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)

Caveolae are cholesterol/sphingolipid-rich microdomains of the plasma membrane that have been implicated in signal transduction and vesicular trafficking. Caveolins are a family of caveolae-associated integral membrane proteins. Caveolin-1 and -2 show the widest range of expression, whereas caveolin-3 expression is restricted to muscle cell types. It has been previously reported that little or no caveolin mRNA species are detectable in the brain by Northern blot analyses or in neuroblastoma cell lines. However, it remains unknown whether caveolins are expressed within neuronal cells. Here we demonstrate the expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion (DRG) neurons by using mono-specific antibody probes. In PC12 cells, caveolin-1 expression is up-regulated on day 4 of nerve growth factor (NGF) treatment, whereas caveolin-2 expression is transiently up-regulated early in the differentiation program and then rapidly down-regulated. Interestingly, caveolin-2 is up-regulated in response to the mechanical injury of differentiated PC12 cells; up-regulation of caveolin-2 under these conditions is strictly dependent on continued treatment with NGF. Robust expression of caveolin-1 and -2 is also observed along the entire cell surface of DRG neurons, including high levels on growth cones. These findings demonstrate that neuronal cells express caveolins.
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PMID:Expression of caveolin-1 and -2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury. 970 34

It is now clear that the plasma membrane is not homogeneous but contains specific subcompartments characterized by their unique lipid and protein composition. Based on their enrichment in various signaling molecules, these microcompartments are now recognized to be sites of localized signal transduction for several extracellular stimuli. At least two different types of microdomains can be identified, largely based on the presence or absence of the caveolin proteins. The generic name of caveolae-like domains is commonly used to refer to both domains indistinguishably. Although caveolin proteins were long thought to be absent from the brain, we have shown that the human neuroblastoma cell line LAN-1 expresses both caveolin-1 and caveolin-2. Basic fibroblast growth factor (FGF)-2 induced a specific signaling response within the caveolae-like domain of LAN-1 cells, characterized by the tyrosine phosphorylation of a 75-80-kDa protein. This protein present in the caveolae-like domains has properties suggesting that it is a member of the SNT family of adapter proteins. The signaling event originating in the caveolae-like domains in response to FGF-2 appeared to require the activation of at least Fyn and Lyn, two members of the Src family of tyrosine kinases. This work suggests that compartmentalized signaling within caveolae-like domains may create a level of specificity for certain growth factors such as FGF.
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PMID:Signaling within a caveolae-like membrane microdomain in human neuroblastoma cells in response to fibroblast growth factor. 1064 19

1. Caveolins are integral proteins of glycolipid/cholesterol-rich plasmalemmal caveolae domains, where, they may function as a plasma membrane scaffold onto which many classes of signalling molecules, including receptors and heterotrimeric G proteins, can assemble. To ascertain whether caveolins influence G protein-mediated signal transduction, we stably expressed caveolin-1 and -3 isoforms in the neuroblastoma x glioma NG108-15 hybrid cell line, lacking endogenous caveolins. Subsequently, using whole-cell voltage clamp methods, we examined whether the modulation of N-type voltage-gated Ca2+ channels by G(o) protein-coupled, delta-type opioid receptors might be affected by recombinant caveolin expression. 2. In transfected NG108-15 cells, caveolins localized at the plasma membrane and, upon subcellular fractionation on sucrose density gradients, they co-localized in Triton-resistant, low buoyancy fractions, with endogenous G(o) protein alpha-subunits. 3. The voltage-dependent inhibition of omega-conotoxin GVIA-sensitive Ba2+ currents following either activation of delta-opioid receptors by the agonist [o-pen2,o-pen5]-enkephalin (DPDPE), or direct stimulation of G proteins with guanosine 5'-O-(thiotriphosphate) (GTPgammaS) was significantly attenuated in caveolin-expressing cells. The kinetics of Ca2+ channel inhibition were also modified by caveolins. 4. Overall, these results suggest that caveolins may negatively affect G protein-dependent regulation of voltage-gated N-type Ca2+ channels, presumably by causing a reduction of the available pool of activated G proteins.
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PMID:Attenuation of G protein-mediated inhibition of N-type calcium currents by expression of caveolins in mammalian NG108-15 cells. 1160 Jun 72

