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)

G protein-coupled receptors activate phospholipase C (PLC)-beta isoforms by the alpha or beta gamma subunits of G proteins, whereas growth-factor receptors activate PLC-gamma isoforms by phosphorylating tyrosine residues of the enzyme. As a common substrate for PLC enzymes, phosphatidylinositol 4,5-bisphosphate [Ptdins(4,5)P2] may play a pivotal role in the regulation of cellular PLC activity. Because small-molecular-weight G proteins have been implicated in the synthesis of Ptdins(4,5)P2, we studied the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates small G proteins of the Rho family, on receptor-stimulated PLC activity. We report here that in N1E-115 neuroblastoma cells, stimulation of inositol phosphate formation by the G protein-coupled receptor agonists bradykinin and lysophosphatidic acid and by the tyrosine kinase receptor agonist platelet-derived growth factor is largely attenuated by toxin B treatment. Furthermore, inositol phosphate production stimulated by the stable GTP analog guanosine 5'-O-(3-thio)-triphosphate in permeabilized N1E-115 cells was inhibited by C3 exoenzyme, which specifically inactivates Rho proteins. The inhibition by toxin B was apparently not caused by its effect on the cytoskeleton. In addition, the level of platelet-derived growth factor receptors, which was studied with immunoblotting, was unaffected by toxin B. Using exogenous Ptdlns(4,5)P2 as PLC substrate, it was found that the intrinsic enzymatic activity of PLC activated either by Ca2+ or by guanosine 5'-O-(3-thio)triphosphate was not altered by toxin B. However, toxin B decreased strongly, by up to 80%, the cellular level of Ptdins(4,5)P2 in a concentration-dependent manner, without changing those of phosphatidylinositol and phosphatidylinositol 4-phosphate. These results, together with the recent finding that Rho family proteins can regulate phosphatidylinositol 4-phosphate 5-kinase activity, demonstrate that Rho proteins are presumably important regulators of Ptdins(4,5)P2 synthesis and, thereby, play an integral role in the regulation of cellular signaling by PLC enzymes.
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PMID:Inhibition by toxin B of inositol phosphate formation induced by G protein-coupled and tyrosine kinase receptors in N1E-115 neuroblastoma cells: involvement of Rho proteins. 886 31

Glia cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily, has been implicated in the survival, morphological and functional differentiation of midbrain dopaminergic neurons and motoneurons in vitro and in vivo. The factor may thus have utility in the treatment of various human neurodegenerative disorders. Mechanisms regulating expression of GDNF in normal and diseased brain as a possible means to increase the local availability of GDNF are only beginning to be explored. We have established and employed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to study and compare levels of expression of GDNF mRNA in several cell types and to investigate its regulation. GDNF expression was clearly evident in primary cultured astrocytes, the glioma B49 and C6 cell, but less pronounced in the Schwannoma RN22 cell lines. Little or no signal could be observed in neuroblastoma cell lines (IMR32, LAN-1) or the pheochromocytoma cell line PC12, emphasizing the glial character of this factor. Using the C6 cell line we found that fibroblast growth factor-2 (FGF-2; bFGF) can increase GDNF mRNA levels, whereas FGF-1, platelet-derived growth factor (PDGF), and vasoactive intestinal polypeptide (VIP) are apparently ineffective. Several other factors (forskolin, kainic acid, triiodothyronine dexamethasone, GDNF, TGF-beta 1, and interleukin-6) appear to have slightly negative effects on GDNF mRNA levels at the concentrations tested. To further explore the relationship between FGF-2 and GDNF, we also addressed the question whether GDNF, like FGF-2, may have an effect on C6 cell proliferation. We conclude that (1) glial and glial tumor cells, rather than neuronal cell lines, express GDNF, (2) that FGF-2 has a prominent inductive effect on GDNF expression and (3) that GDNF stimulates C6 cell proliferation. Finally, these data suggest that neurotrophic actions of FGF-2 in mixed glial-neuronal cell cultures might be mediated in part by GDNF.
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PMID:GDNF mRNA levels are induced by FGF-2 in rat C6 glioblastoma cells. 888 50

