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.
Fletcher
Jamie I
JI
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. fletcher@wehi.edu.au
Huang
David C S
DC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D006801:Humans; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000502:physiology*
D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein