UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The isolation and hormonal regulation of two low molecular weight insulin-like growth factor binding proteins (IGFBPs) present in the conditioned medium (CM) of the rat neuroblastoma cell line B104 cells has been performed. IGFBPs were purified by ZnSO4 precipitation, insulin-like growth factor-I 1IGF-I) affinity chromatography, and reverse phase HPLC. Final isolation and N-terminal analysis was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, electroblotting to polyvinylidene difluoride membranes, and sequencing of the bound proteins. Two IGFBPs, with apparent Mr of 28K and 24K were coisolated and sequenced. Both proteins had identical N-terminal sequences and appear to be two forms of IGFBP-4. Treatment of the IGFBPs with endoglycosidase-F caused a shift in the apparent Mr of the 28K IGFBP to 24K. However, there was no change in the apparent Mr of the 24K IGFBP. The data from this study suggest that the IGFBP-4 exists as both a glycosylated and nonglycosylated protein. Treatment of B104 cells with IGF-I increased the expression of both the 24K and 28K IGFBPs and also resulted in the appearance of IGFBP-3 and an unknown IGFBP at 29K. When added to subconfluent cells, IGF-I was also mitogenic in B104 cells. Similar to IGF-I, IGF-II treatment increased cell number and resulted in the appearance of IGFBP-3 and the 29K IGFBP. However, IGF-II treatment resulted in a significant decrease (approximately 50%) in the 24K IGFBP and also decreased the 28K IGFBP. This decrease in the expression of the 24K and 28K IGFBPs was dose-dependent and was blocked by addition of IGF-I to the cells. When an IGF-II receptor antibody was added to the cells it mimicked the effects of IGF-II on B104 cells, suggesting that the inhibitory effects of IGF-II are mediated through the type II IGF receptor. Although both IGF-I and IGF-II affected the amount of the 24K IGFBP in the CM, neither peptide affected the expression of the messenger RNA for the 24K IGFBP. In conclusion, we have isolated two IGFBPs from the CM of B104 cells. Both the 24K and 28K IGFBPs appear to be isoforms of the same protein, and sequence data suggest these proteins are two forms of IGFBP-4. IGF-I increases the expression of both of these IGFBPs, whereas IGF-II decreases their expression.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential effects of insulin-like growth factor (IGF)-I and IGF-II on the expression of IGF binding proteins (IGFBPs) in a rat neuroblastoma cell line: isolation and characterization of two forms of IGFBP-4. 170 57

Insulin and various growth factors (epidermal growth factor (EGF), insulin-like growth factor, fibroblast growth factor, and transforming growth factor alpha), which fail to modify the resting [Ca2+]i in PC12 rat pheochromocytoma and SKNBE human neuroblastoma cells when administered alone, became capable of inducing [Ca2+]i increases when administered a few (4-20) min after another agent, bradykinin. The latter peptide, working through a B2 receptor, caused hydrolysis of polyphosphoinositides and a large, biphasic [Ca2+]i transient (an initial (1-2 min) spike, originated primarily from intracellular stores, followed by a steady-state elevation dependent on Ca2+ influx). Priming by bradykinin of the growth factor effects was quickly dissipated by the addition of a B2 blocker. Activation of other receptors coupled to polyphosphoinositide hydrolysis: muscarinic and purinergic (in PC12 and SKNBE cells); bombesin and vasopressin receptors (in Swiss 3T3 cells), was without effect in priming. Bradykinin-primed, growth factor-induced [Ca2+]i rises in PC12 cells appeared after a 20-30-s delay; they were relatively small, but persistent; their concentration dependence was similar to that of other effects of the factors; and they included both release of Ca2+ from intracellular stores and stimulation of Ca2+ influx, preceded (in PC12 cells) by a transient increase of polyphosphoinositide hydrolysis. Thus the effect of growth factors (possibly dependent on the tyrosine kinase activity of their receptors) consisted in the reinforcement of the transmembrane signaling at B2 receptors. This is the first direct demonstration of a [Ca2+]i rise induced by insulin and insulin-like growth factor-I, and of such an effect of EGF in cell types endowed with a small number of specific EGF receptors.
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PMID:Reinforcement of signal generation at B2 bradykinin receptors by insulin, epidermal growth factors, and other growth factors. 253 35

