Nature, Vol.391, No.6666, 496-499, 1998
Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c
Following exposure of cells to stimuli that trigger programmed cell death (apoptosis), cytochrome c is rapidly released from mitochondria irate the cytoplasm where it activates proteolytic molecules known as caspases that specifically cleave the amino-acid sequence DEVD and are crucial for the execution of apoptosis(1-4). The protein Bcl-2 interferes with this activation of caspases by preventing the release of cytochrome c(2-4). Here we study these molecular interactions during apoptosis induced by the protein Bax, a pro-apoptotic homologue of Bcl-2 (refs 5, 6). We show that in cells transiently transfected with bar, Bar localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Caspase inibitors do not affect Bar-induced cytochrome c release but block caspase-3 activation and nuclear fragmentation. Unexpectedly, Bcl-2 also fails to prevent Bar-induced cytochrome c release, although it co-localizes with Bar to mitochondria. Cells overexpressing both Bcl-2 and Bar show no signs of caspase activation and survive with significant amounts of cytochrome c in the cytoplasm. These findings indicate that Bcl-2 can interfere with Bar killing downstream of and independently of cytochrome c release.