Controlling the cell death mediators Bax and Bak: puzzles and conundrums.

In spite of the available genetic, biochemical and structural data, precisely how the initiators of apoptosis, the BH3-only proteins, trigger Bax and Bak to cause organellar damage remains highly contentious. A widely accepted model suggests that these two critical mediators of apoptosis remain inert until they are directly activated by a subclass of BH3-only proteins including Bim, Bid, and possibly Puma. However, our recent work showed that these death ligands are dispensable for apoptosis to proceed, whereas neutralization of the pro-survival Bcl-2 proteins is essential. These findings challenge current assumptions about how the BH3-only proteins provoke apoptotic cell death and have implications for the development of therapeutics to interfere with the Bcl-2 regulated apoptotic pathway for treating diseases such as cancer.