Regulation and function of the pro-apoptotic Bcl-2 family member BOK

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Therapeutic strategies in cancer are directed towards inducing cell death. Understanding how cells activate or suppress pro-apoptoic signalling is therefore a key issue if effective anti-cancer therapies are to be developed. The BCL2 family of pro- and anti-apoptotic members plays a crucial role in the choice between cell survival and death by controlling the process of mitochondrial outer membrane permeabilization (MOMP). The three active effectors of MOMP are BAX, BAK and the Bcl-2-related ovarian killer (BOK). In stark contrast to BAX and BAK, BOK is not regulated by anti-apoptotic BCL2 family members (e.g., BCL-2, BCL-xL, BCL-W, MCL-1). In most cell lines examined to date the pro-apoptotic activity of the MOMP effector BOK is suppressed via ubiquitin-mediated degradation. Consequently in cells with “unstable“ BOK the protein is barely detectable. Stabilization of BOK in such cell lines via proteasome inhibition or overexpression of BOK leads to apoptotic cell death. These and other findings suggest that BOK is a constitutively active MOMP effector and that the apoptotic activity of BOK is inhibited by the actions of the cytosolic arm of the ER-associated degradation (ERAD) pathway.By contrast, we observed that several organs and cancer cell lines harbor constitutively “stabilized“ BOK protein, suggesting that BOK’s MOMP effector function is inactivated via an alternative mechanism to proteosomal degradation. Our preliminary data suggest, that certain cellular stresses (e.g., mitotic damage, ER-stress) can activate constitutively stabilized BOK, but how this occurs is unknown.The proposed project will therefore explore the effects of BOK on apoptosis in cells that maintain stabilized BOK protein and will investigate the hypothesis that:i) stabilized BOK contributes to apoptotic cell death under certain cellular stressesii) in addition to regulation of BOK stability by ERAD, BOK’s latent pro-apoptotic function is suppressed by alternative mechanism ways to control apoptotic cell death.We propose that BOK’s activity is modulated by post-translational modifications downstream from these cellular stresses that define its subcellular localization and protein-protein interactions. By characterizing the regulation of BOK in normal and cancer cells we will reveal BOK’s (patho-) physiological role and how BOK is engaged. This project will focus on the identification of novel molecular mechanisms regulating BOK’s pro-apoptotic function in cancer and in physiology.