Fig. 10. Schematic model of the effect of Bcl-2 subcellular location in two forms of apoptosis. During death receptor-mediated apoptosis caspase-8 is the most apical caspase. Once activated, caspase-8 in turn triggers the downstream effector cascade either directly through caspase-3 or through engagement of the mitochondrial pathway. In this process, Bid triggers cytochrome c release, which is needed for caspase-9 activation. Bcl-2 located at mitochondria interferes with the activation of this amplification loop, whereas Bcl-2 at the ER has no influence on death receptor-mediated apoptosis. By contrast, the most apical caspase in radiation-induced apoptosis is caspase-9, which is activated in response to mitochondrial damage. A hypothetical crosstalk between mitochondria and the ER, which is upstream of caspase activation and may involve perturbations in calcium homeostasis or other ER-based pro-apoptotic molecules, may essentially control the initial steps of radiation-induced cell death.
