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)

Nerve growth factor (NGF) is essential for the differentiation and survival of sympathetic and sensory neurones and is thought to play a role in the differentiation of neuroblastoma. In this study we have shown NGF decreased the mRNA level of the two GTPase activating proteins neurofibromin (containing the NF1-GRD) and type 1 GAP120 in two neuroblastoma cell lines, IMR-32 and SK-N-SH. This effect was seen within 15 min exposure to NGF and was maintained up to 2 h after the addition of NGF. Treatment with NGF increased the amount of GTP bound p21ras 3-fold, within 20 min exposure. Western blot analysis showed SK-N-SH and IMR-32 cells to contain equal amounts of p21ras protein and these levels were unchanged by NGF treatment. However, NGF induced an increase in the level of neurofilament L protein, which was accompanied by an increase in neurite extension. These effects of NGF occurred in the absence of growth inhibition. In conclusion, our results demonstrate a decrease in GTPase activating proteins and activation of p21ras by NGF in IMR-32 and SK-N-SH cells, thus implicating p21ras in NGF signal transduction in neuroblastoma.
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PMID:Activation of p21ras by nerve growth factor in neuroblastoma cells. 858 29

Insulin is a well known mitotic agent for neuroblastoma cells. Human SK-N-BE neuroblastoma cells stably transfected with the estrogen receptor, however, undergo growth arrest and differentiation when treated with insulin. These effects were shown to be due to an insulin-dependent activation of the unliganded estrogen receptor. Here, we demonstrate that this activation involves the AF-2 COOH-terminal domain of the estrogen receptor and that the communication between estrogen and insulin receptor systems occurs via selected and specific transduction signals. In fact, by the use of dominant negative and dominant positive mutants we demonstrate that p21ras is essential for insulin and estrogen receptor coupling. With pharmacological tools, we prove that PI 3'kinase does not contribute to this cross-talk and that protein kinase C triggers transduction signals that act in synergism with p21ras. These results prove the intricacy of all these intracellular paths of communication. The finding that, in neuroblastoma cells, selected signal transduction systems are involved in the insulin-dependent activation of estrogen receptor is of particular interest considering that estrogen receptor might restrict the role played by insulin during the differentiation of neural cells and interfere with its proliferative potential while allowing its regulation of other functions related to cell survival.
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PMID:Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells. 873 81

Results of transgenetic studies argue that the scrapie isoform of the prion protein (PrPSc) interacts with the substrate cellular PrP (PrPC) during conversion into nascent PrPSc. While PrPSc appears to accumulate primarily in lysosomes, caveolae-like domains (CLDs) have been suggested to be the site where PrPC is converted into PrPSc. We report herein that CLDs isolated from scrapie-infected neuroblastoma (ScN2a) cells contain PrPC and PrPSc. After lysis of ScN2a cells in ice-cold Triton X-100, both PrP isoforms and an N-terminally truncated form of PrPC (PrPC-II) were found concentrated in detergent-insoluble complexes resembling CLDs that were isolated by flotation in sucrose gradients. Similar results were obtained when CLDs were purified from plasma membranes by sonication and gradient centrifugation; with this procedure no detergents are used, which minimizes artifacts that might arise from redistribution of proteins among subcellular fractions. The caveolar markers ganglioside GM1 and H-ras were found concentrated in the CLD fractions. When plasma membrane proteins were labeled with the impermeant reagent sulfo-N-hydroxysuccinimide-biotin, both PrPC and PrPSc were found biotinylated in CLD fractions. Similar results on the colocalization of PrPC and PrPSc were obtained when CLDs were isolated from Syrian hamster brains. Our findings demonstrate that both PrPC and PrPSc are present in CLDs and, thus, support the hypothesis that the PrPSc formation occurs within this subcellular compartment.
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PMID:Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains. 896 61

Ras protooncogenes encode small guanine nucleotide binding proteins (p21ras) activated by phosphorylation. Phosphorylation of p21ras is predominantly regulated by the GTPase activating proteins type 1 GAP120 and neurofibromin. Increased levels of p21ras-GTP (active) have been associated with increased cell growth and malignant transformation. In this study the relationship between p21ras, type 1 GAP120 and neurofibromin with growth and differentiation has been examined in neuroblastoma and peripheral primitive neuroectodermal tumour (pPNET) cell lines. The level of p21ras protein in neuroblastoma and pPNET cells was the same. However, the amount of p21ras-GTP bound was higher in pPNET than in neuroblastoma cells. This most likely reflects the absence of neurofibromin. Retinoic acid (RA)-induced differentiation and growth inhibition of neuroblastoma cells was associated with an increase in type 1 GAP120 and neurofibromin mRNA, and a decrease in p21ras-GTP. In pPNET cells levels of type 1 GAP120 but not neurofibromin mRNA were increased to similar levels to those in neuroblastoma cells. This was not associated with decreased p21ras-GTP, modulation of growth or change in morphology. In summary, constitutive activation of p21ras may have a role in the biology of pPNET cells. This may reflect abnormalities in neurofibromin expression, and could inpart explain why RA did not induce morphological differentiation and growth inhibition in pPNETs.
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PMID:Contrasting levels of p21ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumour and neuroblastoma cells, and their response to retinoic acid. 961 34