Exogenously added gangliosides are known to promote neurite outgrowth in a variety of cell types, including some neuroblastoma cell lines. To study neuritogenesis in SH-SY5Y human neuroblastoma we serum starved the cells for 24 hr and exposed them to gangliosides (GM1, GM3, or GT1b), platelet-derived growth factor (PDGF), insulin, nerve growth factor (NGF), insulin-like growth factor I (IGF-I), or combinations of these for 3 days. We measured four parameters of neurite outgrowth using image analysis. PDGF induced neurite outgrowth in SH-SY5Y and GM1 inhibited this. Both phenomena were dose-dependent with neurites/cell and neurite length being below controls with 100 microM GM1, and percent of neurite-bearing cells being below controls with 25, 50, and 100 microM GM1. Similar but more inhibitory results were obtained with GM3 and GT1b. Insulin and IGF-I induced a neuritogenic response that was less potent than that of PDGF and was also inhibited by gangliosides. NGF had no effect on neurite outgrowth but gangliosides were still inhibitory even in cells not treated with growth factors. From this we conclude that gangliosides inhibit spontaneous and trophic factor-induced neurite outgrowth in SH-SY5Y cells. For GM1 and GT1b, but not GM3, this probably involves inhibition of trophic factor receptor function.
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PMID:Gangliosides inhibit growth factor-stimulated neurite outgrowth in SH-SY5Y human neuroblastoma cells. 908 10

With respect to a potential role for CD44 in neuronal tumors, we investigated the regulation of variant CD44 exon containing isoforms (CD44V) in the human neuroblastoma cell line SK-N-SH in response to treatment with differentiation-inducing and mitogenic factors. While the standard form of CD44 was expressed at high levels in both treated and untreated cells, variant isoforms were strongly upregulated in response to treatment with 12-O-tetradecanoyl phorbol-13-acetate (TPA), insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor (PDGF) as shown by RT-PCR and immunofluorescence. One of the CD44 isoforms contains sequences encoded by variant exon v6 (CD44V6), which was originally described as a metastasis-associated antigen. Using specific inhibitors, we explored the signal transduction pathways involved in the expression of variant CD44. GF-109203X, a specific inhibitor of protein kinase C effectively blocked TPA- and IGF-1-upregulated expression of CD44v6. Wortmannin, a specific inhibitor of phosphoinositide 3-kinase (PI 3-kinase) partly reduced IGF-1 and PDGF induced CD44v6 expression. The induction of CD44V by TPA, IGF-1 or PDGF was correlated with an increased cellular binding to hyaluronic acid, a major counterreceptor for CD44. The increased binding caused by TPA or IGF-1 could specifically be blocked by the above inhibitors. Thus, PKC and PI 3-kinase are likely to transduce growth factor induced signals that upregulate specific CD44 splice variants.
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PMID:Expression of CD44 isoforms in neuroblastoma cells is regulated by PI 3-kinase and protein kinase C. 919 Aug 98

We have shown previously that platelet-derived growth factor (PDGF) has trophic effects on dopaminergic neurons in vitro. We now examined a mouse neuroblastoma cell line, NB41, for its response to PDGF and studied their phenotypic characteristics following introduction of an antisense PDGF beta-receptor RNA. NB41 cells produce both PDGF-AA and -BB; however, they carry only PDGF beta-receptors, responding to BB but not to AA. Culturing the cells with PDGF-BB induced mRNA for c-fos and PDGF-beta receptor as well as that of neuron-specific enzyme, tyrosine hydroxylase. In contrast, mRNA of chromogranin A, which is produced by chromaffin cells, decreased. Introduction of an antisense PDGF beta-receptor RNA in NB41 cells completely suppressed neurite extension and cell growth. We compared the PDGF-beta receptor sense and antisense clones for their survival. Following serum withdrawal, NB41 cells showed a DNA ladder, which by an addition of the neurotoxin, 6-hydroxy dopamine (6-OHDA), resulted in a further enhancement of the DNA ladder. The addition of PDGF-BB prior to 6-OHDA rescued cells from undergoing apoptosis, seen as a reduction of the DNA ladder. The antisense clone, regardless of the presence of PDGF-BB in the culture, showed a pronounced DNA ladder after serum withdrawal, which was further enhanced by the addition of 6-OHDA.
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PMID:Characterization of platelet-derived growth factor (PDGF) action on a mouse neuroblastoma cell line, NB41, by introduction of an antisense PDGF beta-receptor RNA. 926 95

