Activation of interferon-stimulated genes by gamma-ray irradiation independently of the ataxia telangiectasia mutated-p53 pathway

The ataxia telangiectasia mutated (ATM)-p53 pathway is a well-known main signal transduction pathway for cellular responses, which is activated by γ-ray irradiation. Microarray analysis showed changes in the expressions of IFN-stimulated genes (ISG) in γ-ray-irradiated Balb/cA/Atm-deficient mouse embryonic fibroblasts (MEF) (ATM-KO), indicating that another pathway for cellular responses besides the ATM-p53 pathway was activated by γ-ray irradiation. The basal expression levels of Irf7 and Stat1 in ATM-KO and p53-deficient MEFs (p53-KO) were higher than those in Atm-wild-type MEFs (ATM-WT) and p53-wild-type MEFs (p53-WT), respectively. Irradiation stimulated the expressions of Irf7 and Stat1 in ATM-KO, p53-KO, ATM-WT, and p53-WT, indicating that upregulation of Irf7 and Stat1 expressions by irradiation did not depend on the ATM-p53 pathway. When conditioned medium (CM) obtained from irradiated ATM-WT or ATM-KO was added to nonirradiated MEFs, the expressions of Irf7 and Stat1 increased. We predicted that gene activation in nonirradiated MEFs was caused by IFN-α/β. Unexpectedly, significant amount of IFN-α/β could not be detected in the CM from irradiated ATM-WT or ATM-KO. Meanwhile, increased expression of Ccl5 (RANTES) protein was detected in the CM from irradiated MEFs. These results indicate that ISGs were activated by γ-ray irradiation independently of the ATM-p53 pathway and gene activation was caused by radiation-induced soluble factors.