The molecular mechanisms by which the Bcl-2 family regulates apoptosis

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Apoptosis plays vital roles in normal physiology, and its perturbed regulation underlies many disorders, including autoimmune diseases and cancer. Commitment to apoptosis is determined largely by interactions between members of the Bcl-2 protein family. As well as the pro-survival (Bcl-2-like) proteins, they include the BH3-only proteins, which transmit cytotoxic signals, and Bax and Bak, which permeabilize the mitochondria to initiate cell demolition. This proposal aims to clarify the critical interactions within the family that promote or inhibit cell death. The host laboratory has proposed that the pro-survival Bcl-2- like proteins bind to small subpopulations of the Bax and Bak proteins, residing at the mitochondria in a ‘primed stage’, and keep them in check. Upon a death signal, binding of the BH3-only proteins to the pro-survival proteins is posited to displace the primed Bax or Bak, allowing them to oligomerize and trigger apoptosis. I will test critical features of this novel model by attempting to identify the complexes of Bax with its pro-survival relatives, to prove that they are required for cell survival, to test whether BH3-only proteins can displace Bax, and to show that the freed Bax forms the oligomers that disrupt mitochondria. The findings should greatly clarify how apoptosis is normally controlled and thereby aid the development of the new anti-cancer drugs that target Bcl-2 family members.