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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review VIP (vasoactive intestinal peptide) Terry Moody National Cancer Institute, Center for Cancer Research, Office of the Director, 31 Center Drive, Bldg 31, Rm 4A48, Bethesda, Maryland 20892, USA (TM) Published in Atlas Database: August 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/VIPID44215ch6q25.html DOI: 10.4267/2042/53532 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract 2010). Review on VIP, with data on DNA/RNA, on the protein encoded and where the gene is implicated. Description Identity Transcription Other names: PHM27 HGNC (Hugo): VIP Location: 6q25.2 Local order: The VIP gene has 7 exons. Note: VIP is a secreted protein which binds to membrane G-protein coupled receptors (GPCR) increasing intracellular cAMP signaling. The gene transcript has 1601 bp. The VIP gene spans 8837 bp. Protein Description Said and Mutt (1970) sequenced an acid extractable peptide from the porcine duodenum which decreased systemic arterial pressure and increased heart rate, stroke volume, mesenteric and femoral blood flow in the dog. The 27 amino acid peptide was named vasoactive intestinal peptide (VIP). VIP is metabolized (Bodner et al., 1985) from a 170 amino acid precursor protein (preproVIP). DNA/RNA Note The human VIP gene encodes 7 exons and is localized to chromosome 6q25.2 (Fahrenkrug, Structure of human preproVIP. VIP is derived from the 170 amino acid precursor protein preproVIP. Initially the signal peptide (1-20) is cleaved by signal proteases to generate proVIP. ProVIP (22-170) is metabolized to (22-79), PHM (81-107), (111-122), VIP (125-152) and (156-170) by prohormone convertases. Carboxypeptidase B-like enzymes cleave basic R and K. The Cterminal of PHM and VIP is amidated when G is metabolized by peptidylglycine alpha-amidating monooxygenase (PAM) enzymes. Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4) 239 VIP (vasoactive intestinal peptide) Moody T Each exon encodes a distinct domain of the preproVIP 5' untranslated regions of the mRNA (exon I); signal peptide of preproVIP (exon II); Nterminal peptide (exon III); peptide histidine methionine (PHM) (exon IV); VIP (exon V); Cterminal of preproVIP (exon VI); untranslated region of the mRNA (exon VII). VIP and PHM, which have 48% amino acid homology, are in adjacent exons and the introns surrounding these exons are highly conserved. The substrate prepro-VIP is initially metabolized by a signal protease to form the product 149 amino acid pro-VIP. Pro-VIP is metabolized by prohormone convertases to VIP-GKR (preproVIP(125-155)) and PHM-GKR (preproVIP(81-110)). The basic amino acids are cleaved by carboxypeptidase B and the G is metabolized to an amide by PAM enzymes. Thus the N-terminal of VIP and PHM is free whereas the C-terminal is amidated. VIP is structurally related to pituitary adenylate cyclase activating polypeptide (PACAP) (Arimura, 1992). VIP has a β-turn at residues 2-5 and 7-10 followed by an α-helix at residues 11-26 (Vaudry et al., 2009). VIP binds with high affinity to 2 GPCR (VPAC1 and VPAC2) which are members of the class II or class B secretin-like receptors but not PAC1 which binds PACAP with high affinity (Harmar et al., 2012). The activated VPAC1 or VPAC2 interacts with a stimulatory guanine nucleotide binding protein (Gs) causing increased adenylylcyclase activity resulting in elevated cAMP. The increased cAMP activates protein kinase (PK) A causing phosphorylation of various proteins such as CREB leading to altered gene expression. PKC and cAMP dependent manner (Davidson et al., 1996). VIP is present in neuroblastoma and pheochromocytoma (Beinfeld et al., 1988). The results indicate