Genotoxic stress such as ionizing radiation can induce DNA damage and promote cell-cycle arrest or apoptosis through either a p53-dependent or -independent pathway. Recently, members of the FOXO Forkhead transcription factor family have been implicated in playing a role in both DNA repair and apoptosis in mammalian cells that promoted us to examine the role of FOXO transcription factors in ionizing radiation-induced apoptosis. Here, we show that ionizing radiation can promote FOXO3a (FKHRL1) transcriptional activity and protein expression level, and induce nuclear translocation of FOXO3a in Saos2, a p53-null osteosarcoma cell line. Ionizing radiation stimulates expression of apoptosis-inducing proteins such as Fas ligand and the Bcl-2 interacting mediator of cell death (Bim) leading to cellular apoptosis. The observed upregulation of proapoptotic genes and apoptosis in cells without p53 in response to ionizing radiation suggests a novel p53-independent mechanism underlying ionizing radiation-induced apoptosis in cancer cells.

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