Mouse neuroblastoma N18 cells contain specific high affinity insulin and insulin-like growth factor-I (IGF-I) receptors. Insulin and IGF-I induce phosphorylation, in intact cells, of their respective receptor beta subunits. The insulin receptor beta subunit is represented by a 95-kDa phosphoprotein that is recognized by a specific antiserum (B10). The IGF-I receptor beta subunit is represented by two phosphoproteins of molecular mass 95 and 105 kDa. The hormone-induced phosphorylation was rapid and dose-dependent occurring on both phosphoserine and phosphotyrosine residues. In addition, both insulin and IGF-I induced phosphorylation of an endogenous protein of molecular mass 185 kDa (pp185). The rapidity and dose dependency of the phosphorylation of pp185 suggested that it may represent a common endogenous substrate for the insulin and IGF-I receptors in these neural-derived cells. Phosphorylation was primarily on phosphoserine and phosphotyrosine residues. pp185 did not absorb to wheat germ agglutinin-agarose and was not stimulated by either epidermal growth factor or platelet-derived growth factor. The finding of pp185 in these neural-related cells as well as in non-neural tissues suggests that it may represent a ubiquitous endogenous substrate for both the insulin and IGF-I receptor kinases.
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PMID:Insulin and insulin-like growth factor-I stimulate a common endogenous phosphoprotein substrate (pp185) in intact neuroblastoma cells. 296 Jun 69

A gene encoding a putative third member of the insulin receptor family (called the insulin receptor-related receptor or IRR) was isolated in 1989. However, the naturally occurring protein product encoded by this gene has yet to be described. In the present studies, we have generated four monoclonal antibodies to a recombinantly expressed chimera, which contains the extracellular domain of human IRR. These antibodies were found to specifically recognize the chimeric IRR (and not the insulin or insulin-like growth factor I receptors), and two of the antibodies were capable of acting as partial agonists in the cells expressing the chimeric IRR. These antibodies have therefore been utilized to study the expression and properties of the native receptor. In contrast to the two other members of this receptor family, the endogenous IRR protein had only a very limited expression, being detected only in neuroblastomas. In primary neuroblastomas, the levels of the receptor were highest in samples from stage A tumors (those which are generally more highly differentiated and have higher levels of the nerve growth factor receptor). The endogenous IRR could also be detected in a neuroblastoma cell line (called IMR-5 cells). In these cells, IRR could be shown to be partly present as a hybrid with the insulin and insulin-like growth factor-I receptors but not with the receptor for nerve growth factor. The intrinsic tyrosine kinase activity of this endogenous IRR was activated by the agonist monoclonal antibody to IRR but not by nerve growth factor, insulin-like growth factor I, or insulin. Finally, this monoclonal antibody was found to stimulate mitogen-activated protein kinase activity in these cells. In summary, these studies demonstrate for the first time that the IRR protein is normally expressed, that its levels are highest in neuronal tissues, and that it can form hybrid receptors with the two other members of this receptor family but not with the more distantly related nerve growth factor receptor.
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PMID:Characterization of the endogenous insulin receptor-related receptor in neuroblastomas. 782 25

Insulin-like growth factors are abnormally expressed in some pediatric solid tumors. In addition, tumors that do not show significant alterations in pattern of expression are responsive to and may be dependent upon insulin-like growth factors for proliferation. These can be produced by the tumor cells (autocrine), surrounding stromal cells (paracrine), or at a distance (endocrine). Insulin-like growth factor-II plays a role in Wilm's tumor, neuroblastoma, and rhabdomyosarcoma, either as a proliferation factor, a motility factor, or both. Insulin-like growth factor-I may regulate osteosarcoma and the Ewing's family of tumors (primitive neuroectodermal tumors). Understanding the biology of these growth factors and their receptors can lead to new therapeutic approaches.
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PMID:Diverse roles of insulin-like growth factors in pediatric solid tumors. 805 16

A combination of basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) or 16 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum induces human SH-SY5Y neuroblastoma cells to undergo differentiation and acquire a neuronal phenotype. Nerve growth factor (NGF) added to SH-SY5Y cells stably transfected with the NGF-receptor TRK-A (SH-SY5Y/trk) induces a similar differentiated phenotype. SH-SY5Y cells express protein kinase C (PKC)-alpha, PKC-beta I, PKC-epsilon, and PKC-zeta protein, and phorbol ester- or growth factor-induced differentiation results in a sustained activation of PKC. The specific PKC inhibitor GF 109203X blocked TPA- and bFGF-IGF-I-induced neurite outgrowth in wild-type SH-SY5Y cells and NGF-induced neurite outgrowth in SH-SY5Y/trk cells. When added to differentiated cells, GF 109203X caused rapid retraction of growth cone filopodia. In TPA- and bFGF-IGF-I-treated cells, addition of GF 109203X also blocked induced expression of growth associated protein-43 and neuropeptide tyrosine while the increase in expression of these two genes was only slightly affected by the inhibitor in NGF-treated SH-SY5Y/trk cells. Thus, a portion of the NGF-induced phenotypic changes appears not to be mediated via PKC-dependent signaling. A high concentration of TPA (1.6 microM) down regulated PKC-alpha and PKC-beta I almost completely and PKC-epsilon partially in wild-type SH-SY5Y and SH-SY5Y/trk cells. Cells with down-regulated PKC-alpha and PKC-beta I after 1.6 microM TPA treatment still differentiated with growth factors. In these cells, the PKC-epsilon level was restored, and the PKC-epsilon protein was enriched in the growth cones. The 1.6 microM TPA-induced down-regulation of PKC-epsilon was counteracted by bFGF and NGF but not by platelet-derived growth factor or IGF-I. These data indicate that PKC activity is vital for neurite formation, and that the cells can differentiate under conditions when PKC-alpha and PKC-beta I are extensively down regulated. The close correlation between differentiation and presence of PKC-epsilon protein suggests an important function for this isoform during this process.
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PMID:Protein kinase C-epsilon is implicated in neurite outgrowth in differentiating human neuroblastoma cells. 878 Aug 91

In the current studies, we examined whether focal adhesion kinase (FAK) and paxillin play a role in insulin-like growth factor-I (IGF-I)-stimulated morphological changes in neuronal cells. In SH-SY5Y human neuroblastoma cells, 10 nM IGF-I enhanced the extension of lamellipodia within 30 min. Scanning electron microscopy and staining with rhodamine-phalloidin showed that these lamellipodia displayed ruffles, filopodia, and a distinct meshwork of actin filaments. Immunofluorescent staining identified focal concentrations of FAK, paxillin, and phosphotyrosine within the lamellipodia. Immunoprecipitation experiments revealed that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial extension. Maximal phosphorylation of FAK and paxillin was observed 15-30 min after the addition of 10 nM IGF-I, whereas maximal IGF-I receptor phosphorylation occurred within 5 min. FAK, paxillin, and IGF-I receptor tyrosine phosphorylation had similar concentration-response curves and were inhibited by the receptor blocking antibody alphaIR-3. These results indicate that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial advance and suggest that the tyrosine phosphorylation of these two proteins helps mediate IGF-I-stimulated cell and growth cone motility. These responses contrast directly with recent reports showing insulin-stimulated dephosphorylation of FAK and paxillin.
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PMID:Tyrosine phosphorylation of paxillin and focal adhesion kinase during insulin-like growth factor-I-stimulated lamellipodial advance. 903 May 91

A role in neuronal homeostasis is suggested by the persistent expression of the insulin-like growth factors in the adult nervous system. SH-SY5Y human neuroblastoma cells, a well-characterized in vitro model of human neurons, were used to investigate the effects of hyperosmotic stress on neurons. Neuronal DNA fragmentation was detected within 1 h and pyknotic nuclei were apparent in attached cells after 12 h of hyperosmotic stress. In parallel, flow cytometry measurements revealed a sudden increase in the rate of cells irreversibly undergoing programmed cell death after 12 h of hyperosmotic exposure. Insulin-like growth factor-I delayed the onset of a laddered DNA fragmentation pattern for 24 h and provided continuing protection against hyperosmotic exposure for 72 h. Amino acid uptake was decreased in hyperosmotic medium even in the presence of insulin-like growth factor-I; the protein synthesis inhibitor cycloheximide neither prevented the induction of programmed cell death nor interfered with the ability of insulin-like growth factor-I to act as an osmoprotectant in hyperosmotic medium. Cysteine and serine protease inhibitors each prevented DNA fragmentation under hyperosmotic conditions, suggesting that the osmoprotectant activity of insulin-like growth factor-I involves the suppression of protease activity. Collectively, these results indicate that insulin-like growth factor-I limits the death of neurons under stressful environmental conditions, suggesting that it may provide a candidate therapy in the treatment of hyperosmolar coupled neurological injury.
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PMID:Insulin-like growth factor-I is an osmoprotectant in human neuroblastoma cells. 920 Jul 35