that VIP is present in normal neurons and cancer cells. Localisation PreproVIP is stored in dense core neurosecretory granules in cells. PHM, proVIP and VIP are secreted when cAMP is elevated. While VIP has potent biological activity, PHM and proVIP are also active (Fahrenkrug, 1991). In NSCLC cells, the ratio of PHM/ proVIP/VIP is 1/3/1 respectively (Moody et al., 2003). VIP is metabolized by neutral endopeptidase and has a half life of 2 min (Henning and Sawmiller, 2001). Function VIP is a cotransmitter with nitric oxide and carbon monoxide of nonadrenergic, noncholinergic vascular and nonvascular smooth muscle (Said and Rattan, 2004). It is a cotransmitter with acetylcholine in exocrine glands (Fahrenkrug, 1993). VIP promotes neuronal survival (Brenneman and Eiden, 1986). VIP causes prolactin secretion from the pituitary (Reichlin, 1988) and catecholamine release from the adrenal medulla (Malhotra et al., 1988). In the immune system VIP regulates T cell traffic and proliferation (Ottaway, 1987). Homology VIP has 67% sequence homology with PACAP-27. The sequence for VIP is identical in the human, bovine, porcine and rat. Mutations Expression Note The VIP gene is altered in patients with idiopathic pulmonary arterial hypertension (IPAH) (Haberl et al., 2007). The 3' untranslated region in exon 7 is mutated (g.8129T>C) leading to reduced VIP serum levels and higher pulmonary artery pressure (Zhang et al., 2009). VIP is produced in neurons within the adrenals, brain, gastrointestinal (GI) tract, heart, pituitary and pancreas (Sundler et al., 1988). VIP addition to the adrenals causes catecholamine release (Card et al., 1988). VIP expression in the suprachiasmatic nucleus of the brain is altered by light-dark cycles (Gozes et al., 1989) suggesting that it may play a role in circadian cycles. VIP reduction in knockout mice is associated with human motility disorders (Moody et al., 2011). In the heart, VIP-containing nerve fibers are abundant in arteries but not veins and venules (Sundler et al., 1988). VIP secretion from pancreatic neurons alters enzyme and electrolyte secretion (Konturek et al., 1976). In the pituitary, VIP gene expression is regulated by estrogen leading to altered prolactin secretion (Montagne et al., 1995). VIP is present in and secreted from immune cells especially Th2 cells altering cytokine and chemokine production (Gonzalez-Rey et al., 2007). The VIP gene is in NSCLC cells and its expression is regulated in a Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4) Implicated in Pancreatic cancer Note VIPomas were described by Verner and Morrison (1958). Most of the VIPomas occur in the pancreas leading to diarrheal fluid similar to that seen in patient with cholera, hence the term pancreatic cholera of watery diarrhea, hypokalemic and achlorhydric (WDHA) has been used. The plasma VIP levels are significantly elevated in patients with VIPomas (Long et al., 1981). 240 VIP (vasoactive intestinal peptide) Moody T Lung cancer References Note The VIP gene is expressed in numerous lung cancer cell lines (Davidson et al., 1996). Pro-VIP and VIP are present in lung cancer cell lines (Moody et al., 2003). VIP (10 nM) increases lung cancer colony formation which is inhibited by the VPAC1 antagonist VIPhybrid (Moody et al., 1993). High densities of VPAC1 are present in lung cancer cells (Moody and Gozes, 2007). VERNER JV, MORRISON AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958 Sep;25(3):374-80 Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970 Sep 18;169(3951):1217-8 Konturek SJ, Pucher A, Radecki T. Comparison of vasoactive intestinal peptide and secretin in stimulation of pancreatic secretion. J Physiol. 