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)

Receptor for advanced glycation end products (RAGE) mediates neurite outgrowth and cell migration upon stimulation with its ligand, amphoterin. We show here that RAGE-dependent changes in cell morphology are associated with proliferation arrest and changes in gene expression in neuroblastoma cells. Chromogranin B, a component of secretory vesicles in endocrine cells and neurons, was found to be up-regulated by RAGE signaling during differentiation of neuroblastoma cells along with the two other members of the chromogranin family, chromogranin A and secretogranin II. Ligation of RAGE by amphoterin lead to rapid phosphorylation and nuclear localization of cyclic AMP response element-binding protein (CREB), a major regulator of chromogranin expression. Furthermore, inhibition of ERK1/2-Rsk2-dependent CREB phosphorylation efficiently inhibited up-regulation of chromogranin gene expression upon RAGE activation. To further study the effects of RAGE and amphoterin on cellular differentiation, we stimulated embryonic stem cells expressing RAGE or a signaling-deficient mutant of RAGE with amphoterin. Amphoterin was found to promote RAGE-dependent neuronal differentiation of embryonic stem cells characterized by up-regulation of neuronal markers light neurofilament protein and beta-III-tubulin, activation of CREB, and increased expression of chromogranins A and B. These data suggest that RAGE signaling is capable of driving neuronal differentiation involving CREB activation and induction of chromogranin expression.
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PMID:Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. 1216 13

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

Insulin-like growth factor-I (IGF-I) is translated as a pre-pro-peptide that is posttranslationally processed to its mature form by proteolytic removal of the signal peptide and the E-domain peptide. Contrary to the mature human (h) IGF-I, the recombinant rtEa4 -peptide significantly reduced the anchorage-independent cell growth in human neuroblastoma cells (SK-N-F1), shown by colony formation assay in vitro. Significant inhibition of colony formation is also observed in SK-N-F1 cells stably transfected with a bicistronic expression construct encoding a secretory form of the rtEa4 peptide. Furthermore, treatment with the recombinant rtEa4 peptide, but not the mature hIGF-I, resulted in morphological differentiation of SK-N-F1 cells characterized by long neurite outgrowth. Similar morphological differentiation is also observed in SK-N-F1 cell clones stably transfected with the rtEa4 peptide expression construct. A spectrum of biological activities similar to those of rtEa4 peptide is also observed in the synthetic hEb peptide, but not-the hEa peptide. Results of further characterization reveal that neurites induced by rtEa4 or hEb peptide contain neuronal-specific MAP-2, Tau, and neurofilament (NF-160), accompanied by an increased expression of the neuronal marker gene neuropeptide tyrosine (NPY). Furthermore, effects of signal transduction inhibitors are indicative of the involvement of MAP-kinase PI-3-kinase cascades. The activation of ERK-1/-2 is markedly increased in response to rtEa-4 or hEb peptide stimulation, further indicating the involvement of MAPK signaling cascade. These unique biological activities exhibited by the rtEa4 or hEb peptide suggest that E peptide of the pro-IGF-I may play distinct roles in regulating cell growth and differentiation in neuroblastoma cells.
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PMID:Novel activities of pro-IGF-I E peptides: regulation of morphological differentiation and anchorage-independent growth in human neuroblastoma cells. 1237 41

The recently discovered endogenous peptide orphanin FQ/nociceptin (OFQ/N) activates the opioid receptor-like 1 (ORL1) receptor and produces diverse effects on pain perception. In addition to producing spinal analgesia, OFQ/N also exhibits an 'anti-opioid activity' against functional (supraspinal analgesia) and behavioral (conditioned place preference and withdrawal) properties of morphine. One manifestation of the behavioral changes resulting from chronic use of morphine is the upregulation of tyrosine hydroxylase (TH, the rate-limiting enzyme in catecholamine biosynthesis), which contributes to the dramatic increases in catecholamine release in the target regions of the locus coeruleus (LC) and the ventral tegmental area (VTA). The present study sought to determine the molecular mechanism(s) by which OFQ/N modulates the chronic actions of morphine by utilizing human neuroblastoma cell lines [BE(2)-C and SH-SY5Y] that endogenously express TH, and mu and ORL1 receptors. Activation of mu or ORL1 receptors in these cells in turn activates extracellular signal-regulated protein kinases (ERKs), ERK1 and ERK2. Chronic activation of mu, but not ORL1, receptors upregulated TH levels in these cells as previously reported in rat brain. Morphine-induced TH upregulation was blocked upon inclusion of a MEK-1 (mitogen-activated protein kinase kinase-1) inhibitor (PD98059), confirming the role for ERKs in this adaptive response to morphine. Inclusion of OFQ/N during chronic morphine exposure also blocked morphine-induced TH upregulation. Furthermore, chronic OFQ/N exposure increased levels of the TH gene repressor, Oct-2, irrespective of the presence or absence of morphine. This report suggests a potential role for Oct-2 in mediating the anti-opioid actions of OFQ/N against the behavioral manifestations resulting from chronic use of morphine.
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PMID:Orphanin FQ/nociceptin blocks chronic morphine-induced tyrosine hydroxylase upregulation. 1239 6

Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. Biol. Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H(2)O(2) and O(2)(), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role.
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PMID:Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis. 1241 92

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 the mitogen-activated protein kinases ERK1/2 by the chemotherapeutic agent cisplatin has been shown to result in either survival or cell death. The downstream mediators of these opposing effects are unknown, as are the upstream signaling molecules. Activation of ERK is required for accumulation and phosphorylation of p53 following cisplatin treatment. We studied the role of ERK activation after cisplatin treatment under p53-negative and p53-positive conditions using a tetracycline-dependent expression vector in Saos-2 osteosarcoma cells. Dose-dependent activation of ERK first occurred 3-6 h after a 2-h cisplatin incubation and declined after 12-24 h in several tumor cell lines. Incubation of cell lines with the MEK1 inhibitors PD98059 or UO126 after, but not during, cisplatin treatment completely inhibited cisplatin-induced activation of ERK. The activation of ERK by cisplatin was inhibited by transient transfection with dominant-negative Ras-N17 in Saos-2 cells. Treatment of cells with PD98059 or UO126 after cisplatin incubation or inhibition of signaling through ERK by tetracycline-regulated expression of dominant-inhibitory ERK enhanced resistance to cisplatin in p53-negative osteosarcoma cells and reduced cisplatin-induced apoptosis. P53 was stabilized and phosphorylated in a MEK1-dependent manner after cisplatin incubation in Kelly neuroblastoma cells. Inhibition of signaling through ERK increased cell survival after cisplatin treatment in these cells as well. Expression of functional p53 did not change the proapoptotic effects of ERK activation in response to cisplatin in Saos-2 cells. Our results suggest that cisplatin-induced activation of ERK is mediated by Ras. ERK activation increased cisplatin-induced cell death independently of p53 in osteosarcoma and neuroblastoma cell lines.
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PMID:Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. 1243 98

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

Previous studies showed that nerve growth factor (NGF) decreases the proliferation of neuroectodermal tumor (NET) cells (C-1300 and Neuro2A murine neuroblastoma, PC12 rat pheochromocytoma) within 5-7 days in a dose-dependent manner. This effect is regulated by the concentration of serum in the culture medium. Therefore, we hypothesized that NGF exerts its antimitogenic activities by interfering with the proliferative action of other growth factors. We studied the effects of short-term vs. long-term as well as endogenous vs. exogenous NGF on NET cell proliferation in response to various mitogenic growth factors. Retrovirus-mediated transfer of the beta-NGF gene into NET cells activated TrkA and consistently decreased their proliferative responses to insulin-like growth factor (IGF)-I, IGF-II, fibroblast growth factor-2, and epidermal growth factor (EGF), down-regulating EGF and IGF-I binding sites. It also decreased tyrosine phosphorylation of ERK-1, STAT3, and EGF or IGF receptors after treatment with IGF-I or EGF. Long-term incubation of NET cells with NGF mimicked the responses induced by beta-NGF gene transfer, albeit in a reversible manner. Short-term NGF treatment augmented the proliferative responses to IGF-I or EGF by enhancing cell survival. It also increased tyrosine phosphorylation of signal transducing proteins after exposure to IGF or EGF, an effect opposite to that of long-term NGF treatments. Hence, long-term NGF exposure in vitro might better reproduce the effects of NGF in vivo than short-term treatments. Only long-term exposure to NGF decreased the responses of NET cells to mitogenic growth factors by down-regulating their receptors and attenuating signal transduction events required for cell proliferation. These results suggest that NGF could exert similar actions on cellular responses to growth factors in vivo.
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PMID:Nerve growth factor regulates neuroectodermal tumor cell responses to mitogenic growth factors. 1267 99

Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
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PMID:Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide. 1273 Sep 64


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