In vivo studies show (a) that early exposure to ethanol depletes neurons in the central nervous system (CNS) and (b) that a primary target of ethanol in the developing nervous system is proliferating neuronal precursors. We used a neuronal cell line (B 104 neuroblastoma cells) as an in vitro model for the effects of ethanol on the proliferation of neuronal precursors to test the hypothesis that ethanol interferes with growth factor-regulated proliferation of neuron-like precursors. The effects of ethanol on the mitogenic activity of two growth factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor AA and BB (PDGF-AA and PDGF-BB), were examined. Cell proliferation was monitored by tracing the change in the numbers of cultured cells over 4-5 days and in the cell cycle kinetics was determined using a cumulative labeling technique with bromodeoxyuridine (BrdU). Western immunoblots and immunohistochemical preparations show that B104 cells expressed the high affinity receptors for bFGF, PDGF-AA and PDGF-BB. The three growth factors were potent mitogens for the B104 cells; they promoted an increase in cell number even when the cells were grown in serum-free medium. Ethanol depressed the bFGF-, PDGF-AA- and PDGF-BB-mediated cell proliferation without altering the incidence of cell death. These changes in proliferation were concentration-dependent; at a concentration of 100 mg/dl, ethanol partially, but significantly inhibited growth factor-stimulated proliferation and higher ethanol concentrations (400 mg/dl or more) completely abolished growth factor-regulated cell proliferation. The effects of ethanol on cell growth were a result of ethanol-induced changes in growth factor-regulated cell cycle kinetics, principally the total length of the cell cycle and the fraction of the population that was actively cycling (the growth fraction). Ethanol completely negated the action of bFGF, but only partially blocked PDGF-promoted cycling activity. Thus, B104 cells are a suitable model for studying the effects of ethanol on neuronal proliferation. The blockage of bFGF- and PDGF-mediated cell proliferation by ethanol supports the hypothesis that growth factors are a target of ethanol neurotoxicity. Furthermore, the differential actions and effects of ethanol on the two growth factors mirror effects observed in vivo.
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PMID:Basic fibroblast growth factor- and platelet-derived growth factor-mediated cell proliferation in B104 neuroblastoma cells: effect of ethanol on cell cycle kinetics. 937 13

In human neuroblastoma SH-SY5Y cells, treatment with immunosuppressants such as FK506, cyclosporin A or rapamycin for 4 days induced the enhancement of the 27-kDa Bcl-2alpha protein level. Among immunosuppressants, rapamycin has most potency. Treatment with herbimycin A or wortmannin also enhanced Bcl-2 expression, but the BB type of platelet-derived growth factor decreased the level. These results suggest that Bcl-2 expression is probably regulated by the cascade of tyrosine kinase, phosphatidylinositol 3-kinase and rapamycin-sensitive p70 S6-kinase in human neuroblastoma SH-SY5Y cells.
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PMID:Possible involvement of rapamycin-sensitive pathway in Bcl-2 expression in human neuroblastoma SH-SY5Y cells. 941 36

