two peaks at 0.5-2 h and 24-48 h after GDNF stimulation by Northern blotting and quantitative real-time reverse transcriptase polymerase chain reaction. The late induction was also confirmed at protein levels by Western blotting with anti-SEP1 antibody. Immunostaining revealed that the expression of the SEP1 protein was detected in cell body, elongated neurites and growth cone-like structure of neuroblastoma cells treated with GDNF. In addition, we found a high level of SEP1 expression in neurons of the dorsal root and superior cervical ganglia and motor neurons of the spinal cord of mice in which RET is also expressed. SEP1 was co-immunoprecipitated with alpha- and beta-tubulins from the lysate of mouse brain. These results thus suggested that SEP1 is a GDNF-inducible and microtubule-associated protein that may play a role in the nervous system.
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PMID:Identification of human SEP1 as a glial cell line-derived neurotrophic factor-inducible protein and its expression in the nervous system. 1458 Sep 40

N-Propargyl-l(R)-aminoindan, rasagiline, an anti-Parkinson drug, was found to increase the protein and mRNA levels of glial cell line-derived neurotrophic factor (GDNF) in human neuroblastoma SH-SY5Y cells, whereas an analogue without a propargyl residue, aminoindan, did not. GDNF is known to protect dopaminergic neurons in animal and cellular models of Parkinson's disease, and the supplement has been tried for the treatment of degenerating dopamine neurons in Parkinsonian patients. In this paper, intracellular mechanism underlying the induction of GDNF was studied. Rasagiline induced phosphorylation of inhibitory subunit (IkappaB) of nuclear factor-kappaB (NF-kappaB), and translocation of active p65 subunit from cytoplasm into nuclei. Activation of NF-kappaB was also quantitatively determined by NF-kappaB p65 transcription assay. Sulfasalazine, an inhibitor of IkappaB kinase, suppressed the activation of NF-kappaB and the increase of GDNF by rasagiline simultaneously, further indicating the involvement of the IkappaB kinase-NF-kappaB pathway. The results on the activation of the transcription factor by rasagiline are discussed in relation to its possible application as a neuroprotective drug to halt declining of neurons in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.
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PMID:N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-kappaB transcription factor. 1468 4

Neuroblastoma (NB) is a childhood cancer that arises in the adrenal gland and often shows differentiated neuronal and glial elements. The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype. Thus, we hypothesized that the RET and TRKA signal pathways collaborate to instruct NB differentiation, reminiscent of normal neuronal maturation. Here, we demonstrate that activation of the RET receptor by glial cell line-derived neurotrophic factor (GDNF) increases expression of the RET receptor complex in a panel of malignant human NB cell lines, indicative of a positive feedback mechanism. GDNF also induces growth cessation concomitant with an arrest of cells in the G(0)/G(1) phase of the cell cycle. Furthermore, GDNF synergizes with ciliary neurotrophic factor (CNTF) to enhance TRKA receptor expression, thereby strengthening the NGF-mediated differentiation signal. Differentiated NB cells downregulate expression of the amplified N-myc gene, concurrent with the arrest of cell proliferation, while expressing neuron-specific markers (i.e., SCG10). Interestingly, maintenance of differentiated NB cells in culture is independent of the trophic activity of GDNF, but depends on TRKA signaling, thereby re-enacting the differentiation of normal sympathoadrenal (SA) progenitor cells.
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PMID:The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. 1471 26

Collapsin response mediator protein-2 (CRMP-2) is a mammalian homologue of UNC-33 of Caenorhabditis elegans. Mutations of CRMP-2 result in abnormal axon termination. Recently, it was demonstrated that CRMP-2 binds to tubulin heterodimers to promote microtubule assembly that is critical for axonal differentiation and growth during development. Here we show that glial cell line-derived neurotrophic factor (GDNF) enhances CRMP-2 expression in TGW human neuroblastoma cells via activation of RET receptor tyrosine kinase. GDNF-mediated CRMP-2 expression was regulated mainly by the extracellular regulated kinase (ERK) pathway, but was independent of activation of phosphatidylinositol 3-kinase and Src family kinases. Analysis of the promoter region of the CRMP-2 gene revealed that the region 214-48 bp upstream of the transcriptional start site is important for CRMP-2 expression. The SP1, E2F, and GATA1/2 binding sites appeared to play some roles in regulation of CRMP-2 expression. As expected, the CRMP-2 protein accumulated in extended neurites of TGW cells treated with GDNF. However, neuritogenesis of TGW cells was mostly dependent on Src family kinase activity and not ERK activity, indicating that the increased expression of CRMP-2 alone was not sufficient for neuritogenesis.
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PMID:Induction of CRMP-2 by GDNF and analysis of the CRMP-2 promoter region. 1520 9

The glial cell line-derived neurotrophic factor (GDNF) family of ligands play essential roles in promoting normal neural crest differentiation during embryogenesis, and, may have a therapeutic role in malignancies of neural crest origin, such as neuroblastoma. However, we report here that GDNF and neurturin blocked the growth inhibitory and neuritogenic effects of all-trans-retinoic acid in neuroblastoma cells in vitro. GDNF caused neuroblastoma cells to proliferate in the presence of a range of cytotoxic chemotherapeutic agents at low concentrations. Thus, our findings suggest a role for GDNF signaling in promoting resistance to differentiation or cytotoxic therapy of neuroblastoma, and, preclude their use in this neural crest tumor.
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PMID:Glial cell line-derived neurotrophic factor (GDNF) family ligands reduce the sensitivity of neuroblastoma cells to pharmacologically induced cell death, growth arrest and differentiation. 1612 42

The anti-Parkinson drug, rasagiline (N-propargyl-(1R)-aminoindan) promotes neuronal survival, via neuroprotective activity related to its propargyl moiety (propargylamine). We have investigated the neurorescue effects of propargylamine, in a progressive neuronal death model, induced by long-term serum deprivation in human SH-SY5Y neuroblastoma cells. Propargylamine (0.1-10 microM) dose-dependently reduced the levels of the early apoptosis-associated phosphorylated protein, H2A-X (ser 139), as well as decreased the cleavage of caspase-3 and its substrate poly-ADP ribose polymerase (PARP). In addition, the compound markedly reversed the apoptotic effects induced by long-term serum withdrawal, including down-regulation of the antiapoptotic protein, Bcl-2, as well as up-regulation of the proapoptotic proteins, Bax, Bad, and Bim. Real-time RT-PCR demonstrated that propargylamine elevated gene expression levels of Bcl-2, and the neurotrophic factors glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) and reduced Bax gene expression. Serum deprivation increased mRNA and protein levels of holo-amyloid precursor protein (APP), which was markedly decreased by propargylamine. This was accompanied by inducing the release of the nonamyloidogenic alpha-secretase form of soluble APP (sAPPalpha) into the medium. Similar effects on cell survival and APP regulation/processing were demonstrated for rasagiline. These results indicate that both rasagiline and propargylamine possess neurorescue activity, associated with regulation of Bcl-2 family proteins, neurotrophic factors, and APP metabolism.
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PMID:Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. 1614 27


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