Download Gene Section VIP (vasoactive intestinal peptide) Atlas of Genetics and Cytogenetics

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