Molecular mechanisms of irradiation-induced apoptosis

Abstract

The following review focuses on our current knowledge as to how the cell death regulatory machinery is activated to mediate irradiation-induced cell death. In particular, we will address recent developments related to the following questions: 1.) Which cell death regulatory genes mediate irradiation-induced cell death? 2.) What is the mechanism of irradiation-induced activation or suppression of cell death regulatory genes (proteins)? 3.) How does the condition of the cell death regulatory machinery affect the cell's sensitivity or resistance to irradiation? Now more than ever, it seems clear that irradiation -induced apoptosis is a complex process involving all three major cell death regulatory pathways: the mitochondria pathway (Bcl-2/Apaf-1), the Iap pathway, and the death receptor pathway. Depending on the cellular context, one or multiple pathways may be activated to mediate irradiation-induced cell death. Therefore, a comprehensive understanding of these processes demands systematic strategies in contrast to traditional approaches that focused on one gene/protein. For this reason, we will also examine recent studies applying genomic (proteomic) methods in this area.

Figure 1

Simplified schematic presentation of the three major cell death regulatory pathways, which, when activated, all lead to the activation of caspases (in dashed square). Colors distinguish the organism to which the gene/protein belongs (eg. C. elegans, Drosophila, and Mammals). * Most mammalian genes have multiple names, only one is listed due to space limitation.

Figure 2

The integration of cell death regulatory control by Apaf-1/Hac-1 and Iap antagonists depicted in the “Gas” and “Brake” model. Apaf-1-like molecules function as “gas” for caspase activation, which is checked by the “brake” Iaps.