title: Activation of interferon-stimulated genes by gamma-ray irradiation independently of the ataxia telangiectasia mutated-p53 pathway.
abstract: 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.
authors.affiliation: Department of Radiobiology, Institute for Environmental Sciences, 2-121 Hacchazawa, Takahoko, Rokkasho, Kamikita, Aomori 039-3213, Japan. sugihara@ies.or.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugihara
authors.forename: Hayato
authors.initials: H
authors.lastname: Murano
authors.forename: Masako
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ichinohe
authors.forename: Kimio
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000235:genetics; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000528:radiation effects; D053263:Gene Regulatory Networks / Q000235:genetics / Q000528:radiation effects; D050839:Interferon Regulatory Factor-7 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C503460:Ccl5 protein, mouse; D018797:Cell Cycle Proteins; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases