Role of endonuclease G in senescence-associated cell death of human endothelial cells.
Mitotic cells in culture show a limited replicative potential and after extended subculturing undergo a terminal growth arrest termed cellular senescence. When cells reach the senescent phenotype, this is accompanied by a significant change in the cellular phenotype and massive changes in gene expression, including the upregulation of secreted factors. In human fibroblasts, senescent cells also acquire resistance to apoptosis. In contrary, in human endothelial cells, both replicative and stress-induced premature senescence is accompanied by increased cell death; however mechanisms of cell death are poorly explored. In this communication, we addressed the role of endonuclease G (EndoG), a mitochondrial mediator of caspase-independent cell death, in senescence-associated cell death of human endothelial cells. Using immunofluorescence microscopy, we found, that EndoG is localized in the mitochondria in young cells, but relocalizes to the nucleus upon senescence. When EndoG gene expression was downregulated by lentiviral shRNA vectors, we found a significant reduction in the replicative life span and a corresponding increase in cell death. We also observed a slight shift in the cell death phenotype from necrosis to apoptosis. Together these observations suggest an important role of EndoG in the senescence program of human endothelial cells.
Diener
Thomas
T
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, Innsbruck, Austria.
Neuhaus
Michael
M
Koziel
Rafal
R
Micutkova
Lucia
L
Jansen-Dürr
Pidder
P
D021581:Active Transport, Cell Nucleus; D000375:Aging / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics* / Q000502:physiology*; D004706:Endodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D009336:Necrosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics
D034741:RNA, Small Interfering; D004706:Endodeoxyribonucleases; C052391:endonuclease G