| First Author | Schulze-Osthoff K | Year | 1994 |
| Journal | EMBO J | Volume | 13 |
| Issue | 19 | Pages | 4587-96 |
| PubMed ID | 7523113 | Mgi Jnum | J:20834 |
| Mgi Id | MGI:68904 | Doi | 10.1002/j.1460-2075.1994.tb06780.x |
| Citation | Schulze-Osthoff K, et al. (1994) Divergent signalling via APO-1/Fas and the TNF receptor, two homologous molecules involved in physiological cell death. EMBO J 13(19):4587-96 |
| abstractText | Tumor necrosis factor receptor (TNF-R) and APO-1/Fas (CD95) are members of the tumor necrosis factor/nerve growth factor receptor superfamily involved in various forms of physiological cell death. Due to the structural homology between these receptors and their ligands, it has been suggested that APO-1/Fas and TNF-R kill cells by similar mechanisms. Here, we compared the killing pathways mediated by each receptor molecule in TNF-sensitive L929 cells stably transfected with APO-1/Fas cDNA. Morphological analysis revealed that TNF-induced cell death resembles necrosis, while APO-1/Fas-mediated cell killing shows an apoptotic pattern, evident by the appearance of membrane blebbing, nuclear condensation and non-random DNA degradation. Studies with inhibitors of several intracellular pathways further demonstrate that the mechanisms of TNF- and APO-1/Fas-mediated cell killing are substantially different. TNF cytotoxicity is mediated by reactive oxygen intermediates generated during mitochondrial respiration. However, these mediators are not involved in APO-1/Fas-mediated cell death as neither mitochondrial inhibitors nor antioxidants exert a protecting effect. Moreover, several inhibitors of calcium metabolism, ADP ribosylation and phospholipase action suppress TNF cytotoxicity, but not APO-1/Fas-mediated apoptosis. Additional differences between the two molecules were observed at the transcriptional level. Whereas transcription factor NF-kappa B was readily activated by TNF, activation was not induced by triggering APO-1/Fas. These data suggest that the two molecules, though structurally related, utilize distinct signal transduction pathways, even in a single cell type. Hence, cells may undergo different programs of cell death depending on the activating stimulus. |