Estrogen receptors (ER alpha/ER beta) are expressed in neuronal cells and exhibit a variety of activities in the central nervous system. ER activity is regulated in a ligand-dependent manner and by co-regulatory factors. Caveolin-1 is a recently identified co-activator of ER alpha mediating the ligand-independent activation of this steroid receptor. Here the influence of ERs on caveolin expression in human neuroblastoma SK-N-MC cells as well as in rodent brain was investigated. We found that ectopic expression of ER alpha in SK-N-MC cells (SK-ER alpha) leads to a ligand-independent transcriptional suppression of caveolin-1/-2 genes. This suppression is specifically mediated by ER alpha and not ER beta because ER beta counteracts the observed caveolin-silencing process. Interestingly, decreased caveolin expression in SK-ER alpha is accompanied by changes in the methylation pattern of caveolin promoters. The analysis of selected promoter regions of the human caveolin-1 gene showed that certain CpG dinucleotides were hypermethylated in SK-ER alpha cells, whereas the same sites were unmethylated in control, ER beta-, and ER alpha/beta co-expressing SK-N-MC cells. Inhibition of DNA methylation or histone deacetylation led to partial re-expression of caveolin-1/-2 genes in SK-ER alpha. In vivo analysis revealed a down-regulation of caveolin-1 expression after long term estrogen exposure in certain regions of the mouse brain. In conclusion, we have shown for the first time that ER alpha and not ER beta silences caveolin-1/-2 expression in an epigenetic fashion in neuronal cells. The observed mechanism of gene silencing by ER alpha may have implications for the transcriptional regulation of further ER alpha target genes.
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PMID:Estrogen receptor alpha-mediated silencing of caveolin gene expression in neuronal cells. 1213 16

[3H]Palmitic acid accumulates in neuroblastoma NB-2a cells, being incorporated in lipids (90%) and proteins (10%) fractions. Addition of palmitoylcarnitine, known to modulate activity of protein kinase C and to promote differentiation of neurons, was observed to decrease incorporation of palmitic acid to sphingomyelin, phosphatidylserine, and phosphatidylcholine, with a parallel increase of palmitic acid bound to proteins through a thioester bond (palmitoylation). In the presence of palmitoylcarnitine, one of the palmitoylated proteins expressed at growing neural cones, GAP-43, was observed to co-localize with caveolin-1, what was correlated with the beginning of differentiation. A new function of palmitoylcarnitine in controlling palmitoylation of proteins and their targeting to cholesterol-rich domains has been proposed.
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PMID:Palmitoylcarnitine modulates palmitoylation of proteins: implication for differentiation of neural cells. 1267 56

Activity of the antioestrogen-activated maxi-Cl(-) channel has been recorded in different cell types, including fibroblasts, vascular smooth muscle, endothelial and neuroblastoma cells. Its electrophysiological properties resemble those of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane, a channel of particular relevance to the physiology and pathophysiology of mitochondria. The hypothesis that VDAC could be the molecular correlate of the plasma membrane maxi-Cl(-) channel has been debated over the last few years, with the lack of clear evidence for the presence of VDAC in the plasma membrane constituting the main argument of the detractors. In the present study, we investigated the cellular localisation of VDAC in NIH3T3 fibroblasts. The presence of a plasma membrane VDAC was demonstrated by immunoblotting of membrane fractions with monoclonal antibodies against the VDAC and by RT-PCR using primers that hybridise to a VDAC sequence coding for a N-terminal leader peptide required for its plasma membrane sorting. In addition, confocal microscopy studies showed the colocalisation of VDAC with caveolin-1. As expected, VDAC also localised to mitochondria. Colocalisation studies with TOM-20, a protein also present in the outer mitochondrial membrane, showed that VDAC proteins localised only to peripheral and not to perinuclear mitochondria.
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PMID:Voltage-dependent anion channel localises to the plasma membrane and peripheral but not perinuclear mitochondria. 1269 69

alpha-Synuclein accumulation plays an important role in the pathogenesis of Lewy body disease (LBD) and Parkinson's disease (PD). Although the mechanisms are not yet clear, it is possible that dysregulation of the extracellular signal-regulated kinase (ERK) might play a role. As caveolins form scaffolds onto which signaling molecules such as ERK can assemble, we propose that signaling alterations associated with alpha-synuclein accumulation and neurodegeneration, might be mediated via caveolae. Therefore, the objective of the present study was to investigate the potential contribution of alterations in the caveolar system in mediating alpha-synuclein effects on the ERK signaling pathway. For this, synuclein-transfected B103 neuroblastoma cells were used as a model system. In this cell line, caveolin-1 expression was up-regulated, whereas, ERK was down-regulated. ERK was weakly but consistently co-immunoprecipitated with alpha-synuclein but caveolin-1 did not co-immunoprecipitate with alpha-synuclein. Moreover, treatment of alpha-synuclein- overexpressing cells with caveolin-1 antisense oligonucleotides resulted in stimulation of ERK activity, with amelioration of the neuritic alterations. Transduction of alpha-synuclein-overexpressing cells, with an adenoviral vector directing the expression of ERK, resulted in suppression of caveolin-1 expression and re-establishment of the normal patterns of neurite outgrowth. These results suggest that alpha-synuclein may also interfere with ERK signaling by dysregulating caveolin-1 expression. Thus, the caveolin-1/ERK pathway could be a therapeutic target for the alpha-synuclein-related neurodegenerative disorders.
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PMID:Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease. 1278 66

