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)

1. The calcitonin receptor-like receptor (CRLR) and specific receptor activity modifying proteins (RAMPs) together form receptors for calcitonin gene-related peptide (CGRP) and/or adrenomedullin in transfected cells. 2. There is less evidence that innate CGRP and adrenomedullin receptors are formed by CRLR/RAMP combinations. We therefore examined whether CGRP and/or adrenomedullin binding correlated with CRLR and RAMP mRNA expression in human and rat cell lines known to express these receptors. Specific human or rat CRLR antibodies were used to examine the presence of CRLR in these cells. 3. We confirmed CGRP subtype 1 receptor (CGRP(1)) pharmacology in SK-N-MC neuroblastoma cells. L6 myoblast cells expressed both CGRP(1) and adrenomedullin receptors whereas Rat-2 fibroblasts expressed only adrenomedullin receptors. In contrast we could not confirm CGRP(2) receptor pharmacology for Col-29 colonic epithelial cells, which, instead were CGRP(1)-like in this study. 4. L6, SK-N-MC and Col-29 cells expressed mRNA for RAMP1 and RAMP2 but Rat-2 fibroblasts had only RAMP2. No cell line had detectable RAMP3 mRNA. 5. SK-N-MC, Col-29 and Rat-2 fibroblast cells expressed CRLR mRNA. By contrast, CRLR mRNA was undetectable by Northern analysis in one source of L6 cells. Conversely, a different source of L6 cells had mRNA for CRLR. All of the cell lines expressed CRLR protein. Thus, circumstances where CRLR mRNA is apparently absent by Northern analysis do not exclude the presence of this receptor. 6. These data strongly support CRLR, together with appropriate RAMPs as binding sites for CGRP and adrenomedullin in cultured cells.
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PMID:Comparison of the expression of calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) with CGRP and adrenomedullin binding in cell lines. 1208 88

Evidence has accumulated showing that vasoactive peptides, such as endothelin-1, adrenomedullin and urotensin-II, are expressed in various kinds of tumour cells. In the present study, the expression of endothelin-1 and endothelin receptors was studied in eight human tumour cell lines: T98G (glioblastoma), IMR-32 and NB69 (neuroblastoma), BeWo (choriocarcinoma), SW-13 (adrenocortical carcinoma), DLD-1 (colonic carcinoma), HeLa (cervical carcinoma) and VMRC-RCW (renal carcinoma). Reverse transcriptase-PCR showed expression of endothelin-1 mRNA in seven out of the eight cell lines, the exception being BeWo cells. ET(A) receptor mRNA was expressed in T98G, IMR-32 and NB69 cells, but weakly in the other cells. ET(B) receptor mRNA was expressed in IMR-32, NB69 and BeWo cells, but only weakly in T98G and HeLa cells. Immunoreactive endothelin was detected in the culture media of six out of the eight cell lines, but not in that of IMR-32 or BeWo cells. Treatment of T98G cells with an anti-endothelin-1 antibody or an anti-adrenomedullin antibody for 24 h decreased cell numbers to approx. 84% and 90% of control respectively. Treatment with the ET(A) receptor antagonist BQ-610 (1 microM) significantly decreased cell number to about 90% of control, whereas the ET(B) receptor antagonist BQ-788 had no significant effect. On the other hand, exogenously added endothelin-1, adrenomedullin or urotensin-II (0.1 microM) had no significant effects on cell number. These results suggest that endothelin-1 acts as a paracrine or autocrine growth stimulator in tumours. The effect of endothelin-1 on tumour growth appears to be mediated by the ET(A) receptor.
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PMID:Three vasoactive peptides, endothelin-1, adrenomedullin and urotensin-II, in human tumour cell lines of different origin: expression and effects on proliferation. 1219 50