1976 Feb;255(2):497-509 Long RG, Bryant MG, Mitchell SJ, Adrian TE, Polak JM, Bloom SR. Clinicopathological study of pancreatic and ganglioneuroblastoma tumours secreting vasoactive intestinal polypeptide (vipomas). Br Med J (Clin Res Ed). 1981 May 30;282(6278):1767-71 Breast cancer Note VIP addition to breast cancer cells causes transactivation of the EGF receptor and HER2 (Valdehita et al., 2009). Addition of VIPcamptothecin conjugates causes apoptosis of breast cancer cells (Moody et al., 2007). Bodner M, Fridkin M, Gozes I. Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3548-51 Renal cell carcinoma Brenneman DE, Eiden LE. Vasoactive intestinal peptide and electrical activity influence neuronal survival. Proc Natl Acad Sci U S A. 1986 Feb;83(4):1159-62 Note Addition of 100 nM VIP to renal cancer cells decreases proliferation (Vacas et al., 2012). High concentrations of VIP may cause differentiation of cancer cells (Hoosein et al., 1989). Ottaway CA. Selective effects of vasoactive intestinal peptide on the mitogenic response of murine T cells. Immunology. 1987 Oct;62(2):291-7 Beinfeld MC, Brick PL, Howlett AC, Holt IL, Pruss RM, Moskal JR, Eiden LE. The regulation of vasoactive intestinal peptide synthesis in neuroblastoma and chromaffin cells. Ann N Y Acad Sci. 1988;527:68-76 Prostate cancer Note High densities of VPAC1 were detected in prostate cancer cell lines (Reubi et al., 2000). Card JP, Fitzpatrick-McElligott S, Gozes I, Baldino F Jr. Localization of vasopressin-, vasoactive intestinal polypeptide-, peptide histidine isoleucineand somatostatin-mRNA in rat suprachiasmatic nucleus. Cell Tissue Res. 1988 May;252(2):307-15 Colon cancer Note 123 I-VIP can be used to visualize colon cancer tumors in patients (Raderer et al., 1998). Malhotra RK, Wakade TD, Wakade AR. Vasoactive intestinal polypeptide and muscarine mobilize intracellular Ca2+ through breakdown of phosphoinositides to induce catecholamine secretion. Role of IP3 in exocytosis. J Biol Chem. 1988 Feb 15;263(5):2123-6 Diabetes Note Overexpression of the VIP gene in mouse pancreatic beta cells resulted in reduced blood glucose and insensitivity to glucose intolerance (Passemard et al., 2011). Reichlin S. Neuroendocrine significance of vasoactive intestinal polypeptide. Ann N Y Acad Sci. 1988;527:431-49 Sundler F, Ekblad E, Grunditz T, Håkanson R, Uddman R. Vasoactive intestinal peptide in the peripheral nervous system. Ann N Y Acad Sci. 1988;527:143-67 Bronchial asthma Gozes I, Avidor R, Biegon A, Baldino F Jr. Lactation elevates vasoactive intestinal peptide messenger ribonucleic acid in rat suprachiasmatic nucleus. Endocrinology. 1989 Jan;124(1):181-6 Note VIP nerves are absent in severely asthmatic subjects. Mice with targeted deletion of the VIP gene exhibit histopathologic features of airway inflammation (Said et al., 2010). Hoosein NM, Black BE, Brattain DE, Brattain MG. Promotion of differentiation in human colon carcinoma cells by vasoactive intestinal polypeptide. Regul Pept. 1989 Jan;24(1):15-26 Cardiomyopathy Note Hearts were dilated in VIP knockout mice with thinning of the left ventricular wall and increases in right ventricular and left ventricular chamber size resulting from overexpression of cardiomyophathy genes (Szema et al., 2013). VIP is a potent vasodilator and increases the heart rate (Henning and Sawmiller, 2001). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4) Fahrenkrug J. Glycine-extended processing intermediate of proVIP: a new form of VIP in the rat. Biochem Biophys Res Commun. 1991 Jul 15;178(1):173-7 Arimura A. Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research. Regul Pept. 1992 Feb 18;37(3):287-303 Fahrenkrug J. Transmitter role of vasoactive intestinal peptide. Pharmacol Toxicol. 