Growth factors are known to regulate glioma proliferation. The glioma cell lines U87 and T98G were examined for evidence of an autocrine stimulatory loop involving the neurotrophin family of growth factors. Although neurotrophin-3 and TrkC RNA were detected by reverse transcription-PCR, there was no evidence of significant interaction between neurotrophin-3 and its cognate receptor TrkC. The microbial alkaloid K252a has been described to inhibit both Trk tyrosine kinase activity and neuroblastoma cell proliferation. K252a inhibited proliferation in U87 (IC50 = 1170 nM) and T98G (IC50 = 529 nM) but induced apoptosis in U87 cells only. At concentrations of 500 nM to 1 microM, K252a blocked only platelet-derived growth factor (PDGF)-mediated receptor autophosphorylation. These results suggest that an autocrine loop involving PDGF is functional and important for maintaining tumor growth. There is no evidence to support the existence of a neurotrophin-mediated autocrine loop. K252a, through inhibition of PDGF signal transduction, may be a novel therapeutic agent in the treatment of human gliomas.
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PMID:K252a inhibits proliferation of glioma cells by blocking platelet-derived growth factor signal transduction. 981 48

The expression and activity of factors influencing early neuronal development are altered by ethanol. Such factors include growth factors, for example, platelet-derived growth factor and basic fibroblast growth factor (for cell proliferation), and cell adhesion molecules (for neuronal migration). One agent, transforming growth factor beta1 (TGFbeta1), may affect both events. We tested the hypothesis that ethanol alters myriad TGFbeta1-mediated activities [i.e., cell proliferation and neural cell adhesion molecule (N-CAM) expression] using B104 neuroblastoma cells. TGFbeta1 inhibited the proliferation of B104 cells as evidenced by decreases in cell number and [3H]thymidine ([3H]dT) incorporation. TGFbeta1 induced sustained activation of extracellular signal-regulated kinases (ERKs), which are part of the family of mitogen-activated protein kinases (MAPKs). Treatment with PD98059 (a MAPK kinase blocker) abolished TGFbeta1-regulated inhibition of [3H]dT incorporation. TGFbeta1-mediated growth inhibition was potentiated by ethanol exposure. Ethanol also produced prolonged activation of ERK, an effect that was partially eliminated by treatment with PD98059. On the other hand, TGFbeta1 up-regulated N-CAM expression, and this up-regulation was not affected by treatment with PD98059. Ethanol inhibited the TGFbeta1-induced up-regulation of N-CAM expression in a concentration-dependent manner. Thus, TGFbeta1 affects ERK-dependent cell proliferation and ERK-independent N-CAM expression in B104 cells. Both activities are sensitive to ethanol and may underlie the ethanol-induced alterations in the proliferation and migration of CNS neurons.
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PMID:Transforming growth factor beta1-regulated cell proliferation and expression of neural cell adhesion molecule in B104 neuroblastoma cells: differential effects of ethanol. 1034 37

Neuroblastoma is a childhood tumor of the peripheral nervous system that remains largely uncurable by conventional methods. Mannitol induces apoptosis in neuroblastoma cell types and insulin-like growth factor I (IGF-I) protects these cells from hyperosmotic-induced apoptosis by affecting apoptosis-regulatory proteins. In the current study, we investigate factors that enable SH-SY5Y neuroblastoma cells to survive in the presence of an apoptotic stimulus. When SH-SY5Y cells are exposed to high mannitol concentrations, more than 60% of the cells are apoptotic within 48 h. Normal CS prevents hyperosmotic-induced apoptosis in a dose-dependent manner, with 0.6% CS protecting 50% of the cells, and 3% CS rescuing more than 70% of the cells from apoptosis. Serum also delays the commitment point for SH-SY5Y cells from 9 h to 35 h. A survey of several growth factors, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), fibroblast growth factor (FGF), and IGF-I reveals that IGF-I is a component of serum necessary for protection of neuroblastoma cells from death. Mitochondrial membrane depolarization occurs in greater than 40% of the cells after mannitol exposure and caspase-3 activation is increased in high mannitol conditions after 9 h. IGF-I blocks both the mitochondrial membrane depolarization and caspase-3 activation normally induced by hyperosmotic treatment in neuroblastoma cells. Our results suggest that (1) IGF-I is a key factor in serum necessary for protection from death and (2) IGF-I acts upstream from the mitochondria and the caspases to prevent apoptosis in human neuroblastoma.
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PMID:Insulin-like growth factor I is the key growth factor in serum that protects neuroblastoma cells from hyperosmotic-induced apoptosis. 1056 13


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