Understanding and Tracking Pro- and Anti-Apoptotic BCL-2 protein Interactions and their Relation to Cancer in Extrinsic Apoptosis

Abstract

We describe a systems approach to combine mathematical modeling and experimental measurement in the study of signal transduction in mammalian cells. Our focus is on the BCL-2 family of proteins and their interplay in extrinsic apoptosis. Construction of mathematical signal transduction models that recapitulate key features of signaling pathways as they exist in cells is currently very difficult. To circumvent this, we employ a novel rules-based modeling approach to manage and track high-level biological knowledge and translate this knowledge to mathematical models of extrinsic apoptosis. We present results that use experimental data as a foundation to explain seemingly contradictory interactions among Bcl-2 proteins and their contributions to mitochondrial outer membrane permeabilization as inhibitors, promoters, or sensitizers of apoptosis.