The BCL-2 family of proteins, consisting of both anti-apoptotic and pro-apoptotic members, constitutes a crucial checkpoint in the cell death pathway. These members are essential for maintenance of major organ homeostasis, and mutations affecting them can result in cancer. The """"""""BH3-only"""""""" molecules activate """"""""multi-domain"""""""" pro-apoptotic members BAX and BAK to trigger a mitochondrion-dependent cell death pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction. Conversely, anti-apoptotic BCL-2/BCL-XL sequesters translocated """"""""BH3-only"""""""" molecules in stable mitochondrial complexes, thus preventing the activation of BAX/BAK. Loss of function studies revealed that the absence of pro-apoptotic BAX and BAK creates a profound block in apoptosis triggered by diverse death signals initiated at multiple sites including plasma membrane, nucleus, and endoplastic reticulum. Thus, activation of a """"""""multidomain"""""""" pro-apoptotic member, BAX or BAK, appears to be an essential gateway to the mitochondria-mediated cell death program. What maintains BAK in an inactive conformation at mitochondria and precisely how it is activated to manifest in cell death are still unclear. I reasoned that an additional death regulatory protein might exist and have identified a BAK-interacting protein that only interacts with the inactive conformer of BAK and is displaced form BAK upon its activation by """"""""BH3-only"""""""" molecules. Further characterization of this novel participant (entitled X) and its precise effects will further understanding of how """"""""BH3-only"""""""" proteins activate BAK and the mitochondrial death pathway. In this context, I propose the following specific aims: (1) Dissect the mechanisms by which """"""""multidomain"""""""" pro-apoptotic BAX and BAK mediate mitochondrial dysfunction and cell death; (2) Determine the role of BAK-interacting protein (X) in regulating apoptosis.
| Tu, Ho-Chou; Ren, Decheng; Wang, Gary X et al. (2009) The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage. Proc Natl Acad Sci U S A 106:1093-8 |
| Ren, Decheng; Kim, Hyungjin; Tu, Ho-Chou et al. (2009) The VDAC2-BAK rheostat controls thymocyte survival. Sci Signal 2:ra48 |
| Kim, Hyungjin; Tu, Ho-Chou; Ren, Decheng et al. (2009) Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis. Mol Cell 36:487-99 |
