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)

Neuroblastoma, a tumor of the sympathetic nervous system, is the most common solid malignancy of childhood outside the central nervous system. Vasoactive intestinal peptide (VIP) is produced by some of these tumors, and elevated serum levels correlate with tumor cell differentiation and a favorable prognosis. It has previously been demonstrated that human neuroblastoma cell lines LA-N-5 and IMR-32 will differentiate in vitro when exposed to retinoic acid. It is now shown that VIP also induces in vitro differentiation of these neuroblastoma lines. LA-N-5 or IMR-32 cells were grown in the presence of different concentrations of VIP. Cell proliferation was suppressed, as measured by cell count, incorporation of [3H]thymidine, and measurement of the proliferation index. The degree of suppression correlated with the concentration of VIP, and the effect was indistinguishable, on a molar basis, from that seen when cells were treated with retinoic acid. Similarly, the morphological changes seen in the VIP-treated cells were the same as those seen in retinoic acid-treated ones. The effects of VIP on both cell lines, like those of retinoic acid, are reversible. The human neuroepithelioma line CHP-100, is much less sensitive to either agent. Vasoactive intestinal peptide is the first substance shown to cause differentiation of neuroblastoma cells in vitro which is also known clinically to have a specific association with that tumor. It is postulated that VIP may play a key role in the well-documented maturation of these tumors in vivo and in the normal development of the sympathetic nervous system. These findings may also have therapeutic implications for the management of this frustrating childhood malignancy.
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PMID:In vitro differentiation of human neuroblastoma cells caused by vasoactive intestinal peptide. 237 78

Vasoactive intestinal peptide (VIP) and secretin are two related peptides that activate adenylate cyclase on membranes of striatal neurons and glial cells from embryonic mouse brain grown in primary culture. On the two cell types, the maximal activation that could be induced by secretin was only 40% above basal activity, which represented less than 15% of the maximal effect obtainable with VIP. From competition experiments performed on glial cells and the neuroblastoma X glioma hybrid, NG 108-15, a cell line known to possess both VIP and secretin sensitive-adenylate cyclase, we demonstrate that secretin does not activate VIP receptors. Furthermore, secretin has an apparent high affinity (EC50 10(-8) M) for its receptors on striatal neurons and NG 108-15 whereas an apparent low affinity (EC50 7 X 10(-6) M) was found on striatal glial cells. This suggests the existence of either two distinct secretin receptors or a desensitized form.
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PMID:Do secretin and vasoactive intestinal peptide have independent receptors on striatal neurons and glial cells in primary cultures? 301 77

Secretin is a 27-amino acid neuroendocrine peptide that stimulates fluid and electrolyte secretion in the gastrointestinal tract, activates tyrosine hydroxylase activity in the central nervous system, and affects cardiac and renal function. Specific receptors for secretin have been previously characterized on neuroblastoma cells, pancreatic acini, gastric glands, and liver cholangiocytes. We report here the isolation of a 1616-base pair cDNA from human lung tissue that encodes a 440-amino acid, 50-kDa, G protein-coupled human secretin receptor (HSR), with homology of 80% with the rat secretin receptor and 37% with the human type I vasoactive intestinal peptide receptor. Northern blot analysis of human tissue mRNA revealed that the relative intensity for expression of a 2.1-kilobase HSR transcript was pancreas > kidney > small intestine > lung > liver, with trace levels in brain, heart, and ovary. Stable transfectants of HSR in human embryonic kidney 293 cells, termed 293S12, expressed 10(5) binding sites/cell for 125I-secretin, with an apparent Kd of 3.2 nM. Vasoactive intestinal peptide, pituitary adenylyl cyclase-activating peptide-38, and glucagon were less potent (by 3 orders of magnitude) than secretin in competitively inhibiting 125I-secretin binding to 293S12 cells. Secretin evoked concurrent dose-dependent increases in intracellular cAMP and calcium levels in 293S12 cells and stimulated a 4-fold increase in phosphatidylinositol hydrolysis. Thus, the HSR expressed by stable transfectants can couple to two distinct intracellular signaling pathways.
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PMID:Molecular cloning and expression of a human secretin receptor. 770 Feb 44

Vasoactive intestinal peptide (VIP) is a neuromodulator, growth regulator and secretagogue for neuronal survival factors. Moreover, VIP has been suggested to be a mitogenic factor for embryonic neurons in the sympathetic nervous system. We now show that VIP had mitogenic activity in a human neuroblastoma cell line (NMB), as measured by cell number and thymidine incorporation. This mitogenic activity was dose dependent and was decreased with culture maturation. Northern blot analysis revealed VIP mRNA transcripts in this cell line suggesting an autocrine role for VIP in neurogenesis.
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PMID:Vasoactive intestinal peptide: a growth promoter in neuroblastoma cells. 825 11