The alpha-estrogen receptor (ER alpha) transcriptional activity can be regulated either by binding to the cognate ligand or by intracellular signaling pathways responsive to a variety of factors acting through cell membrane receptors. Studies carried out in HeLa and COS-1 cells demonstrated that the cross-coupling between estrogen and growth factor receptors is mediated by p21ras and requires phosphorylation of a specific serine residue (Ser 118 in the human ER alpha and Ser 122 in mouse ER alpha) located in the ER alpha N-terminal activation function 1 (AF-1). Likewise, in the SK-N-BE neuroblastoma cell line p21ras is involved in the cross-coupling between insulin and ER alpha receptors. However, in this cell line Ser 122 is not necessary for insulin-dependent activation of unliganded ER alpha. In addition, after insulin activation, the electrophoretic mobility associated to serine hyperphosphorylation of ER alpha in SK-N-BE and in COS-1 cells is different. Our study rules out the possibility of tyrosine phosphorylation in unliganded ER alpha activation by means of transactivation studies of ER alpha tyrosine mutants and analysis of Tyr phosphorylation immunoreactivity. The two cofactors for steroid receptors RIP 140 and SRC-1 do not seem to be specifically involved in the insulin-induced ER alpha transactivation. The present study demonstrates the possibility of an alternative, cell-specific pathway of cross-coupling between intracellular and membrane receptors, which might be of importance for the understanding of the physiological significance of this mode of activation in the nervous system.
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PMID:Divergent pathways regulate ligand-independent activation of ER alpha in SK-N-BE neuroblastoma and COS-1 renal carcinoma cells. 962 59

Hydroxymethyl-glutaryl-CoA-reductase (HMG-CoA-reductase), the key enzyme for cholesterol synthesis and essential for the synthesis of the precursor for p21ras farnesylation, was inhibited in neuroblastoma cells by lovastatin or L-ascorbic acid. Both compounds inhibited clonogenic colony formation of neuroblastoma cells in soft agar. However, while the addition of mevalonate, the product of HMG-CoA-reductase, circumvented the inhibition by lovastatin it had no reversing effect on the inhibition by L-ascorbic acid. The role of reactive oxygen compounds generated by the degradation of catecholamines, and the pro-oxidative effects of L-ascorbic acid are discussed as mechanisms of action of L-ascorbic acid.
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PMID:Growth inhibition of neuroblastoma cells by lovastatin and L-ascorbic acid is based on different mechanisms. 1037 38

Differentiation and neuritogenesis of mouse neuroblastoma Neuro2a cells are induced by exogenous ganglioside but are not induced by nerve growth factor because its receptor is absent in these cells. In view of the emerging concept of the "glycosphingolipid-enriched domain" (GEM), we studied the mechanism of the ganglioside effect, focusing on the structure and function of such a domain. GEM in Neuro2a cells, separated as a low density membrane fraction, contains essentially all glycosphingolipids and sphingomyelin, together with five signal transducer molecules (c-Src, Lyn, Csk, Rho A, Ha-Ras). (3)H-Labeled Il(3)NeuAc-LacCer (GM3), Gb4Cer (globoside), and Il(3)NeuAc-Gg4Cer (GM1) added exogenously to cells were incorporated and concentrated in the low density GEM fraction. In contrast, more than 50% of glycerophospholipids and 30% of cholesterol were found in the high density fraction. (3)H-Labeled phosphatidylcholine added exogenously to cells was incorporated exclusively in the high density fraction. c-Src, the predominant signal transducer in the microdomain, was coimmunoprecipitated with anti-GM3 antibody DH2 or with anti-Csk; reciprocally, Csk was coimmunoprecipitated with anti-c-Src, indicating a close association of GM3, c-Src, and Csk. Brief stimulation of an isolated GEM fraction by the exogenous addition of GM3, but not lactosylceramide, caused enhanced c-Src phosphorylation with a concomitant decrease of Csk level in GEM. A decreased Csk/c-Src ratio in GEM may cause activation of c-Src because Csk is a negative regulator of c-Src. The effect of exogenous GM3 on c-Src activity was also observed in intact Neuro2a cells. Activation of c-Src was followed by rapid and prolonged (60 min) enhancement of mitogen-activated protein kinase activity leading to neuritogenesis. Thus, the ganglioside induction of neuritogenesis in Neuro2a cells is mediated by GEM structure and function.
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PMID:Glycosphingolipid-enriched signaling domain in mouse neuroblastoma Neuro2a cells. Mechanism of ganglioside-dependent neuritogenesis. 1040 36

