Download Gene Section TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15)

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Gene Section
Review
TNFSF15 (tumor necrosis factor (ligand)
superfamily, member 15)
Gui-Li Yang, Jian-Wei Qi, Zhi-Song Zhang, Lu-Yuan Li
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA (LYL);
College of Pharmacy and College of Life Sciences, Nankai University, 94 Wei Jin Road, 300071 Tianjin,
China (LYL, GLY, JWQ, ZSZ)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TNFSF15ID42638ch9q32.html
DOI: 10.4267/2042/44800
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
DNA/RNA
Other names: MGC129934; MGC129935; TL1;
TL1A; VEGI; VEGI192A
HGNC (Hugo): TNFSF15
Location: 9q32
Local order: TNFSF15 gene at 9q32, near the CD30L
gene at 9q33.
Description
The human VEGI gene spans about 17 kb and consists
of four exons.
Transcription
The size of VEGI mRNA is approximately 6.5 kb.
Boxes with roman numerals above represent exons and horizontal lines represent intronic sequence. The putative transcription start site
is indicated by a double arrowhead. R denotes the 5' untranslated sequence unique to each respective transcript, and stippled boxe
represents the common 3' untranslated region.
Figure A. All three isoforms.
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TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15)
Yang GL, et al.
Figure B. A ribbon diagram of the TL1A trimer. (Jin et al. BBRC 364:1, 2007).
It is unusual for a human gene of 6.5 kb to contain only
a small open reading frame of 522 nucleotides.
Multiple VEGI transcripts generated by the use of
cryptic splice sites and alternate exons.
Expression
VEGI is specifically expressed in endothelial cells.
Analysis of total RNA preparations from many cell
lines and primary cell cultures by Northern blot
analysis confirmed the specificity of VEGI expression,
with only HUVEC and human venous endothelial cells
demonstrating detectable levels of expression. Using
multiple tissue Northern blots, the VEGI transcript was
found in many adult human tissues, including placenta,
lung, skeletal muscle, kidney, pancreas, spleen,
prostate, small intestine, and colon, suggesting that the
gene product may play a role in the function of a
normal vasculature.The failure to detect the transcripts
of this new gene in some of the human tissues probably
is due to relatively small proportion of endothelial cells
in these tissues. Using isoform-specific probes, we
have determined that the distribution profiles of VEGI
isoforms in human organs and tissues appear to be
different. The 7.5 kb transcript encoding VEGI-251
was expressed at high levels in the placenta, kidney,
lung and liver, whereas the 2 kb transcript
corresponding to VEGI-174 was observed in liver,
kidney, skeletal muscle and heart. VEGI-174 mRNA
was more abundant in heart, skeletal muscle, pancreas,
adrenal gland, and liver, while VEGI-251 was more
abundant in fetal kidney and fetal lung. Overlapping
expression of VEGI-251 and VEGI-174 mRNA was
detected in prostate, salivary gland and placenta,
whereas VEGI-192 mRNA was not readily detected by
Northern blot. These expression patterns suggest the
possibility of tissue or developmentally specific
functions for VEGI isoforms.
Pseudogene
Not known.
Protein
Description
Hydrophobicity analysis of VEGI predicts a 13 amino
acid hydrophobic region that follows the amino
terminal segment of 12 amino acids, suggesting a
structure characteristic of a type II transmembrane
protein, with residues 26-174 constituting an
extracellular domain analogous to domains found in
other TNF family members.
VEGI isoforms exhibit a carboxyl terminal domain of
151 amino acid residues, which is encoded by part of
the fourth exon, termed IVb. The initially characterized
VEGI isoform, designated VEGI-174, is encoded by
the fourth exon (parts IVa and IVb) alone, which
includes both the putative transmembrane domain and
the conserved extracellular domain. There are two
additional endothelial-specific transcripts of 7.5 and 2.0
kb, which encode peptides of 251 (VEGI-251) and 192
(VEGI-192) residues, respectively. The VEGI-251 and
-192 isoforms differ in their amino terminal regions,
but share the conserved 151-amino acid residue
carboxy terminal domain. VEGI-251 possesses a
putative secretory signal peptide and its overexpression
causes apoptosis of endothelial cells and inhibition of
tumor growth.
