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)

Interleukin-6 (IL-6) is involved in the pathophysiology of various diseases of the CNS. Because the molecular mechanism of action of this cytokine in human neurons is not well understood, we were interested in characterizing and defining a model system for IL-6-induced activation of signal transduction cascades, transcriptional activation, and protein synthesis in human neuronal cells. We show that IL-6 leads to transcriptional activation of signal transducer and activator of transcription 3 (STAT3) in human SH-SY5Y neuroblastoma cells. IL-6-induced activation and translocation of STAT3 and to a lesser degree STAT1 but not STAT5 are demonstrated. STAT3 is phosphorylated on Tyr705 and Ser727 residues on stimulation with IL-6, suggesting maximal activation of transcription. We also show IL-6-induced phosphorylation of p42/44 mitogen-activated protein (MAP) kinase, providing evidence for MAP kinase pathway activation. The physiological relevance of our results is confirmed by IL-6-induced phosphorylation of key signaling proteins of both STAT and MAP kinase pathway in rat primary hippocampal neurons. Furthermore, de novo protein synthesis on IL-6 activation is demonstrated.
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PMID:Interleukin-6 activates signal transducer and activator of transcription and mitogen-activated protein kinase signal transduction pathways and induces de novo protein synthesis in human neuronal cells. 1053 60

The effect of ethanol on insulin-like growth factor-1 (IGF-I)-mediated signal transduction and functional activation in neuronal cells was examined. In human SH-SY5Y neuroblastoma cells, ethanol inhibited tyrosine autophosphorylation of the IGF-I receptor. This corresponded to the inhibition of IGF-I-induced phosphorylation of p42/p44 mitogen-activated/extracellular signal-regulated protein kinase (MAPK) by ethanol. Insulin-related substrate-2 (IRS-2) and focal adhesion kinase phosphorylation were reduced in the presence of ethanol, which corresponded to the prevention of lamellipodia formation (30 min). By contrast, ethanol had no effect on Shc phosphorylation when measured up to 1 h, and did not affect the association of Grb-2 with Shc. Neurite formation at 24 h was similarly unaffected by ethanol. The data indicate that the IGF-I receptor is a target for ethanol in SH-SY5Y cells However, there is diversity in the sensitivity of signaling elements within the IGF-I receptor tyrosine kinase signaling cascades to ethanol, which can be related to the inhibition of specific functional events in neuronal activation.
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PMID:Inhibition of insulin-like growth factor-1 receptor and IRS-2 signaling by ethanol in SH-SY5Y neuroblastoma cells. 1120 20

Lipid analysis of gestational day E14.5 mouse brain revealed elevation of ceramide to a tissue concentration that induced apoptosis when added to the medium of neuroprogenitor cells grown in cell culture. Elevation of ceramide was coincident with the first appearance of b-series complex gangliosides (BCGs). Expression of BCGs by stable transfection of murine neuroblastoma (F-11) cells with sialyltransferase-II (ST2) resulted in a 70% reduction of ceramide-induced apoptosis. This was most likely due to an 80% reduced expression of prostate apoptosis response-4 (PAR-4). PAR-4 expression and apoptosis were restored by preincubation of ST2-transfected cells with N-butyl deoxinojirimycin (NB-DNJ) or PD98059, two inhibitors of ganglioside biosynthesis or p42/44 mitogen-activated protein (MAPK) kinase, respectively. In sections of day E14.5 mouse brain, the intermediate zone showed intensive staining for complex gangliosides, but only low staining for apoptosis (TUNEL) and PAR-4. Apoptosis and PAR-4 expression, however, were elevated in the ventricular zone which only weakly stained for complex gangliosides. Whole cell patch clamping revealed a 2-fold increased calcium influx in ST2-transfected cells, the blocking of which with nifedipine restored apoptosis to the level of untransfected cells. In serum-free culture, supplementation of the medium with IGF-1 was required to maintain MAPK phosphorylation and the anti-apoptotic effect of BCG expression. BCG-enhanced calcium influx and the presence of insulin-like growth factor-1 may thus activate a cell survival mechanism that selectively protects developing neurons against ceramide-induced apoptosis by up-regulation of MAPK and reduction of PAR-4 expression.
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PMID:Regulation of apoptosis during neuronal differentiation by ceramide and b-series complex gangliosides. 1157 45

