The large family of Bcl-2 proteins is crucial for regulating the intrinsic pathway of apoptosis. It predominantly acts at the level of the mitochondrial outer membrane (MOM) through complex molecular interactions within the three family subgroups: the initiating BH3-only proteins with pro-apoptotic activity, their anti-apoptotic antagonists, and the downstream effector proteins Bak, Bak and probably Box. After activation by BH3-only proteins Bax and Bak perforate the MOM, leading to cytochrome c release and subsequent cell death execution. Noteworthy, small molecules inactivating anti-apoptotic Bcl-2 proteins by mimicking critical protein-protein interactions within the family have proven effective to kill cancer cells and have already found their way into phase-II/III clinical trials.
Investigations of the Bcl-2 network over the last two decades have successfully defined key biological functions of most Bcl-2 family proteins in normal physiology. However, numerous questions remain to be answered in order to fully understand the effects of individual family members and their reciprocal interactions. First, it is still unknown for most stress signals how exactly they are transmitted to the Bcl-2 family network. Next, it has not yet been clarified how Bax/Bak effectors are activated by BH3-only proteins, how this activation is inhibited by the anti-apoptotic family members, and how Bax/Bak effectors finally release cytochrome c. Furthermore, the role of certain "neglected" Bcl-2 family members, such as A1 and Bok, has remained enigmatic.
The Research Group "New insights into Bcl-2 family interactions: from biophysics to function" aims at clarifying some of these remaining questions by scientists who are experienced in Bcl-2 family research and dedicated to exchange methods and information. The application focuses on few selected biological problems and molecular players, and uses highly integrated approaches of biophysics, cell and molecular biology, biochemistry, proteomics, mouse genetics, and human pathology. One part will try to unravel how activator BH3-only proteins such as Bim and Puma activate Bax, how these BH3-only proteins integrate pro-apoptotic signals and how the disturbance of the "Bcl-2 rheostat" leads to disease.
Computational models will further help to understand the complexity of these mechanisms. The second part will study the poorly investigated, "neglected" Bcl-2-family members A1/Bfl-1 and Bok, and incorporate them into the revised concept of Bcl-2 protein signaling. Finally, translational projects will identify Bcl-2 family members, which are crucially involved in the development, growth and maintenance of normal and malignant haematopoiesis.