A novel secreted splice variant of vascular endothelial cell growth inhibitor.
Vascular endothelial cell growth inhibitor (VEGI), a member of the tumor necrosis factor (TNF) family, is an endothelial cell-specific inhibitor of angiogenesis. Overexpression by cancer cells of a secretable VEGI fusion protein resulted in abrogation of xenograft tumor progression, but overexpression of full-length VEGI was completely without effect. This finding indicates that secretion is essential for VEGI action. Here we report the identification of two new VEGI isoforms consisting of 251 and 192 amino acid residues. Both isoforms show endothelial cell-specific expression and share a C-terminal 151-residue segment with the previously described VEGI, which comprises 174 residues. The isoforms are generated from a 17 kb human gene by alternative splicing. Their expression is regulated in parallel by inflammatory cytokines TNF-alpha and interferon-gamma. VEGI-251, the most abundant isoform, contains a putative secretion signal. VEGI protein is detected in conditioned media of endothelial cells and VEGI-251-transfected mammalian cells. Overexpression of VEGI-251 in endothelial cells causes dose-dependent cell death. VEGI-251-transfected cancer cells form xenograft tumors of reduced growth rate and microvessel density compared with tumors of empty vector transfectants. These findings support the view that endothelial cell-secreted VEGI may function as an autocrine inhibitor of angiogenesis and a naturally existing modulator of vascular homeostasis.
Chew
Li-Jin
LJ
Department of Oncology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Pan
Hongguang
H
Yu
Jingyi
J
Tian
Song
S
Huang
Wei-Qun
WQ
Zhang
John Y
JY
Pang
Shen
S
Li
Lu-Yuan
LY
D017398:Alternative Splicing; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D002455:Cell Division; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016207:Cytokines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016207:Cytokines; D020033:Protein Isoforms; D012333:RNA, Messenger; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha