Fig. 8.

A simplified model of the signaling pathways regulating radiation-induced bystander effects. DNA damage induces ATM activation in α-particle irradiated cells. ATM further activates the NF-κB pathway, which targets gene expression of numerous cytokines and COX2. Cytokines initiate specific signaling pathways in directly irradiated and bystander cells resulting in the secondary activation of IKK-NF-κB, JAK2-STAT3 and the MAPK pathways with the subsequent induction of cytokine, COX2 and iNOS gene expression. COX-2-produced PGE2 is involved in regulation of ROS production, iNOS controls synthesis of NO. Effects of ROS and NO in the mitochondrial damage and bystander response were previously described [12]. On the other hand, NF-κB regulates expression of numerous genes controlling a general cell survival and anti-apoptotic activity. Exogenous IGF-1 via ligation of IGF-1R activates the PI3K-AKT pathway that using suppression of GSK3β stabilizes β-catenin protein levels; LEF1--β-catenin heterodimer goes to the nucleus and further controls gene expression. Furthermore, AKT controls numerous general metabolic, survival and anti-apoptotic functions in the cell. IGFBP-3 stabilizes the exogenous IGF-1 and extends its action time further activating the basal PI3K-AKT pathway.