Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunctionand death

Multiple death signals influence mitochondria during apoptosis, yet the cri tical initiating event for mitochondrial dysfunction in vivo has been uncle ar. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family me mber, triggers the homooligomerization of "multidomain" conserved proapopto tic family members BAK or BAX, resulting in the release of cytochrome c fro m mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-indu ced cytochrome c release and apoptosis. Moreover, doubly deficient cells ar e resistant to multiple apoptotic stimuli that act through disruption of mi tochondrial function: staurosporine, ultraviolet radiation, growth factor d eprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsig argin and tunicamycin. Thus, activation of a "multidomain" proapoptotic mem ber, BAX or BAK, appears to be an essential gateway to mitochondrial dysfun ction required for cell death in response to diverse stimuli.