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Amino acid sequence alignment of three VEGI isoforms. The putative hydrophobic regions of VEGI-251 and VEGI-174 are underlined.
Asterisk denotes the start of shared sequences for all three isoforms.
Alternatively, this expression pattern also supports the
view that one VEGI isoform is the functional cytokine,
while the others act in regulatory roles to modulate the
activity of the active isoform. In this case, it is possible
that the non-functional isoforms do not exist at the
protein level. VEGI isoform expression has also been
examined in cultured cells by RNase protection assay.
All three known VEGI isoforms were detected in
human endothelial cells, including coronary artery
endothelial (HCAE), HUVE cells, and human
microvascular endothelial (HMVE) cells. Very low
levels are sometimes detected in adult bovine aortic
endothelial (ABAE) cells. Little VEGI expression was
detectable in human coronary artery smooth muscle
(CASM) and mouse endothelioma bEND.3 cells. More
than one isoform is detectable simultaneously, with
VEGI-251 being the most abundant. The expression of
this protein is inducible by TNF and IL-1 alpha, but not
by gamma-interferon.
VEGI by cancer cells or systemic administration of
recombinant VEGI to tumor-bearing mice inhibits
tumor growth in numerous tumor models. Recent
studies show that VEGI helps modulate the immune
system by activating T cells and stimulating dendritic
cell maturation, suggesting that VEGI is directly
involved in modulating the interaction between the
endothelium and the immune system. Recombinant
VEGI has an inhibitory activity on mouse bone
marrow-derived EPCs in culture, preventing their
differentiation toward endothelial cells.
Interaction of TL1A with DR3 promotes T cell
expansion during an immune response (Migone et al.,
2002).
Homology
VEGI exhibits 20-30% sequence homology to human
TNF-alpha, TNF-beta, and the Fas ligand, similar to
that among other TNF family members.
Localisation
Implicated in
Endothelial cells and monocytes. However, VEGI was
not expressed in either B or T cells.
Colon carcinoma
Note
Local production of a secreted form of VEGI via gene
transfer caused complete suppression of the growth of
MC-38 murine colon cancers in syngeneic
C57BL/6mice. Histological examination showed
marked reduction of vascularization in MC-38 tumors
that expressed soluble but not membrane-bound VEGI
or were transfected with control vector. The
conditioned media from soluble VEGI-expressing cells
showed marked inhibitory effect on in vitro
proliferation of adult bovine aortic endothelial cells.
Function
VEGI is an endogenous inhibitor of angiogenesis
produced largely by vascular endothelial cells and
exerts a specific inhibitory activity on the proliferation
of endothelial cells. VEGI enforces growth arrest of
endothelial cells in G0 and early G1 phases of the cell
cycle but induces apoptosis in proliferating endothelial
cells. The MAPKs p38 and jun N-terminal kinase
(JNK) are required for VEGI-mediated endothelial
inhibition. Engineered overexpression of secreted
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
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TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15)
Breast cancer
References
Note
The anticancer potential of VEGI was examined in a
breast cancer xenograft tumor model in which the
cancer cells were co-injected with Chinese hamster
ovary cells overexpressing a secreted form of the
protein. The co-injection resulted in potent inhibition of
xenograft tumor growth. Our findings are consistent
with the view that VEGI is an endothelial cell-specific
negative regulator of angiogenesis.
Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J,
Moore G, Truneh A. Characterization of a novel TNF-like
ligand and recently described TNF ligand and TNF receptor
superfamily genes and their constitutive and inducible
expression in hematopoietic and non-hematopoietic cells.
Gene. 1997 Dec 19;204(1-2):35-46
Yue TL, Ni J, Romanic AM, Gu JL, Keller P, Wang C, Kumar S,
Yu GL, Hart TK, Wang X, Xia Z, DeWolf WE Jr, Feuerstein GZ.
