Abstract
ATM-dependent p53 activation is well recognized main pathway after gamma-irradiation. However, molecular mechanisms for ATM-independent cellular responses after irradiation are unknown. Comparative microarray analysis was done on gene expression profiles in cultures of ATM-deficient mouse embryonic fibroblasts (MEFs) and normal MEFs with 4.32 Gy of gamma-rays at middle-dose-rate (MDR; 60 mGy/h) or high-dose-rate (HDR; 0.9Gy/min), interferon-related genes such as Irf7 and Stat1 were up-regulated in ATM-deficient MEFs irradiated with MDR or HDR radiation. These gene expressions were also observed in cultures of normal MEFs irradiated with MDR or HDR radiation in the presence of ATM-specific inhibitor (KU55933). Up-regulation of Irf7 and Stat1 genes in normal MEFs were induced by HDR-irradiation alone or treatment of ATM-specific inhibitor alone, but not by MDR-irradiation alone. Furthermore, the addition of conditioned medium from HDR-irradiated normal MEFs augmented gene-expressions of Irf7 and Stat1 in non-irradiated normal MEFs. Analysis of the effect of conditioned medium from ATM-inactivated MEFs is under investigation. These results indicate that Irf7 and Stat1 genes were up-regulated by inactivation of ATM or HDR-irradiation, and the ATM-independent interferon-related gene expressions after irradiation might be due to bystander effect mediated by soluble factor(s). This study was performed under contract with the Aomori Prefectural Government, Japan.