Oncogenic Ras is responsible for malignant transformation in a variety of tumors. Farnesylation of Ras by farnesyl-protein-transferase (FPTase) is necessary for membrane localization of Ras-proteins, a prerequisite for its biological activity. Although mutations in ras genes are rare in neuroblastoma inactivation of Ras by inhibition of the FPTase is of interest in neuroblastoma. In this tumor, amplification of N-myc is frequently observed and expression of N-myc is induced via Ras signaling. Farnesyl-protein-transferase of neuroblastoma cells is inhibited by alpha-hydroxyfarnesylphosphonate. In homogenates of the cell line SK-N-AS an ID50 = 6.5 microM is estimated, in SK-N-SH the ID50 is 3.4 microM. The consequences of the inhibition of FPTase on the membrane localization was examined by immunoblots. Western blots of membrane proteins analysed with H-ras and N-ras specific antibodies revealed that H-ras protein is more sensitive to the inhibition of FPTase than N-ras protein. After culturing neuroblastoma cells for 24 hrs in the presence of 20 microM alpha-hydroxyfarnesylphosphonate H-ras protein completely dissappeared from the membrane fraction whereas N-ras protein was only affected by 50%. K-ras was not detectable on Western blots of three neuroblastoma cell lines. The experiments showed that FPTase inhibitors are effective in neuroblastoma cells but for complete inactivation of N-ras stronger conditions are required than for H-ras.
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PMID:Inhibition of farnesyl-protein-transferase in neuroblastoma cells by alpha-hydroxyfarnesylphosphonate. 1065 79

In neuroblastoma, amplification of the protooncogene N-myc is the most important molecular characteristic predicting a bad outcome for the patients. Despite the importance of the N-myc gene, little is known about the mechanisms regulating its expression. We found evidence that insulin-like growth factor II stimulates the growth of neuroblastoma in a paracrine fashion. Two neuroblastoma cell lines predominantly expressed IGF-II whereas two other cell lines expressed the IGF-receptor. In a receptor-positive cell line, N-myc expression was enhanced by stimulation with IGF-II. As the growth-stimulating signals of the IGF receptor are transmitted via Ras proteins, inactivation of Ras is one promising tool to prevent the induction of N-myc expression by IGF-II. Treatment of neuroblastoma cells with an inhibitor of the farnesyl-protein-transferase (FPTase) inactivated H-ras protein completely and N-ras protein by more than 50 %. Cell growth of neuroblastoma cells in serum containing medium was clearly diminished by inhibition of FPTase. The growth-promoting effect of IGF-II was reduced to exactly half the amount observed in non-inhibited cells.
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PMID:Neuroblastoma: inhibition of progression (Part II). Basic science in pediatric surgery. 1180 63

Prenylcysteine carboxymethyltransferase (pcCMT) is an enzyme that catalyzes the post-translational carboxymethylation of isoprenylated proteins ensuring a more efficient membrane attachment and proper guiding to a specific target membrane. In this paper, we report on modulation of pcCMT activity in retinoic acid (RA)-treated SH-SY5Y neuroblastoma cells using N-acetyl-S-farnesyl-L-cysteine (AFC) as artificial methyl acceptor. In addition, the methylation of endogenous proteins was followed by the vapor phase equilibrium assay and the storage phosphor screen (P-screen) technique with S-adenosyl-[3H-methyl] methionine (AdoMet) as methyl donor. Methylation of AFC was reduced to 75% of that of the control, the most prominent decrease being observed with the post-nuclear membrane fraction as enzyme source. With regard to protein methylation both screening methods yielded analogous results showing the [3H]-labeling of endogenous proteins in the 21-25kDa molecular mass (MM) range to be diminished by nearly 50%. This questions the role of protein carboxymethylation as an essential component of the differentiation process in SH-SY5Y neuroblastoma cells. The P-screen technique revealed that the methylation of other molecular mass proteins was also affected. Both S-adenosylhomocysteine (AdoHcy) and AFC (AdoHcy being the most effective) inhibited endogenous methylation. An interesting feature was that AFC inhibited the protein methylation proportionally more effective in RA-treated cells. Finally, the levels of three small guanosine-5'-triphosphate (GTP) binding proteins were screened upon differentiation showing rab3A to be increased while rhoA and H-ras were decreased.
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PMID:Prenylcysteine carboxymethyltransferase type III activity is decreased in retinoic acid-treated SH-SY5Y neuroblastoma cells. 1190 19


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