Cleavage of BID during cytotoxic drug and UV radiation-induced apoptosis occurs downstream of the point of Bcl-2 action and is catalysed by caspase-3: a potential feedback loop for amplification of apoptosis-associated mitochondrial cytochrome c release

BID, a pro-apoptotic Bcl-2 family member, promotes cytochrome c release dur ing apoptosis initiated by CD95L or TNF, Activation of caspase-8 in the lat ter pathways results in cleavage of BID, translocation of activated BID to mitochondria, followed by redistribution of cytochrome c to the cytosol, Ho wever, it is unclear whether BID participates in cytochrome c release in ot her (non-death receptor) cell death pathways. Here, we show that BID is cle aved in response to multiple death-inducing stimuli (staurosporine, UV radi ation, cycloheximide, etoposide), However BID cleavage in these contexts wa s blocked by Bcl-2, suggesting that proteolysis of BID occurred distal to c ytochrome c release. Furthermore, addition of cytochrome c to Jurkat post-n uclear extracts triggered breakdown of BID at Asp-59 which was catalysed by caspase-3 rather than caspase-8, We provide evidence that caspase-3 cataly sed cleavage of BID represents a feedback loop for the amplification of mit ochondrial cytochrome c release during cytotoxic drug and UV radiation-indu ced apoptosis.