This study describes the effect of signalling through muscarinic acetylcholine receptors on two transcription factors implicated in long-term synaptic plasticity and memory formation, EGR1 and the cyclic AMP response element binding protein (CREB). In SK-N-SH neuroblastoma cells, treatment with the cholinergic agonist carbachol led to maximal induction of EGR1 1 h after stimulation. This was preceded by the phosphorylation of CREB, which peaked as early as 5 minutes after carbachol treatment. The levels of both EGR1 and phosphorylated CREB (pCREB) slowly decayed over 4-8 h. CREB phosphorylation and EGR1 induction showed similar sensitivity to carbachol concentration, with EC(50) values in the range of 1-10 microM, and the changes in both transcription factors were blocked by the muscarinic antagonist atropine. As has been described elsewhere, EGR1 induction was dependent on activation of p42/44 MAP kinase, as it was blocked by the MEK inhibitor U0126. However, CREB phosphorylation by carbachol was largely unaffected by MAP kinase blockade. As both CREB phosphorylation and EGR1 induction have been linked to long-term potentiation and some forms of memory consolidation, these results may implicate CREB and EGR1 in independent or partially independent cholinergic signalling pathways involved in memory processes.
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PMID:Muscarinic receptor-mediated phosphorylation of cyclic AMP response element binding protein in human neuroblastoma cells. 1212 40

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.
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PMID:Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. 1220 96

Imidacloprid (IMI) is the principal neonicotinoid (the only major new class of synthetic insecticides of the past three decades). The excellent safety profile of IMI is not shared with a metabolite, desnitro-IMI (DNIMI), which displays high toxicity to mammals associated with agonist action at the alpha4beta2 nicotinic acetylcholine receptor (nAChR) in brain. This study examines the hypothesis that IMI, DNIMI, and (-)-nicotine activate the extracellular signal-regulated kinase (ERK) cascade via primary interaction with the alpha4beta2 nAChR in mouse neuroblastoma N1E-115 cells. These three nicotinic agonists induce phosphorylation of ERK (p44/p42) in a concentration-dependent manner with an optimal incubation period of 30 min. DNIMI (1 microM)-induced ERK activation is blocked by nicotinic antagonist mecamylamine but not by alpha-bungarotoxin and muscarinic antagonist atropine. This activation is prevented by intracellular Ca(2+) chelator BAPTA-AM but not by removal of external Ca(2+) using EGTA and Ca(2+)-free medium. 2-Aminoethoxy-diphenylborate, a blocker for inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from intracellular stores, inhibits DNIMI-induced ERK activation but a high level of ryanodine (to block ryanodine receptor-mediated Ca(2+) release) does not. The inhibitor U-73122 for phospholipase C (to suppress IP(3) production) prevents ERK activation evoked by DNIMI. Inhibitors for protein kinase C (PKC) (GF109203X) and ERK kinase (PD98059) block this activation whereas an inhibitor (H-89) for cyclic AMP-dependent protein kinase does not. Thus, neonicotinoids activate the ERK cascade triggered by primary action at the alpha4beta2 nAChR with an involvement of intracellular Ca(2+) mobilization possibly mediated by IP(3). It is further suggested that intracellular Ca(2+) activates a sequential pathway from PKC to ERK.
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PMID:Desnitro-imidacloprid activates the extracellular signal-regulated kinase cascade via the nicotinic receptor and intracellular calcium mobilization in N1E-115 cells. 1246 Jul 46

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326 and TV3279 [(N-propargyl-(3R) and (3S) aminoindan-5-yl)-ethyl methyl carbamate], respectively were derived from rasagiline, for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and B, while its S-isomer, TV3279, lacks MAO-inhibitory activity. The actions of these drugs in the regulation of the amyloid precursor protein (APP) processing using rat PC12 and human SH-SY5Y neuroblastoma cells were examined. Both isomers stimulated the release of the non-amyloidogenic alpha-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 micro M) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via alpha-secretase activity. Using several signal transduction inhibitors, the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279 was identified. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism, whereby these ChE inhibitors regulate the secretary processes of APP via activation of the MAP kinase pathway.
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PMID:Amyloid processing and signal transduction properties of antiparkinson-antialzheimer neuroprotective drugs rasagiline and TV3326. 1285 32