1993 Jun;72(6):354-63 241 VIP (vasoactive intestinal peptide) Moody T Moody TW, Zia F, Draoui M, Brenneman DE, Fridkin M, Davidson A, Gozes I. A vasoactive intestinal peptide antagonist inhibits non-small cell lung cancer growth. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4345-9 Valdehita A, Bajo AM, Schally AV, Varga JL, Carmena MJ, Prieto JC. Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells. Mol Cell Endocrinol. 2009 Apr 10;302(1):41-8 Montagne MN, Dussaillant M, Chew LJ, Berod A, Lamberts SJ, Carter DA, Rostene W. Estradiol induces vasoactive intestinal peptide and prolactin gene expression in the rat anterior pituitary independently of plasma prolactin levels. J Neuroendocrinol. 1995 Mar;7(3):225-31 Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BK, Hashimoto H, Galas L, Vaudry H. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 2009 Sep;61(3):283-357 Davidson A, Moody TW, Gozes I. Regulation of VIP gene expression in general. Human lung cancer cells in particular. J Mol Neurosci. 1996 Summer;7(2):99-110 Zhang Y, Zhang JQ, Liu ZH, Xiong CM, Ni XH, Hui RT, He JG, Pu JL. VIP gene variants related to idiopathic pulmonary arterial hypertension in Chinese population. Clin Genet. 2009 Jun;75(6):544-9 Raderer M, Kurtaran A, Hejna M, Vorbeck F, Angelberger P, Scheithauer W, Virgolini I. 123I-labelled vasoactive intestinal peptide receptor scintigraphy in patients with colorectal cancer. Br J Cancer. 1998 Jul;78(1):1-5 Fahrenkrug J. VIP and PACAP. Results Probl Cell Differ. 2010;50:221-34 Said SI, Hamidi SA, Gonzalez Bosc L. Asthma and pulmonary arterial hypertension: do they share a key mechanism of pathogenesis? Eur Respir J. 2010 Apr;35(4):730-4 Reubi JC, Läderach U, Waser B, Gebbers JO, Robberecht P, Laissue JA. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 2000 Jun 1;60(11):3105-12 Moody TW, Ito T, Osefo N, Jensen RT. VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies. Curr Opin Endocrinol Diabetes Obes. 2011 Feb;18(1):61-7 Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001 Jan;49(1):27-37 Passemard S, Sokolowska P, Schwendimann L, Gressens P. VIP-induced neuroprotection of the developing brain. Curr Pharm Des. 2011;17(10):1036-9 Moody TW, Chan D, Fahrenkrug J, Jensen RT. Neuropeptides as autocrine growth factors in cancer cells. Curr Pharm Des. 2003;9(6):495-509 Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol. 2012 May;166(1):4-17 Said SI, Rattan S. The multiple mediators of neurogenic smooth muscle relaxation. Trends Endocrinol Metab. 2004 Jul;15(5):189-91 Moody TW, Mantey SA, Fuselier JA, Coy DH, Jensen RT. Vasoactive intestinal peptide-camptothecin conjugates inhibit the proliferation of breast cancer cells. Peptides. 2007 Sep;28(9):1883-90 Vacas E, Fernández-Martínez AB, Bajo AM, SánchezChapado M, Schally AV, Prieto JC, Carmena MJ. Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation. Biochim Biophys Acta. 2012 Oct;1823(10):1676-85 Gonzalez-Rey E, Varela N, Chorny A, Delgado M. Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. Curr Pharm Des. 2007;13(11):1113-39 Szema AM, Hamidi SA, Smith SD, Benveniste H. VIP gene deletion in mice causes cardiomyopathy associated with upregulation of heart failure genes. PLoS One. 2013;8(5):e61449 Haberl I, Frei K, Ramsebner R, Doberer D, Petkov V, Albinni S, Lang I, Lucas T, Mosgoeller W. Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension. Eur J Hum Genet. 2007 Jan;15(1):18-22 This article should be referenced as such: Moody T. VIP (vasoactive intestinal peptide). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4):239-242. Moody TW, Gozes I. Vasoactive intestinal peptide receptors: a molecular target in breast and lung cancer. Curr Pharm Des. 2007;13(11):1099-104 Atlas Genet Cytogenet Oncol Haematol. 2014; 18(4) 242