Apoptotic Pathways Paper Wraps Stone Blunts Scissors

The mitochondrial pathway, shown in Figure 1A, is triggered by proapoptotic members of the Bcl-2 family, initially by a subset of these called the " BH3-only sub-family " proteins because they possess only one of the Bcl-2 homology (BH) domains. These include Bid, Bim, Harikari, Noxa, and a number of others. In response to environmental cues these proteins engage another set About 2.2 billion years ago, as the oxygen levels on the planet were rising, a new sort of life-form emerged, of proapoptotic Bcl-2 members, the Bax subfamily forged from a shaky alliance of what were to become (which includes Bax, Bak, and probably Bok), loosely the mitochondria and the remainder of the cell. The residing on the mitochondrial outer membranes or in protomitochondria brought respiration to the partner-the cytosol. The interaction causes the latter to oligo-ship, and with it the power to kill the new cell through merize and insert into the mitochondrial membrane the production of reactive oxygen species, a mechanism (Eskes et al., 2000). Here the complex acts to trigger of cell death that still exists throughout the eukaryotes. the sudden and complete release of cytochrome c and However, it was about 1.5 billion years later, as multicel-other proteins from all of the mitochondria in the cell. lular animals emerged, that our story probably begins. The released cytochrome c binds to Apaf-1, a cyto-Apoptosis has now evolved as a physiological cell death solic protein. This induces Apaf-1 oligomerization, and in response to environmental and developmental sig-the Apaf-1 " apoptosome " recruits and activates procas-nals, a complex decision-making system with the mito-pase-9 (Cain et al., 2000). The active caspase-9 now chondria at its heart. Apoptotic cell death is found recruits and activates the executioner procaspase-3. throughout the animal kingdom, and it culminates in the Cells lacking cytochrome c are remarkably resistant to execution, packaging, and disposal of the dying cells. stress-induced apoptosis and maintain clonogenicity Several recent advances have contributed to an emerg-under some conditions where wild-type cells die (Li et ing (and evolving) view of how apoptosis proceeds once al., 2000). Cells lacking Apaf-1 or caspase-9 are also initiated, to the point that we can speculate on a pathway resistant to the induction of apoptosis via the mitochon-for this remarkable process. This is a pathway, however, drial pathway (reviewed in Green, 1998). that may differ in interesting ways between different types Bcl-2 and Bcl-xL (and probably other …