Volume 102, Issue 1, Pages 1-4 (July 2000) Apoptotic Pathways  Douglas R Green  Cell  Volume 102, Issue 1, Pages 1-4 (July 2000) DOI: 10.1016/S0092-8674(00)00003-9

Figure 1 The Mitochondrial Pathway Stress-induced signals are transduced to the mitochondria by the action of one or more members of the BH3-only subfamily of the proapoptotic Bcl-2 proteins, acting on the Bax subfamily of proapoptotic Bcl-2 proteins. The mitochondria release cytochrome c and Smac/DIABLO. (A) Cytochrome c induces the oligomerization of Apaf-1, which recruits and activates procaspase-9. The active caspase-9 recruits and activates procaspase-3. The active caspase-3, and other executioner caspases, such as caspase-7, act on key substrates in the cell to orchestrate apoptotic death. (B) IAPs (such as XIAP), can bind to activated caspase-9 and prevent its action on procaspase-3. The complex, perhaps, is then ubiquitinated by the action of XIAP and degraded in the proteasome. (C) Smac/DIABLO binds XIAP, leaving caspase-9 free to recruit and activate caspase-3, as in (A). Apoptosis therefore proceeds. Cell 2000 102, 1-4DOI: (10.1016/S0092-8674(00)00003-9)

Figure 2 Possible Control of Death Receptor–Mediated Apoptosis by Bcl-2 in a “Type II” Cell Ligation of the death receptor recruits adaptor molecules (such as FADD) and procaspases (such as procaspase-8 and -10) to the receptor, where the caspases activate by proximity. (A) The active initiator caspases then act on procaspase-3, introducing a cut between the small and large subunits. The active caspase-3 is now bound and inhibited by an IAP such as XIAP. (Although shown to occur in vitro, this scenario in death receptor signaling is currently speculative.) (B) The active initiator caspases also cleave and activate Bid, which translocates to the mitochondria and triggers Bax-subfamily proteins to induce the release of Smac/DIABLO (as well as cytochrome c, which in this speculative scenario may be ancillary). Smac/DIABLO binds to and neutralizes the IAP, allowing full activation of the caspase-3 to occur (either via caspase-8, or by cytochrome c–activated caspase-9). Apoptosis proceeds. However, if the cells express Bcl-2 (or Bcl-xL) then inhibition of the effect of Bid will prevent the release of Smac/DIABLO, and apoptosis will be inhibited. Although speculative, this scheme helps to explain a number of reported phenomena and makes a number of testable predictions. Cell 2000 102, 1-4DOI: (10.1016/S0092-8674(00)00003-9)