TL1, a novel tumor necrosis factor-like cytokine, induces
apoptosis in endothelial cells. Involvement of activation of
stress protein kinases (stress-activated protein kinase and p38
mitogen-activated protein kinase) and caspase-3-like protease.
J Biol Chem. 1999 Jan 15;274(3):1479-86
Mucosal vaccine adjuvant
Note
Kayamuro et al., (2009) reported that TL1A induced
the strongest immune response and augmented OVAspecific IgG and IgA responses in serum and mucosal
compartments, respectively. The OVA-specific
immune response of TL1A was characterized by high
levels of serum IgG1 and increased production of IL-4
and IL-5 from splenocytes of immunized mice,
suggesting that TL1A might induce Th2-type
responses. These findings indicate that TL1A has the
most potential as a mucosal adjuvant among the TNFS
cytokines.
Zhai Y, Ni J, Jiang GW, Lu J, Xing L, Lincoln C, Carter KC,
Janat F, Kozak D, Xu S, Rojas L, Aggarwal BB, Ruben S, Li
LY, Gentz R, Yu GL. VEGI, a novel cytokine of the tumor
necrosis factor family, is an angiogenesis inhibitor that
suppresses the growth of colon carcinomas in vivo. FASEB J.
1999 Jan;13(1):181-9
Zhai Y, Yu J, Iruela-Arispe L, Huang WQ, Wang Z, Hayes AJ,
Lu J, Jiang G, Rojas L, Lippman ME, Ni J, Yu GL, Li LY.
Inhibition of angiogenesis and breast cancer xenograft tumor
growth by VEGI, a novel cytokine of the TNF superfamily. Int J
Cancer. 1999 Jul 2;82(1):131-6
Yu J, Tian S, Metheny-Barlow L, Chew LJ, Hayes AJ, Pan H,
Yu GL, Li LY. Modulation of endothelial cell growth arrest and
apoptosis by vascular endothelial growth inhibitor. Circ Res.
2001 Dec 7;89(12):1161-7
Inflammatory bowel disease
Note
Bamias et al., (2003) provided evidence that the novel
cytokine TL1A may play an important role in a Th1mediated disease such as Crohn's disease. Takedatsu et
al., (2008) revealed that TL1A is an important
modulator in the development of chronic mucosal
inflammation by enhancing T(H)1 and T(H)17 effector
functions. The central role of TL1A represents an
attractive, novel therapeutic target for the treatment of
Crohn's disease patients.
Chew LJ, Pan H, Yu J, Tian S, Huang WQ, Zhang JY, Pang S,
Li LY. A novel secreted splice variant of vascular endothelial
cell growth inhibitor. FASEB J. 2002 May;16(7):742-4
Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong
JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S,
Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu
D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei
P. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and
functions as a T cell costimulator. Immunity. 2002
Mar;16(3):479-92
Bamias G, Martin C 3rd, Marini M, Hoang S, Mishina M, Ross
WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT,
Wei P, Cominelli F. Expression, localization, and functional
activity of TL1A, a novel Th1-polarizing cytokine in
inflammatory bowel disease. J Immunol. 2003 Nov
1;171(9):4868-74
Inflammatory arthritis
Note
Bull et al., (2008) demonstrated that the DR3-TL1A
pathway regulates joint destruction in two murine
models of arthritis and represents a potential novel
target for therapeutic intervention in inflammatory joint
disease. Bamias et al., (2008) concluded that TL1A
may serve as an inflammatory marker in rheumatoid
arthritis. Interactions between TL1A and its receptors
may be important in the pathogenesis of rheumatoid
arthritis.
Zilberberg L, Shinkaruk S, Lequin O, Rousseau B, Hagedorn
M, Costa F, Caronzolo D, Balke M, Canron X, Convert O, Laïn
G, Gionnet K, Goncalvès M, Bayle M, Bello L, Chassaing G,
Deleris G, Bikfalvi A. Structure and inhibitory effects on
angiogenesis and tumor development of a new vascular
endothelial growth inhibitor. J Biol Chem. 2003 Sep
12;278(37):35564-73
Asahara T, Kawamoto A. Endothelial progenitor cells for
postnatal vasculogenesis. Am J Physiol Cell Physiol. 2004
Sep;287(3):C572-9
Renal inflammation and injury
Note
Al-Lamki et al., (2008) suggested that TL1A may
contribute to renal inflammation and injury through
DR3-mediated activation of NF-kappaB and caspase-3,
respectively, but that an unidentified receptor may
mediate the NF-kappaB-independent induction of
TNFR2 in tubular epithelial cells.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
Yang GL, et al.
