Sci. Aging Knowl. Environ., 20 November 2002
BAD Time for Suicide
Growth factors save cells by foiling mitochondrial disrupter
Key Words: Akt apoptosis BID kinases transgenic mice
Abstract: Like captured spies fingering the suicide pills in their pocket, cells caught in stressful situations must opt for life or death. Scientists have now unveiled the molecular details that underlie this choice: Growth factors change a suicide protein into one that prevents the cell's energy-production factory from spurring hara-kiri. The results also suggest how cells in live animals decide whether to destroy themselves.
In organisms, cells subjected to insults such as radiation often die through a suicide process called apoptosis, but molecules known as growth factors can prevent such death. Previous research suggested that growth factors inactivate proteins that would otherwise lead cells to their doom. One of these proteins, BAD, is a member of the Bcl-2 family of apoptosis-promoting molecules (see "Death in the Balance") and triggers a cell's demise by mucking with the energy-production facilities called mitochondria--at least in the test tube. Datta and colleagues wanted to know how important BAD's function is to an organism, so they created mice with a genetic mutation that permanently activates the suicide pusher.
Mice with unstoppable BAD develop almost normally, the team found, although the animals are slightly smaller than normal and lack a full supply of immune system cells. These results suggested that BAD doesn't assert itself during embryonic growth. The researchers therefore tested whether turning off the protein helps keep adult cells alive; perhaps, they reasoned, the immune cell loss stemmed from the BAD mutation. They added the growth factor interleukin-7 to cultured immune cells carrying unquenchable BAD. After 24 hours, half the normal number of these cells survived. These observations indicated that a growth factor encourages cell survival by exorcising BAD's death wish. Growth factors protect against stresses such as radiation, so the researchers tested whether that defense system requires BAD suppression. The growth factor IGF-1 killed more irradiated cultured skin cells with gung-ho BAD than those with a normal version of the protein, and irradiated mice with uncontrollable BAD died faster than did normal irradiated mice. These observations reveal that growth-promoting molecules must squelch BAD activity for beleaguered cells to survive.
Because BAD kills cells in test tubes by mangling mitochondria, the researchers wondered whether the protein acts similarly in mice. They purified the organelles from immune cells and added a protein that causes suicide by disgorging a mitochondrial molecule called cytochrome c. Mitochondria with tenacious BAD regurgitated almost twice as much cytochrome c as did organelles with an unaltered version of the protein, indicating that normal BAD thwarts mitochondrial vomiting.
"All the evidence that BAD had a role in apoptosis was [gathered from] contrived systems," says cell biologist Morris Birnbaum of the University of Pennsylvania Medical School in Philadelphia; the new work shows for the first time that live mice use the BAD apoptotic pathway. The results "add weight to the emerging idea of an 'apoptotic threshold,' " where BAD and other molecules poise cells at the edge and wait for additional cues to push them toward life or death. Through such studies, researchers might eventually learn what's so BAD about suicidal tendencies.
--Mary Beckman; suggested by Arjumand Ghazi
S. R. Datta, A. M. Ranger, M. Z. Lin, J. F. Sturgill, Y.-C. Ma, C. W. Cowan, P. Dikkes, S. J. Korsmeyer, M. E. Greenberg, Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev. Cell 3, 631-643 (2002). [Abstract] [Full text]
Citation: M. Beckman, BAD Time for Suicide. Science's SAGE KE (20 November 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/46/nw157
Science of Aging Knowledge Environment. ISSN 1539-6150