How do the Bax and Bak proteins function to permit apoptotic cell death?
Unwanted or dangerous cells are normally deleted by a process of cellular suicide known as apoptosis. Importantly, impaired apoptosis is a key step in the development of several pathological conditions, including the progression of tumours. Anti-cancer treatments generally operate by activating apoptosis in cancer cells, often via indirect mechanisms resulting in damage to normal tissues. Recent investigations based on targeting the apoptotic pathway directly, have shown significant potential for the development of potent and specific anti-cancer treatments.
The principle regulators of the apoptotic pathway, and therefore targets for anti-cancer treatments, are the Bcl-2 family of proteins. Two pro-apoptotic members, Bax and Bak, lie at the heart of apoptotic cell death, as either Bax or Bak is essential for most forms of apoptotic cell death. Bax and Bak are inhibited by prosurvival members such as Bcl-2 itself, and are activated by the third subfamily of Bcl-2 proteins, the pro-apoptotic BH3-only proteins. Once activated, Bax and Bak are thought to permeabilize mitochondria, initiating the certain demise of the cell. Despite much progress, exactly how Bax and Bak are regulated by other Bcl-2 proteins, and how Bax and Bak then permeabilize mitochondria, remain unclear.
We aim to clarify how Bax and Bak mediate cell death using several novel approaches. Random mutagenesis of Bax and Bak has not been performed previously and will provide an unbiased analysis of both proteins. Bax and Bak mutants that cannot kill yeast will identify protein regions important for permeabilizing mitochondria. Bax/Bak mutants that cannot re-sensitise Bax and Bak deficient mammalian cells to proapoptotic BH3-only signals, will identify regions important for regulation by other Bcl-2 proteins.
Thus, the proposed studies will more clearly define targets for anti-cancer therapies, at the level of Bcl-2 protein signalling and at the level of mitochondrial membrane permeability.
Dr Ruth Kluck & Professor Andreas Strasser