We have recently found that cells derived from human neuroblastoma, a sympathetic nervous system (SNS) tumor, dedifferentiate and acquire a neural crest-like phenotype when exposed to hypoxia. In the present study, global analysis of gene expression and quantitative PCR of relevant genes showed that hypoxia provokes a general adaptive response in neuroblastoma cells and confirm loss of the neuronal phenotype and gain of stem-cell characteristics. Of the approximately 17,000 genes and ESTs analyzed, 199 were consistently upregulated and 36 were downregulated more than 2-fold by hypoxia. As anticipated, several genes involved in glucose and iron metabolism and neovascularization were upregulated, the latter group we here show to include the gene encoding chromogranin C and its cleavage product, secretoneurin, a vascular smooth muscle cell mitogen. We also observed upregulation of genes implicated in cell survival and growth, such as vascular endothelial growth factor (VEGF), neuropilin 1, adrenomedullin, and IGF-2. Several metallothioneins, which are linked to tumor drug resistance, were upregulated, whereas the expression of MDR1 decreased. In hypoxic neuroblastoma cells, proneuronal lineage specifying transcription factors, and their dimerization partner E2-2, were downregulated, whereas their inhibitors Id2 and HES-1 were induced, providing a molecular mechanism for the hypoxia-provoked dedifferentiation of neuroblastoma cells.
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PMID:Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior. 1509 45

We used SK-N-SH human neuroblastoma cells to test the hypothesis that adrenomedullin (ADM), a multifunctional neuropeptide, stimulates nitric oxide (NO) release by modulating intracellular free calcium concentration ([Ca2+]i) in neuron-like cells. We used a nitrite assay to demonstrate that ADM (10 pM to 100 nM) stimulated NO release from the cells, with a maximal response observed with 1 nM at 30 min. This response was blocked by 1 nM ADM(22-52), an ADM receptor antagonist or 2 microM vinyl-L-NIO, a neuronal NO synthase inhibitor. In addition, 5 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, an intracellular calcium chelator, eliminated the ADM-induced NO release. Similar results were observed when the cells were incubated in calcium-free medium or when L-type calcium channels were inhibited with 5 microM nifedipine or 10 microM nitrendipine. Depletion of calcium stores in the endoplasmic reticulum (ER) with 1 microM cyclopiazonic acid or 150 nM thapsigargin, or inhibition of ryanodine-sensitive receptors in the ER with 10 microM ryanodine attenuated the ADM-induced NO release. NO responses to ADM were mimicked by 1 mM dibutyryl cAMP, a cAMP analog, and were abrogated by 5 microM H-89, a protein kinase A inhibitor. Furthermore, Fluo-4 fluorescence-activated cell sorter analysis showed that ADM (1 nM) significantly increased [Ca2+]i at 30 min. This response was blocked by nifedipine (5 microM) or H-89 (5 microM) and was reduced by ryanodine (10 microM). These results suggest that ADM stimulates calcium influx through L-type calcium channels and ryanodine-sensitive calcium release from the ER, probably via cAMP-protein kinase A-dependent mechanisms. These elevations in [Ca2+)]i cause activation of neuronal NO synthase and NO release.
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PMID:Adrenomedullin stimulates nitric oxide release from SK-N-SH human neuroblastoma cells by modulating intracellular calcium mobilization. 1567 61

Calcitonin gene-related peptide (CGRP) is a highly potent vasodilator known to be involved in many physiological functions within the cardiovascular, gastrointestinal, immune, and nervous systems. This study assessed the desensitization of CGRP receptors by measuring agonist-mediated activation of adenylate cyclase in a model system employing human neuroblastoma-derived SK-N-MC cells. In these cells, we demonstrated that pre-incubation with CGRP (20 nM) induces a rapid desensitization of CGRP signaling (t(1/2)<or=3 min) by causing a decrease in potency and efficacy. CGRP's desensitization potency (DC(50)=0.29 nM) is similar to its activation potency on non-desensitized cells (EC(50)=0.20 nM). The desensitized receptors exhibited slow and incomplete re-sensitization upon removal of the pre-incubated ligand, resulting in 52-65% functional recovery after 3-5 h while CGRP binding sites were completely restored. Additional agonists within the calcitonin/CGRP family of peptides (calcitonin, amylin, adrenomedullin, and adrenomedullin 2) were compared to CGRP with regard to their ability to activate and desensitize CGRP receptors. Calcitonin and amylin did not cause receptor activation nor did they produce desensitization. Adrenomedullin and adrenomedullin 2 activated the receptors and produced desensitization, but at a slower rate and with a weaker desensitization potency than CGRP-induced desensitization. Adrenomedullin exhibited similar potency for receptor activation and desensitization, whereas adrenomedullin 2 has a 4-fold higher preference for receptor desensitization than for receptor activation. Activation and desensitization induced by CGRP, adrenomedullin and adrenomedullin 2 were blocked by the CGRP receptor antagonist CGRP8-37. These data indicate that CGRP receptors are desensitized by select peptides in the calcitonin/CGRP family. Slow recovery from the desensitized state may provide a strategy for timed modulation of the CGRP signaling pathway.
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PMID:Desensitization and re-sensitization of CGRP receptor function in human neuroblastoma SK-N-MC cells. 1782 80

