Death in the Balance: Pro- and antiapoptotic proteins counteract each other in vivo (Apoptosis)
Authors: Davenport R. John 
Published: August 2003

When cells sustain damage or outlive their usefulness, they threaten to undermine the integrity of the entire organism. As a protective measure, molecular juries issue a harsh punishment to potential troublemakers: death by genetically programmed cell suicide, a process known as apoptosis. But damaged cells sometimes escape their death sentence and turn cancerous. And even when the ax does fall, justice isn't always served. Removing irreplaceable cells leaves a gap that can contribute to degenerative diseases. On the basis of test tube and cell culture studies, scientists have suspected that the cell death verdict depends on the opposing actions of proteins that stimulate and prevent apoptosis. New results provide dramatic evidence that this scenario occurs in vivo.

Like bitter cousins on opposite sides of a courtroom battle, members of the Bcl-2 family of proteins serve as both defense and prosecution: Some proteins, such as Bcl-2 itself, argue against apoptosis, whereas others, such as Bim, advocate for cell death. Each side enlists the help of multiple proteins, and discerning which pro-apoptotic players grapple with which antiapoptotic ones has proven difficult. In order to understand who's in which camp, researchers have knocked the suspected players out of commission one by one and documented which way the verdict swung. Mice without the
bcl-2
gene suffer from multiple degenerative conditions: They are gray-haired runts with kidney problems and deteriorated spleens and thymuses; and their lymphocytes--white blood cells produced by the spleen and thymus--readily undergo apoptosis. Mice that lack the
bim
gene, on the other hand, boast an excess of blood-cell precursors and lymphocytes; without
bim,
those cells resist apoptotic triggers. Because removal of
bcl-2
or
bim
has opposite effects on the lymphoid system, Bouillet and colleagues wondered what would happen when both genes were knocked out in the same animal.

The researchers engineered mice that carried neither the
bcl-2
gene nor the
bim
gene. Animals with both defects developed as controls did: Their weight was normal, their fur retained its black color, and their kidneys functioned properly. Furthermore, the majority of the problems associated with a
bcl-2
defect could be reversed with only a 50% reduction in Bim:
bcl-2
-deficient mice with a single copy of
bim
sported gray fur but otherwise resembled control animals. The researchers suggest that absence of Bcl-2 frees Bim to incite rampant apoptosis; when both proteins are missing, cells survive. Studies of cultured lymphocytes extend this idea: Cells treated with apoptosis-inducing molecules survived more readily if they lacked both
bim
and
bcl-2
than if they lacked only
bcl-2.

This work provides evidence that Bim and Bcl-2 regulate apoptosis by opposing each other's function in whole animals--at least in certain tissues. This notion had already garnered support from studies of cells removed from organisms, which hinted that the relative amounts of pro- and antiapoptotic proteins determine whether a cell lives or dies. The results also suggest that degenerative disorders--such as Alzheimer's disease--in which apoptosis might play a role could be treated by small molecules that target apoptosis-promoting proteins in specific tissues. Perhaps such an action could sway the jury in favor of life.

--R. John Davenport; suggested by Greg Liszt

P. Bouillet, S. Cory, L.-C. Zhang, A. Strasser, J. M. Adams, Degenerative disorders caused by Bcl-2 deficiency prevented by loss of its BH3-only antagonist Bim.
Dev. Cell
1
, 645-653 (2001).
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