TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15)

	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.
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. 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.
Pseudogene	Not known.

	Figure A. All three isoforms. Figure B. A ribbon diagram of the TL1A trimer. (Jin et al. BBRC 364:1, 2007).
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.
	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.
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. 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.
Localisation	Endothelial cells and monocytes. However, VEGI was not expressed in either B or T 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 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.

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