The calcitonin gene-related peptide (CGRP) is a neuropeptide involved in vasodilation and other physiological functions throughout the body. The receptor for CGRP has been cloned and well studied, but the mechanism of CGRP receptor desensitization has not been fully elucidated. In the present study, we evaluated the kinetics for agonist-mediated desensitization of the adenylate cyclase response in human neuroblastoma SK-N-MC cells. Distinct CGRP receptor agonists were used, including alpha and beta isoforms of CGRP, the linearized derivative cys(Et)2,7 alphaCGRP, adrenomedullin, and adrenomedullin 2. betaCGRP was 4-600 times more potent at desensitizing the cAMP production as compared to the other receptor-activating ligands, and all of the desensitization effects were blocked by a CGRP receptor antagonist. Although the different agonists vary in their ability to induce functional desensitization, a pretreatment/washout sequence with each peptide was able to reduce the activation potency of the other members of the calcitonin/CGRP peptide family. Next we tested whether the desensitizing effects of the distinct peptides involve protein kinase C (PKC) or protein kinase A (PKA). A PKC inhibitor, Ro 31-8220, concentration-dependently reduced the desensitization induced by the 5 CGRP receptor agonists, while having little effect on their desensitization potencies. PKA inhibitors KT-5720 and H-89, on the other hand, showed little effect on the induced level of desensitization. The findings indicate that functional desensitization is produced by distinct peptides acting through the active site of CGRP receptors, and involves the activation of PKC as a common component necessary to achieve maximal desensitization of receptor signaling.
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PMID:Protein kinase C is a common component of CGRP receptor desensitization induced by distinct agonists. 1842 Jan 88

Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a key role in the pathophysiology of migraine headache. MK-0974 (telcagepant) is a potent and selective antagonist of the human and rhesus CGRP receptors and is currently in Phase III clinical studies for the acute treatment of migraine. The pharmacology of MK-0974 has been studied extensively, but there has not been a thorough characterization of its binding properties. Here, we characterize the binding of a tritiated analog of MK-0974 on human neuroblastoma (SK-N-MC) membranes and rhesus cerebellum. [(3)H]MK-0974 displayed reversible and saturable binding to both SK-N-MC membranes and rhesus cerebellum with a K(D) of 1.9 nM and 1.3 nM, respectively. Agonists and antagonists of the CGRP receptor displaced [(3)H]MK-0974 in a concentration-dependent manner in competition binding experiments. Both CGRP and adrenomedullin demonstrated biphasic competition while MK-0974 and the peptide antagonist CGRP(8-37) displaced [(3)H]MK-0974 in a monophasic fashion. In competitive binding studies with [(3)H]MK-0974 and CGRP, the fraction of high-affinity binding was reduced significantly by incubating the membranes with GTPgammaS. In kinetic binding experiments, the off-rate of [(3)H]MK-0974 was determined to be 0.51 min(-1) with a half-life of 1.3 min. In conclusion, the radioligand [(3)H]MK-0974 has proven to be a useful tool for studying the binding characteristics of MK-0974 and has broadened our understanding of this promising molecule.
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PMID:Examining the binding properties of MK-0974: a CGRP receptor antagonist for the acute treatment of migraine. 1908 2


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