Bax deficiency affects caspase-2 activation during ultraviolet radiation-induced apoptosis

There has been a considerable debate as to whether caspase-2 is an initiator or effector caspase. Recently, a new model of intrinsic pathway of apoptosis has been proposed, which suggests caspase-2 to be an initiator caspase. For example, ultraviolet radiation (UV) and other DNA damage-inducing agents were shown to first activate caspase-2 and then regulate the mitochondrial and postmitochondrial events. Active caspase-2 was found to engage mitochondria by promoting Bax translocation to the mitochondria. Consequently, Bax was proposed to play a central role in bridging the active caspase-2 with mitochondria by affecting mitochondrial permeability, cytochrome c release into the cytosol and caspase- 9 activation. In the present study, we investigated the role of Bax in UV-induced apoptosis and caspase- 2 activation. Our results indicate that UV-induced apoptosis and caspase- 2 activation were diminished in Bax-deficient cells, suggesting that Bax appears to play an important role in UV-induced apoptosis as well as caspase- 2 activation, and that it also appears to reside upstream of caspase-2. Bax deficiency also affected the activation of caspase- 3 and - 8 and abolished caspase- 9 activation during UV-induced apoptosis, suggesting that the absence of caspase- 9 activation may affect caspase- 2, - 3 and - 8 activation in Bax-deficient cells. Based on our results, we propose that activation of caspases is not a linear cascade of events, but is rather connected via complex feedback loops.