Vasoactive intestinal peptide (VIP) has been considered as an autocrine growth factor in neuroblastomas. Pituitary adenylate cyclase activating polypeptides (PACAPs) are newly recognized members of the VIP family of neurohormones. As compared to VIP, PACAP has been reported to be biologically more potent and more efficient in tissues expressing selective PACAP receptors rather than common VIP/PACAP receptors. PACAPs and VIP interact with the same affinity and stimulate adenylate cyclase activity with the same efficacy and potency on the VIP receptors, but PACAPs act also on a more selective PACAP receptor that also recognizes VIP but with a 100- to 1,000-fold lower affinity. Thus, depending on the type of receptors expressed at a cell surface, PACAP may be more potent and efficient than VIP. The capacity of 22 surgical specimens of neuroblastomas and of 5 established cell lines to synthesize PACAP and VIP and to synthesize and express PACAP receptors and VIP receptors was studied. Using the reverse transcriptase-polymerase chain (RT-PCR) method with specific primers, we detected the mRNAs coding for PACAP and VIP in 19 and 3 out of 22 samples, respectively. PACAP mRNA was expressed in 3 of the 5 cell lines studied and VIP mRNA in 4. Using the same techniques, PACAP and VIP receptors mRNA were detected in 21, and 13 of the 22 tumor samples and in 5 and 1 of the cell lines studied, respectively. The expression of the PACAP receptor was demonstrated by direct binding studies and/or by the relative potency of PACAPs and VIP to stimulate adenylate cyclase activity in 16 of the 22 tumors and in all the cell lines. In addition, there was no correlation between tumor stage and the expression of mRNA coding for the peptides and the receptors. The present results demonstrated that PACAP could also be a candidate as an autocrine regulator of neuroblastoma which a higher activity than VIP.
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PMID:Pituitary adenylate cyclase activating peptide and its receptors are expressed in human neuroblastomas. 869 38

Vasoactive intestinal peptide (VIP) is known as a potent regulator for the development of the central nervous system (CNS). The neonatal period of brain development is characterised by rapid cellular proliferation in parallel with neuronal differentiation and angiogenesis. We examined the expression of native VIP and the VIP receptor-associated protein by immunohistochemistry as well as the expression of VIP mRNA by in situ hybridisation in the brain stem of newborn piglets. We found both the mRNA and the protein of VIP as well as the VIP receptor-associated protein in endothelial cells of veins, arteries and capillaries in the marginal zone of brain stem tissue sections, especially in pons and mesencephalon, as well as in pial vessels. The coexpression of native VIP, VIP mRNA and the VIP receptor-associated protein within the endothelium suggests the presence of an autocrine loop, which has been detected so far only in neuroblastoma cells. This expression pattern gives evidence to the immaturity of endothelial cells at birth and the presence of an adaptive response in the VIP-regulated system during the change from intra- to extrauterine life.
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PMID:Autocrine endothelial regulation in brain stem vessels of newborn piglets. 1042 52

Vasoactive intestinal peptide (VIP) gene expression is highly restricted throughout the neuroaxis and regulated by extracellular factors that activate tyrosine- or serine/threonine-directed protein kinase pathways. Cytokine, cyclic AMP, and tissue-specific response elements on the VIP gene have been characterized. Those mediating responsiveness to protein kinase C have not. The endogenous VIP gene and a 5.2-kilobase pair (kb) VIP-luciferase reporter gene, are up-regulated by phorbol 12-myristate 13-acetate (PMA) in SK-N-SH neuroblastoma cells. PMA stimulation was abolished by deletion of sequences at -1.37 to -1.28 or -1.28 to -0.904 kb, but not by removal of the single phorbol ester response element (TRE; TGACTCA) located at -2.25 kb. Mutation of sites at -1.32 or -1.20 that mediate neurotrophin responsiveness of the VIP gene (Symes, A., Lewis, S., Corpus, L., Rajan, P., Hyman, S. E., and Fink, J. S. (1994) Mol. Endocrinol. 8, 1750-1763) each reduced PMA induction in SK-N-SH cells by >50%, and double mutation abolished it. The two mutations also reduced basal VIP reporter gene transcription in SH-EP neuroblastoma cells expressing VIP constitutively. Both cis-active elements bound pre-existing AP-1 proteins in SH-EP- or PMA-stimulated SK-N-SH cell nuclear extracts. The AP-1 complex at both sites contained a Fos-related protein with c-Jun in SH-EP cells and c-Fos with a Jun-related protein in SK-N-SH cells. Recruitment of combinatorially distinct AP-1 complexes to these elements may underlie cell type-specific regulation of the VIP gene.
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PMID:Two separate cis-active elements of the vasoactive intestinal peptide gene mediate constitutive and inducible transcription by binding different sets of AP-1 proteins. 1046 93