Cannabinoids activate several members of the mitogen-activated protein kinase superfamily including p44 and p42 extracellular signal-regulated kinase (ERK). We used N1E-115 neuroblastoma cells and the cannabinoid receptor agonist WIN 55,212-2 (WIN) to examine the signal transduction pathways leading to the activation of ERK. ERK phosphorylation (activation) was measured by Western blot. The EC50 for stimulation of ERK phosphorylation was 10 nm, and this effect was blocked by pertussis toxin and the CB1 (cannabinoid) receptor antagonist SR141716A. The MEK inhibitors PD 98059 and U0126 blocked ERK phosphorylation, as did the adenylate cyclase activator forskolin. The phosphatidylinositol (PI) 3-kinase inhibitor LY 294002 and the Src kinase inhibitor PP2 partially occluded the response but also decreased basal levels of phospho-ERK. The PI 3-kinase and Src pathways are known to promote cell survival in many systems; therefore, MTT (1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan) conversion was used to examine the effects of these inhibitors on cellular viability. LY 294002 decreased the number of viable cells after 18 h of treatment; therefore, the inhibition of ERK by this inhibitor is probably because of cytotoxicity. Forskolin blocked ERK phosphorylation with an EC50 of <3 microm, and the protein kinase A (PKA) inhibitor H-89 enhanced ERK phosphorylation. c-Raf phosphorylation at an inhibitory PKA-regulated site (Ser259) was also reduced by WIN. This is probably due to constitutive phosphatase activity because WIN did not directly stimulate PP1 or PP2A activity when measured using 6,8-difluoro-4-methylumbelliferyl phosphate as a fluorogenic substrate. These data implicate the inhibition of PKA as the predominant pathway for ERK activation by CB1 receptors in N1E-115 cells. PI 3-kinase and Src appear to contribute to ERK activation by maintaining activation of kinases, which prime the pathway and maintain cellular viability.
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PMID:A predominant role for inhibition of the adenylate cyclase/protein kinase A pathway in ERK activation by cannabinoid receptor 1 in N1E-115 neuroblastoma cells. 1451 12

Rasagiline [N-propargyl-(1R)-aminoindan] a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor exerts neuroprotective and antiapoptotic effects against a variety of insults in cell cultures and in vivo and has finished its phase III clinical trials for Parkinson's disease. In the present study, we show that rasagiline (1 and 10 microM) significantly protected rat PC12 cells against beta-amyloid (Abeta1-42) toxicity. In addition, rasagiline significantly increased (approximately threefold) the secretion of the nonamyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) from SH-SY5Y neuroblastoma and PC12 cells. The increase of sAPPalpha was dose-dependent and was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790 (100 microM), suggesting that the effect is mediated via alpha-secretase activity. Rasagiline-induced sAPPalpha release was significantly reduced by the inhibitors of protein kinase C (PKC), GF109203X, and ERK mitogen-activated protein kinase (MAPK) PD98059. Moreover, rasagiline dose dependently (0.1-10 microM) increased the phosphorylation of p44 and p42 MAPK, which was abolished by PD98059 (30 microM) and GF109203X (2.5 microM). By comparing the actions of rasagiline with those of its S-isomer TVP1022, which is not an MAO inhibitor, we have been able to demonstrate that MAO-B inhibition is not a prerequisite for either sAPPalpha-induced release or ERK phosphorylation. In addition, structure-activity relationship among rasagiline-related compounds suggests the crucial role of the propargyl moiety in these molecules, because propargylamine itself significantly induced the secretion of sAPPalpha and increased MAPK phosphorylation with similar potency to that of rasagiline and its derivatives.
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PMID:The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing. 1452 44

Most G protein-coupled receptors are internalized after interaction with their respective ligand, a process that subsequently contributes to cell desensitization, receptor endocytosis, trafficking, and finally cell resensitization. Although cellular mechanisms leading to cell desensitization have been widely studied, those responsible for cell resensitization are still poorly understood. We examined here the traffic of the high affinity neurotensin receptor (NT1 receptor) following prolonged exposure to high agonist concentration. Fluorescence and confocal microscopy of Chinese hamster ovary, human neuroblastoma (CHP 212), and murine neuroblastoma (N1E-115) cells expressing green fluorescent protein-tagged NT1 receptor revealed that under prolonged treatment with saturating concentrations of neurotensin (NT) agonist, NT1 receptor and NT transiently accumulated in the perinuclear recycling compartment (PNRC). During this cellular event, cell surface receptors remained markedly depleted as detected by both confocal microscopy and (125)I-NT binding assays. In dividing cells, we observed that following prolonged NT agonist stimulation, NT1 receptors were removed from the PNRC, accumulated in dispersed vesicles inside the cytoplasm, and subsequently reappeared at the cell surface. This NT binding recovery allowed for constant cell sensitization and led to a chronic activation of mitogen-activated protein kinases p42 and p44. Under these conditions, the constant activation of NT1 receptor generates an oncogenic regulation. These observations support the potent role for neuropeptides, such as NT, in cancer progression.
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PMID:Receptor trafficking via the perinuclear recycling compartment accompanied by cell division is necessary for permanent neurotensin cell sensitization and leads to chronic mitogen-activated protein kinase activation. 1469 44


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