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)

We investigated the effects of different apolipoprotein E (apoE) isoforms, Abeta (1-42), and apoE/Abeta complexes on PKC-alpha translocation and APP processing in human SH-SY5Y neuroblastoma cells and fibroblasts. Treatment of cells with either 10 nM apoE3 or apoE4, 10 microM Abeta (1-42), or apoE/Abeta complexes induced significant translocation of PKC-alpha in both cell types. Effects were seen using both human recombinant apoE and apoE loaded into beta-very low density lipoprotein (beta-VLDL) particles. Time course (5-24 h) studies of APP processing revealed that some conditions induced transient or moderate increases in the secretion of proteins detected by 22C11. In contrast, the secretion of alpha-secretase cleaved APP was either not modified or transiently decreased, as determined by immunoblotting with the antibody 6E10. These results suggest that apoE, Abeta (1-42) and apoE/Abeta complexes can modulate PKC activity but do not have major consequences for APP processing. These effects could contribute to the reported PKC alterations seen in AD. However, it is unlikely that the contribution of different apoE isoforms to AD pathology occurs via effects on APP processing.
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PMID:Effects of apolipoprotein E (apoE) isoforms, beta-amyloid (Abeta) and apoE/Abeta complexes on protein kinase C-alpha (PKC-alpha) translocation and amyloid precursor protein (APP) processing in human SH-SY5Y neuroblastoma cells and fibroblasts. 1129 Mar 87

Brain connections depend on a stable association between dendrites and axons whose cytoskeleton is stabilized by the proteins MAP-2 and tau, respectively. The glial protein S-100beta inhibits the phosphorylation by PKC of these two microtubule-associated proteins. In order to determine if exogenous S-100beta can directly influence the cytoskeleton of living cells, cultures of N-18 cells (neuroblastoma clonal cell line) are treated for 30 min in serum-free medium with 10(-6) M colchicine. In normal media, colchicine induces a rapid retraction of processes, membrane blebbing, nuclear collapse, and cell death. The observed cellular changes, due to cytoskeletal collapse after exposure to colchicine, are similar and consistent with the loss of processes and cytoplasmic blebbing seen in cells undergoing apoptosis. The addition of 20 ng/ml of S-100beta after the initial 30-min exposure to colchicine prevents apoptosis, nuclear collapse and induces the regrowth of retracted processes. Cells were treated with the Hoechst Stain, a fluorescent marker that binds to nuclear material, to determine the occurrence of apoptosis in our cultures. In our control cultures, receiving no drugs, we found that 15.1% of the cells were apoptotic. When colchicine was added to the culture medium we found that 31.6% of the cells became apoptotic. However, when colchicine was followed by exposure to S-100beta we found that only 5.4% of the cells were apoptotic. Our results suggest that extracellular application of the glial protein S-100beta is sufficient to reverse colchicine-induced cytoskeletal collapse and prevent the resultant apoptosis of the cells. The increased levels of S-100beta seen after brain injury and in certain neurological and psychiatric disorders may be considered as beneficial for brain recovery.
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PMID:Colchicine-induced cytoskeletal collapse and apoptosis in N-18 neuroblastoma cultures is rapidly reversed by applied S-100beta. 1152 Apr 88

Protein kinase C (PKC) activation induces neuronal differentiation of SH-SY5Y neuroblastoma cells. This study examines the role of PKCbeta isoforms in this process. The PKCbeta-specific inhibitor LY379196 had no effect on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced neurite outgrowth from SH-SY5Y neuroblastoma cells. On the other hand, PKCbeta inhibition suppressed the TPA-stimulated increase in neuropeptide Y mRNA, activation of neuropeptide Y gene promoter elements, and phosphorylation of Erk1/2. The TPA-induced increase in neuropeptide Y expression was also inhibited by the MEK inhibitor PD98059. These data indicate that activation of a PKCbeta isoform, through a pathway involving Erk1/2, leads to increased expression of neuronal differentiation genes in neuroblastoma cells.
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PMID:A PKCbeta isoform mediates phorbol ester-induced activation of Erk1/2 and expression of neuronal differentiation genes in neuroblastoma cells. 1170 82

Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for opioid receptor-like (ORL1) receptor, transduces signaling cascades implicated in MAPK, PKC, PLC, and calcium, etc. This study was designed to investigate the intracellular signaling mechanism of N/OFQ in human dopaminergic neuroblastoma SH-SY5Y cells. N/OFQ rapidly induced the phosphorylation of CREB, which was significantly suppressed by pretreatment of PKA inhibitor, but not by MAPK inhibitors. It also time-dependently increased the phosphorylation of MAPK, which was proven as ERKs, whereas it did not affect the PI3K activity. Interestingly, KT5720, a specific inhibitor of PKA, markedly suppressed the phosphorylation of MAPK by N/OFQ in SH-SY5Y cells. Furthermore, BAPTA-AM, an intracellular chelator of Ca(2+), completely abolished the phosphorylation of CREB as well as MAPK in N/OFQ-treated SH-SY5Y cells. Taken together, these results suggest that N/OFQ independently induces the activation of CREB prior to MAPK phosphorylation, which was also modulated by PKA. Furthermore, Ca(2+)-related signaling implicates in the phosphorylation processes of CREB and MAPK simultaneously.
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PMID:Regulation of cyclic AMP-dependent response element-binding protein (CREB) by the nociceptin/orphanin FQ in human dopaminergic SH-SY5Y cells. 1185 41

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
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PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33

AVP(4-8), one of endogenous metabolite of argipressin(AVP) in brain, can enhance learning and memory. To understand further the molecular mechanism of its function, human neuroblastoma SK-N-SH cell line was chosen as a model to study its signal transduction pathway. Radioligand binding assay showed the existence of binding sites for AVP(4-8) on SK-N-SH cells. The activity of PKC and MAPK in SK cells was significantly enhanced by AVP(4-8), and the enhancement of PKC and MAPK was suppressed by ZDC(C)PR, an antagonist of AVP(4-8).
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PMID:AVP(4-8) Enhances PKC and MAPK Activities in SK-N-SH Cells. 1209 84

Protein kinase C (PKC) isoforms are present in the cell nucleus in diverse cell lines and tissues. Since little is known about proteins interacting with PKC inside the cell nucleus, we used Neuro-2a neuroblastoma cells, in which PKCalpha is present in the nucleus, to screen for nuclear binding partners for PKC. Applying overlay assays, we detected several nuclear proteins which bind to PKCalpha. Specificity of binding was shown by its dependence on PKC activation by phorbol ester, calcium, and phosphatidylserine. The PKC-binding proteins were partially purified and analyzed by microsequencing and mass spectrometry. Four proteins could be identified: PTB-associated splicing factor (PSF), p68 RNA helicase, and the heterogeneous nuclear ribonucleoprotein (hnRNP) proteins A3 and L. In the case of PSF, binding to PKC could also be demonstrated in a GST-pull-down assay using GST-PKCalpha, expressed in insect cells. Phosphorylation experiments revealed that PSF is a weak in vitro substrate for PKCalpha.
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PMID:Identification of PSF as a protein kinase Calpha-binding protein in the cell nucleus. 1211 8

The signalling pathways by which muscarine and epidermal growth factor (EGF) regulate the secretion of the alpha-secretase cleavage product (sAPPalpha) of the amyloid precursor protein (APP) were examined in the human neuroblastoma SH-SY5Y. Using specific inhibitors it was found that over 80% of sAPPalpha secretion, enhanced by muscarine, occurred via the extracellular signal-regulated kinase (ERK1/2) member of the mitogen-activated protein kinase (MAPK) family and was dependent on protein kinase Calpha (PKCalpha) and a member of the Src family of non-receptor tyrosine kinases (Src-TK). In contrast the stimulation of sAPPalpha secretion by EGF was not affected by inhibitors of PKC nor Src-TK but was dependent on ERK1/2. In addition muscarine-enhanced sAPPalpha secretion and ERK1/2 activation were inhibited 60 and 80%, respectively, by micromolar concentrations of the phosphatidylinositol 3 kinase (PI-3K) inhibitor wortmannin. In comparison wortmannin decreased EGF stimulation of sAPPalpha secretion and ERK 1/2 activation by approximately 40%. Unexpectedly, U73122, an inhibitor of phosphoinositide-specific phospholipase C, did not inhibit muscarine enhancement of sAPPalpha secretion. These data are discussed in relation to a pathway for the enhancement of sAPPalpha secretion by muscarine which involves the activation of a Src-TK by G-protein beta/gamma-subunits leading to activation of PKCalpha, and ERK1/2 by a mechanism not involving phospholipase C.
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PMID:Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein kinase C(alpha), src-tyrosine kinase and extracellular signal-regulated kinase but not phospholipase C. 1219 95