Vasoactive intestinal peptide (VIP) provides neuroprotection against beta-amyloid toxicity in models of Alzheimer's disease. A superactive analogue, stearyl-Nle17-VIP (SNV) is a 100-fold more potent than VIP. In primary neuronal cultures, VIP protective activity may be mediated by femtomolar-acting glial proteins such as activity-dependent neurotrophic factor (ADNF), activity-dependent neuroprotective protein (ADNP), peptide derivatives ADNF-9 (9aa) and NAP (8aa), respectively. It has been hypothesized that beta-amyloid induces oxidative stress leading to neuronal cell death. Similarly, dopamine and its oxidation products were suggested to trigger dopaminergic nigral cell death in Parkinson's disease. We now examined the possible protective effects of VIP against toxicity of dopamine, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP+) in neuronal cultures [rat pheochromocytoma (PC12), human neuroblastoma (SH-SY5Y) and rat cerebellar granular cells]. Remarkably low concentrations of VIP (10(-16)-10(-8) M), ADNF-9 and NAP (10(-18)-10(-10) M) protected against dopamine and 6-OHDA toxicity in PC12 and neuroblastoma cells. VIP (10(-11)-10(-9) M) and SNV (10(-13)-10(-11) M), protected cerebellar granule neurons against 6-OHDA. In contrast, VIP did not rescue neurons from death associated with MPP+. Since dopamine toxicity is linked to the red/ ox state of the cellular glutathione, we investigated neuroprotection in cells depleted of reduced glutathione (GSH). Buthionine sulfoximine (BSO), a selective inhibitor of glutathione synthesis, caused a marked reduction in GSH in neuroblastoma cells and their viability decreased by 70-90%. VIP, SNV or NAP (over a wide concentration range) provided significant neuroprotection against BSO toxicity. These results show that the mechanism of neuroprotection by VIP/SNV/NAP may be mediated through raising cellular resistance against oxidative stress. Our data suggest these compounds as potential lead compounds for protective therapies against Parkinson's disease.
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PMID:Vasoactive intestinal peptide (VIP) prevents neurotoxicity in neuronal cultures: relevance to neuroprotection in Parkinson's disease. 1078 33

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has several functions, including the regulation of water and electrolyte secretion, hormone and cytokine release, bronchodilitation, and neurogenesis. VIP effects are mediated by specific G-protein coupled receptors. Three distinct receptor subtypes, with differing affinity for VIP, have been cloned and characterized as receptors 1 and 2 (VPAC1 and VPAC2) and pituitary adenylate cyclase activating polypeptide receptor (PAC1). Our laboratory has demonstrated that upregulation of VPAC1 in SK-N-SH neuroblastoma cells results in marked shift in cell type to the glial lineage with a corresponding loss of neuronal lineage and suppression of xenograft tumor growth. To understand the molecular mechanisms responsible for regulation of the VPAC1 gene in neuronal lineage, we have cloned and sequenced 2.6-kb of the 5'-flanking sequences of the human VPAC1 gene. Sequence analysis demonstrated that the human VPAC1 promoter sequence contains putative binding sites for several known transcription factors, including Sp1, NFkB, and cETS-1. To study the temporal and spatial expression pattern of human VPAC1 promoter sequences, we have generated transgenic mice expressing the bacterial beta-galactosidase gene under the control of the 2.6-kb 5'-flanking and promoter sequence of the human VPAC1 gene. Transgene expression was detected in brain, spinal cord, and lung in 14-day-old animals. Taken together, these results demonstrate that VPAC1 may play an important role in the nervous system, and suggest a role for VIP in neuronal differentiation.
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PMID:Regulation of vasoactive intestinal peptide receptor expression in developing nervous systems. 1119 20

Vasoactive intestinal peptide (VIP) stimulates the neuroblastoma cell line (NMB) to proliferate. Neuropeptide activity can be inhibited by neutral endopeptidases that function intracellularly and in the extracellular milieu. NMB cells express neutral endopeptidase (NEP) activity that can be specifically inhibited by phosphoramidon (PA). Our data now show that phosphoramidon treatment increases the efficacy of VIP-stimulated neuroblastoma proliferation. These results suggest that membrane endopeptidases modulate VIP-associated cell proliferation and enhancement of endopeptidase activity may serve as a target for cancer therapy.
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PMID:The increased proliferation of cultured neuroblastoma cells treated with vasoactive intestinal peptide is enhanced by simultaneous inhibition of neutral endopeptidase. 1222 Jul 42


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