The cell membrane large conductance voltage-dependent chloride channel (Maxi Cl- channel) has been recorded in different cell types following excision of membrane patches or stimulation by antiestrogens under whole-cell recording conditions. However, both its molecular nature and relevance to cell physiology await elucidation. Its electrophysiological properties resemble those of the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. This observation has led to the controversial hypothesis that VDAC could be the molecular correlate of the plasma membrane Maxi Cl- channel. We have investigated the cellular localization of VDAC and its relationship with the antiestrogen-activated Maxi Cl- current in C1300 neuroblastoma cells. The presence of a plasma membrane VDAC was demonstrated by immunoblotting of membrane fractions with monoclonal antibodies against the VDAC and by reverse transcription-PCR using primers that hybridize to a VDAC sequence coding for an N-terminal leader peptide required for its plasma membrane sorting. Besides, VDAC colocalized with markers of plasma membrane lipid rafts (cholera toxin beta subunit) but not caveolin-1. Transfection of C1300 cells with an antisense oligonucleotide directed against the specific membrane leader sequence of VDAC markedly reduced both VDAC immunostaining and antiestrogen-activated Maxi Cl- currents, suggesting that VDAC forms the plasma membrane Maxi Cl- channel or a part thereof.
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PMID:Plasma membrane voltage-dependent anion channel mediates antiestrogen-activated maxi Cl- currents in C1300 neuroblastoma cells. 1279 78

NrCAM is a cell adhesion molecule of the L1 family that is implicated in the control of axonal growth. Adhesive contacts may promote advance of the growth cone by triggering the coupling of membrane receptors with the F-actin retrograde flow. We sought to understand the mechanisms leading to clutching the F-actin at the site of ligand-mediated clustering of NrCAM. Using optical tweezers and single particle tracking of beads coated with the ligand TAG-1, we analyzed the mobility of NrCAM-deletion mutants transfected in a neuroblastoma cell line. Deletion of the cytoplasmic tail did not prevent the coupling of NrCAM to the actin flow. An additional deletion of the FNIII domains to remove cis-interactions, was necessary to abolish the rearward movement of TAG-1 beads, which instead switched to a stationary behavior. Next, we showed that the actin-dependent retrograde movement of NrCAM required partitioning into lipid rafts as indicated by cholesterol depletion experiments using methyl-beta-cyclodextrin. Recruitment of the raft component caveolin-1 was induced at the adhesive contact between the cell surface and TAG-1 beads, indicating that enlarged rafts were generated. Photobleaching experiments showed that the lateral mobility of NrCAM increased with raft dispersion in these contact areas, further suggesting that TAG-1-coated beads induced the coalescence of lipid rafts. In conclusion, we propose that anchoring of NrCAM with the retrograde actin flow can be triggered by adhesive contacts via cooperative processes including interactions with the cytoplasmic tail, formation of cis-complex via the FNIII repeats, and lipid raft aggregation.
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PMID:NrCAM coupling to the cytoskeleton depends on multiple protein domains and partitioning into lipid rafts. 1525 65

Integrin-linked kinase (ILK) and caveolin-1 (cav-1) are implicated in the pathogenesis of cancer. Overexpression of ILK leads to altered expression of cell cycle regulators, a decreased level of cell adhesion to the extracellular matrix, a decreased level of apoptosis, in vitro phosphorylation of Akt, and tumor formation in nude mice. Conversely, cav-1 expression is frequently downregulated in many forms of cancer. We examined whether ILK and cav-1 interact in SHEP human neuroblastoma cells because ILK is present in caveolae-enriched membranes and contains a putative cav-binding domain. SHEP cells were stably transfected with vector, wild-type ILK (ILK-wt), kinase-deficient ILK (ILK-kd), or mutant cav-binding domain ILK (ILK-mutCavbd). Control SHEP cells and ILK transfectants express high levels of ILK and cav-1. Immunoprecipitation with anti-cav-1 co-immunoprecipitates a 59 kDa protein that is immunoreactive with the anti-ILK antibody, and this interaction is partially prevented in cells expressing ILK-mutCavbd. Cav-1 and ILK partially colocalize in SHEP cells, also supporting these data. Last, affinity chromatography with a biotinylated cav-scaffolding domain peptide precipitates ILK-wt but not ILK-mutCavbd. These data suggest that the cav-binding domain of ILK and the cav-scaffolding domain of cav-1 mediate complex formation in human neuroblastoma cells.
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PMID:Integrin-linked kinase complexes with caveolin-1 in human neuroblastoma cells. 1565 49


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