The molecular mechanism(s) underlying cross-tolerance between mu and opioid receptor-like 1 (ORL1) receptor agonists were investigated using two human neuroblastoma cell lines endogenously expressing these receptors and G protein-coupled receptor kinases (GRKs). Prolonged (24 h) activation of the mu receptor desensitized both mu and ORL1 receptor-mediated inhibition of forskolin-stimulated cAMP accumulation and upregulated GRK2 levels in SH-SY5Y and BE(2)-C cells. Prolonged ORL1 activation increased GRK2 levels and desensitized both receptors in SH-SY5Y cells. Upregulation of GRK2 correlated with increases in levels of transcription factors Sp1 or AP-2. PD98059, an upstream inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2), reversed all these events. Pretreatment with orphanin FQ/nociceptin (OFQ/N) also upregulated GRK3 levels in both cell lines, and desensitized both receptors in BE(2)-C cells. Protein kinase C (PKC), but not ERK1/2, inhibition blocked OFQ/N-mediated GRK3 induction and mu and ORL1 receptor desensitization in BE(2)-C cells. Antisense DNA treatment confirmed the involvement of GRK2/3 in mu and ORL1 desensitization. Here, we demonstrate for the first time a role for ERK1/2-mediated GRK2 induction in the development of tolerance to mu agonists, as well as cross-tolerance to OFQ/N. We also demonstrate that chronic OFQ/N-mediated desensitization of ORL1 and mu receptors occurs via cell-specific pathways, involving ERK1/2-dependent GRK2, or PKC-dependent and ERK1/2-independent GRK3 induction.
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PMID:Induction of G protein-coupled receptor kinases 2 and 3 contributes to the cross-talk between mu and ORL1 receptors following prolonged agonist exposure. 1242 67

Activation of G-protein coupled muscarinic acetylcholine receptors and MAPKs/ERK-1/2 has been found to inhibit neural cell apoptosis and promote neural cell survival. Bcl-2 protein family also plays an important role in regulating neural cell apoptosis and survival. However, signaling pathways coupling muscarinic receptors to Bcl-2 family remains to be elucidated. In the present study, it was found that carbachol not only activated MEK/ERK-1/2 signaling pathways, but also increased the expression levels of Bcl-2 and phospho-Bad proteins in human neuroblastoma SH-SY5Y cells. These effects were blocked by a muscarinic receptor antagonist (atropine) and a MEK inhibitor(PD98059) and were significantly attenuated by a Src family kinases inhibitor(PP1) and a PKC inhibitor (bisindolymaleimide-I), but were not influenced by a G(i/o)-uncoupling reagent (pertussin toxin) and a PI-3 kinase inhibitor (wortmannin). Furthermore, carbachol also stimulated Bcl-2 promoter-driven luciferase gene expression in transfected SH-SY5Y cells. Co-transfection of Ras or Raf dominant negative mutants with the pBcl-2-Luc plasmid abolished carbachol s effects. These data suggested that muscarinic acetylcholine receptors regulated the expression of Bcl-2 protein family by Ras-ERK-1/2 signaling pathway involving the pertussin toxin-insensitive G-proteins, PKC and Src.
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PMID:[G-protein-coupled muscarinic acetylcholine receptor activation up-regulates Bcl-2 and phospho-bad via Ras-ERK-1/2 signaling pathway]. 1251 26


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