Hou W, Medynski D, Wu S, Lin X, Li LY. VEGI-192, a new
isoform of TNFSF15, specifically eliminates tumor vascular
endothelial cells and suppresses tumor growth. Clin Cancer
Res. 2005 Aug 1;11(15):5595-602
Bamias G, Mishina M, Nyce M, Ross WG, Kollias G, RiveraNieves J, Pizarro TT, Cominelli F. Role of TL1A and its
receptor DR3 in two models of chronic murine ileitis. Proc Natl
Acad Sci U S A. 2006 May 30;103(22):8441-6
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TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15)
Yang GL, et al.
Metheny-Barlow LJ, Li LY. Vascular endothelial growth
inhibitor (VEGI), an endogenous negative regulator of
angiogenesis. Semin Ophthalmol. 2006 Jan-Mar;21(1):49-58
Cai J, Wei R, Cheng J. Preparation and characterization of a
novel chimeric protein VEGI-CTT in Escherichia coli. J Biomed
Biotechnol. 2008;2008:564969
Jin T, Kim S, Guo F, Howard A, Zhang YZ. Purification and
crystallization of recombinant human TNF-like ligand TL1A.
Cytokine. 2007 Nov;40(2):115-22
Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal
V. Endothelial progenitor cells control the angiogenic switch in
mouse lung metastasis. Science. 2008 Jan 11;319(5860):1958
Tian F, Grimaldo S, Fujita M, Cutts J, Vujanovic NL, Li LY. The
endothelial cell-produced antiangiogenic cytokine vascular
endothelial growth inhibitor induces dendritic cell maturation. J
Immunol. 2007 Sep 15;179(6):3742-51
Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS,
Dhall D, Braun J, Targan SR. TL1A (TNFSF15) regulates the
development of chronic colitis by modulating both T-helper 1
and T-helper 17 activation. Gastroenterology. 2008
Aug;135(2):552-67
Al-Lamki RS, Wang J, Tolkovsky AM, Bradley JA, Griffin JL,
Thiru S, Wang EC, Bolton E, Min W, Moore P, Pober JS,
Bradley JR. TL1A both promotes and protects from renal
inflammation and injury. J Am Soc Nephrol. 2008
May;19(5):953-60
Kayamuro H, Yoshioka Y, Abe Y, Katayama K, Yoshida T,
Yamashita K, Yoshikawa T, Hiroi T, Itoh N, Kawai Y, Mayumi
T, Kamada H, Tsunoda S, Tsutsumi Y. TNF superfamily
member, TL1A, is a potential mucosal vaccine adjuvant.
Biochem Biophys Res Commun. 2009 Jul 3;384(3):296-300
Bamias G, Siakavellas SI, Stamatelopoulos KS, Chryssochoou
E, Papamichael C, Sfikakis PP. Circulating levels of TNF-like
cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in
rheumatoid arthritis. Clin Immunol. 2008 Nov;129(2):249-55
Tian F, Liang PH, Li LY. Inhibition of endothelial progenitor cell
differentiation by VEGI. Blood. 2009 May 21;113(21):5352-60
Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP,
Elford C, Evans BA, Rowley TF, Slebioda TJ, Taraban VY, AlShamkhani A, Wang EC. The Death Receptor 3-TNF-like
protein 1A pathway drives adverse bone pathology in
inflammatory arthritis. J Exp Med. 2008 Oct 27;205(11):245764
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
This article should be referenced as such:
Yang GL, Qi JW, Zhang ZS, Li LY. TNFSF15 (tumor necrosis
factor (ligand) superfamily, member 15). Atlas Genet
Cytogenet Oncol Haematol. 2010; 14(7):665-669.
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