Evidence for a Novel, Caspase-8-Independent, Fas Death Domain-Mediated Apoptotic Pathway

[摘要] Certain caspase-8 null cell lines demonstrate resistance toFas-induced apoptosis, indicating that the Fas/FasL apoptoticpathway may be caspase-8-dependent. Some reports, however, haveshown that Fas induces cell death independent of caspase-8. Herewe provide evidence for an alternative, caspase-8-independent,Fas death domain-mediated apoptotic pathway. Murine 12B1-D1 cellsexpress procaspase-3, -8, and -9, which were activated upon thedimerization of Fas death domain. Bid was cleaved andmitochondrial transmembrane potential was disrupted in thisapoptotic process. All apoptotic events were completely blockedby the broad-spectrum caspase inhibitor Z-VAD-FMK, but not byother peptide caspase inhibitors. Cyclosporin A (CsA), whichinhibits mitochondrial transition pore permeability, blockedneither pore permeability disruption nor caspase activation.However, CsA plus caspase-8 inhibitor blocked all apoptoticevents of 12B1-D1 induced by Fas death domain dimerization. Ourdata therefore suggest that there is a novel,caspase-8-independent, Z-VAD-FMK-inhibitable, apoptotic pathway in12B1-D1 cells that targets mitochondria directly.

[学科分类] 基础医学