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)

Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3beta) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine(9) -phosphorylation of GSK3beta, which inhibits GSK3beta activity. Overexpression of GSK3beta did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3beta-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3beta selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.
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PMID:BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents. 1209 67

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

Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons within the peripheral and central nervous systems. Neurophilin ligands, including FK506, potentiate NGF-induced neurite outgrowth in several experimental models, although the mechanism of this potentiation is unclear. Therefore, we tested which signaling pathways were involved in FK506-potentiated neurite outgrowth in SH-SY5Y neuroblastoma cells using specific pharmacological inhibitors of various signaling molecules. Inhibitors of Ras (lovastatin), Raf (GW5074), or MAP kinase (PD98059 and U0126) blocked FK506 activity, as did inhibitors of phospholipase C (U73122) and phosphatidylinositol 3' kinase (LY294002). Protein kinase C inhibitors (Go6983 and Ro31-8220) slightly but significantly inhibited neurite outgrowth, whereas inhibitors of p38 MAPK (SB203580) or c-Jun N-terminal kinase (SP600125) had no effect. These data suggest that FK506 potentiates neurite outgrowth through the Ras/Raf/MAP kinase signaling pathway downstream of phospholipase C and phosphatidylinositol 3' kinase.
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PMID:FK506 potentiates NGF-induced neurite outgrowth via the Ras/Raf/MAP kinase pathway. 1455 56

Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation. Necdin shows a moderate homology to the MAGE family proteins, the functional roles of which are largely unknown. Human genes encoding necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with neurodevelopmental disorders such as Prader-Willi syndrome, Angelman syndrome, and autistic disorder. The necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these necdin-related MAGE proteins. The colony formation and bromodeoxyuridine incorporation analyses revealed that necdin and MAGE-G1, but not MAGEL2, induced growth arrest. Necdin and MAGE-G1 interacted with the transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115 neuroblastoma cells. In addition, necdin and MAGE-G1 interacted with the p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these necdin interactors, suggesting that MAGEL2 has no necdin-like function in developing brain. Overexpression of p75 translocated necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of neuroblastoma cells. These results suggest that necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.
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PMID:Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor. 1459 16

The clinical use of N-myc amplification in neuroblastoma management has served as a paradigm for "bench to bedside" medicine. It is hoped that the quest for molecular markers such as neurotrophin, TrkA, and TrkB will continue to advance the understanding of neuroblastoma. In addition, animal models of neuroblastoma (N-myc transgenic mice, and neuroblastoma xenografts) have been established to assess the efficacy of novel treatments. These advances are likely to improve clinical practice in the future.
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PMID:Neuroblastoma: management, recurrence, and follow-up. 1468 Mar 22

Neuroblastomas are the most frequently occurring solid tumors in children under 5 years. Spontaneous regression is more common in neuroblastomas than in any other tumor type, especially in young patients under 12 months. Unfortunately, the full clinical spectrum of neuroblastomas also includes very aggressive tumors, unresponsive to multi-modality treatment and accounting for most of the pediatric cancer mortalities under 5 years of age. It is generally emphasized that more than one biological entity of neuroblastoma exists. Structural genetic defects such as amplification of MYCN, gain of chromosome 17q and LOH of 1p and several other chromosomal regions have proven to be valuable as prognostic factors and will be discussed in relation to their clinical relevance. Recent research is starting to uncover important molecular pathways involved in the pathogenesis of neuroblastomas. The aim of this review is to discuss several important aspects of the biology of the neuroblast, such as the role of overexpressed oncogenes like MYCN and cyclin D1, the mechanisms leading to decreased apoptosis, like overexpression of BCL-2, survivin, NM23, epigenetic silencing of caspase 8 and the role of tumor suppressor genes, like p53, p73 and RASSF1A. In addition, the role of specific proteins overexpressed in neuroblastomas, such as the neurotrophin receptors TrkA, B and C in relation to spontaneous regression and anti-angiogenesis will be discussed. Finally, we will try to relate these pathways to the embryonal origin of neuroblastomas and discuss possible new avenues in the therapeutic approach of future neuroblastoma patients.
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PMID:Pediatric neuroblastomas: genetic and epigenetic 'danse macabre'. 1469 5