Insulin-like growth factor-I (IGF-I) induces neuronal differentiation in vitro. In the present study, we examined the signaling pathway underlying IGF-I-mediated neurite outgrowth. In SH-SY5Y human neuroblastoma cells, treatment with IGF-I induced concentration- and time-dependent tyrosine phosphorylation of the type I IGF receptor (IGF-IR) and extracellular signal-regulated protein kinases (ERK) 1 and 2. These effects of IGF-I were blocked by a neutralizing antibody against IGF-IR. Whereas IGF-IR phosphorylation was observed within 1 min, maximal phosphorylation of ERKs was not reached for 30 min. Both IGF-IR and ERK phosphorylation were maintained for at least 24 h. Also, the concentration dependence of IGF-I-stimulated IGF-IR and ERK tyrosine phosphorylation paralleled that of IGF-I-mediated neurite outgrowth. We further examined the role of mitogen-activated protein kinase activation in IGF-I-stimulated neuronal differentiation using the mitogen-activated protein kinase/ERK kinase inhibitor PD98059. Whereas PD98059 had no effect on IGF-IR phosphorylation, PD98059 reduced IGF-I-mediated ERK tyrosine phosphorylation and ERK phosphorylation of the substrate Elk-1. PD98059 also produced a parallel reduction of IGF-I-stimulated neurite outgrowth. Finally, consistent with its ability to block neuronal differentiation, PD98059 inhibited IGF-I-dependent changes of GAP-43 and c-myc gene expression. Together these results suggest that activation of ERKs is essential for IGF-I-stimulated neuronal differentiation.
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PMID:Insulin-like growth factor-I-mediated neurite outgrowth in vitro requires mitogen-activated protein kinase activation. 926 Nov 37

Early ethanol exposure depletes neurons in the developing nervous system, however the effects on neuronal precursors are not homogeneous. Some cells are more susceptible to ethanol toxicity than others. Growth factors are important mitogens for neuronal precursors. We tested the hypothesis that the differential sensitivity of neuronal precursors to ethanol is determined by their responses to growth factors using an in vitro model (SH-SY5Y, SK-N-SH, and IMR32 neuroblastoma cells) of neuronal precursors. The three cell lines were raised in a medium containing 10% or 0% fetal calf serum. Cells were exposed to ethanol and/or a growth factor. These factors included basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor-I, nerve growth factor, and platelet-derived growth factors AA and BB. The numbers of cells per culture were counted both before and after 3 days of ethanol and/or growth factor treatment. In addition, the effect of ethanol exposure on the expression of receptors for these growth factors was examined. Neuroblastoma cells displayed differential sensitivity to ethanol. The growth of SH-SY5Y and SK-N-SH cells was inhibited by ethanol in a concentration-dependent manner. Ethanol did not affect cell viability. Thus, this inhibition resulted from a reduction of cell proliferation. In contrast, IMR32 cells were not affected by ethanol (even at concentrations as high as 800 mg/dl). The response to growth factors was also heterogeneous. In serum-supplemented medium, SH-SY5Y and SK-N-SH cells were stimulated by all of the tested growth factors. For cells raised in a serum-free medium, only the nerve growth factor was ineffective. IMR32 cells, however, were unaffected by most of these growth factors, regardless of the medium conditions. Ethanol blocked the action of all growth factors tested. In general, all cells expressed the specific receptors for the six growth factors. Only the expression of the basic fibroblast growth factor, insulin-like growth factor-I, and nerve growth factor receptors were reduced by ethanol exposure. In summary, neuroblastoma cells exhibit differential susceptibility to ethanol, and this correlates with their response to mitogenic growth factors. Some growth factors are a target of ethanol toxicity. These heterogeneous effects seem to parallel ethanol-induced changes of proliferating neuronal precursors in vivo.
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PMID:Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. 934 77

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