Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomain shedding.
Tumor necrosis factor-like cytokine 1A (TL1A) is expressed in endothelial cells and contributes to T-cell activation, via an extracellular fragment TL1A(L72-L251), generated by ectodomain shedding. Fragments of TL1A, referred to as vascular endothelial growth inhibitor, were found to induce growth arrest and apoptosis in endothelial cells; however, the underlying mechanisms remained obscure. Here, we show that full-length TL1A is the major detectable gene product in both human umbilical vein endothelial cells and circulating endothelial progenitor cells. TL1A expression was significantly enhanced in senescent circulating endothelial progenitor cells, and knockdown of TL1A partially reverted senescence. TL1A overexpression induced premature senescence in both circulating endothelial progenitor cells and human umbilical vein endothelial cells. We also identified a novel extracellular fragment of TL1A, TL1A(V84-L251), resulting from differential ectodomain shedding, which induced growth arrest and apoptosis in human umbilical vein endothelial cells. These findings suggest that TL1A is involved in the regulation of endothelial cell senescence, via a novel fragment produced by differential ectodomain shedding.
Mück
Christoph
C
Department of Molecular and Cell Biology, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Herndler-Brandstetter
Dietmar
D
Micutkova
Lucia
L
Grubeck-Loebenstein
Beatrix
B
Jansen-Dürr
Pidder
P
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology; D018274:Electroporation / Q000379:methods; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020033:Protein Isoforms / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D004151:Dipeptides; D006877:Hydroxamic Acids; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D020033:Protein Isoforms; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D001616:beta-Galactosidase