Neuroblastoma is one of the most common pediatric solid tumors originating from the sympathoadrenal lineage of neural crest. The tumor shows extremely different clinical phenotypes such as spontaneous regression on one hand and aggressive growth on the other hand. The different biological behavior of neuroblastoma appears to be determined by the genetic abnormalities including amplification of MYCN oncogene, DNA ploidy and some allelic imbalances. However, the spontaneous regression of neuroblastoma mimics the programmed cell death normally occurring in developing sympathetic cells expressing both TrkA tyrosine kinase A and p75NTR neurotrophin receptor. Indeed, TrkA expression is the most important factor related to the induction of tumor cell differentiation and/or programmed cell death because without its expression spontaneous regression of neuroblastoma never occurs. Thus, the enigmatic clinical behaviors of neuroblastoma are strictly linked to the molecular mechanism of neural crest development.
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PMID:Neural crest development and neuroblastoma: the genetic and biological link. 1469 67

Neurotrophins are key signalling molecules in the development of the nervous system. They elicit diverse cellular responses such as proliferation, differentiation, survival and apoptosis. Neurotrophins (NTs) bind to two different classes of cell surface receptors, Trk receptor tyrosine kinases and p75NTR, both of which are expressed by neuroblastoma cells. Neurotrophin signalling via Trks was shown to promote both survival and differentiation of neuroblastoma cells in vitro. The expression of certain Trk receptors is considered to be a prognostic indicator. The p75NTR receptor is the founding member of the Fas/TNF-R family, which is best known for its function in the induction of apoptosis. Its function in neuroblastomas is thus far poorly understood. We analysed neurotrophin receptor (NTR) expression of neuroblastoma cells by surface biotinylation assays and applied recombinant nerve growth factor (NGF), brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 to these cell lines assessing their survival and proliferation in long-term assays lasting 6 days. NGF increased proliferation of Neuro 2a cells, which express p75NTR but no TrkA receptors on their surface. On the other hand, SK-N-BE cell proliferation was decreased after NGF treatment, even though these cells also express p75NTR but no TrkA receptors on their surface. Interestingly, neurotrophin-scavenger proteins (TrkB-Fc and TrkC-Fc) as well as chemical blockers of Trk receptor signalling (K252a, Wortmannin, PD98059) slowed down the proliferation of both cell lines in medium containing serum. Taken together, our results indicate that p75NTR activation has diverse effects on neuroblastomas, depending on the specific neuroblastoma clone. In addition, our studies point towards TrkB-Fc or TrkC-Fc receptor bodies as useful tools to influence the survival of neuroblastoma cells.
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PMID:Neurotrophin effects on neuroblastoma cells: correlation with trk and p75NTR expression and influence of Trk receptor bodies. 1501 75

Differentiation of precursor into specialized cells involves an increasing restriction in proliferative capacity, culminating in cell cycle exit. In this report we used a human neuroblastoma cell line to study the molecular mechanisms that coordinate cell cycle arrest and neuronal differentiation. Exposure to retinoic acid (RA), a differentiation agent in many cell types, causes an upregulation of neurotrophin receptor TrkB and the cyclin kinase inhibitor p21(Cip1) at a transcriptional level. Full transcriptional activation of these two genes requires canonical E-box sequences found in the TrkB and p21(Cip1) promoters. As reported for other E-box-regulated promoters, ectopic expression of E47 and E12 basic helix-loop-helix (bHLH) proteins enhances RA-dependent expression of TrkB and p21(Cip1), whereas the inhibitory HLH Id2 exerts opposite effects. In addition, ectopic expression of E47 and NeuroD, a neuronal bHLH protein, is able to activate TrkB transcription in the absence of RA. More importantly, we show that E47 and NeuroD proteins bind the TrkB and p21(Cip1) promoter sequences in vivo. Since they establish a direct transcriptional link between a cell cycle inhibitor, p21(Cip1), and a neurotrophic receptor, TrkB, bHLH proteins would play an important role in coordinating key events of cell cycle arrest and neuronal differentiation.
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PMID:Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking differentiation and cell cycle arrest in neuroblastoma cells. 1502 57

Activation of several immediate early genes (IEGs) is crucial for long-term memory formation in vivo. In vitro methods of inducing these genes have not been investigated extensively. Here we present data demonstrating that application of the neurotrophin, nerve growth factor (NGF), to both rat primary neuronal cultures and differentiated mouse neuroblastoma 2A (N2A) cultures reliably induces expression of several IEGs, including Zif268, Nur77 and Arc, each of which have been linked to memory consolidation. These findings provide an in vitro model in which to test other agents that might modulate the induction of memory-associated genes.
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PMID:Induction of memory-associated immediate early genes by nerve growth factor in rat primary cortical neurons and differentiated mouse Neuro2A cells. 1526 80


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