title: DNA damage response pathway in radioadaptive response.
abstract: Radioadaptive response is a biological defense mechanism in which low-dose ionizing irradiation elicits cellular resistance to the genotoxic effects of subsequent irradiation. However, its molecular mechanism remains largely unknown. We previously demonstrated that the dose recognition and adaptive response could be mediated by a feedback signaling pathway involving protein kinase C (PKC), p38 mitogen activated protein kinase (p38MAPK) and phospholipase C (PLC). Further, to elucidate the downstream effector pathway, we studied the X-ray-induced adaptive response in cultured mouse and human cells with different genetic background relevant to the DNA damage response pathway, such as deficiencies in TP53, DNA-PKcs, ATM and FANCA genes. The results showed that p53 protein played a key role in the adaptive response while DNA-PKcs, ATM and FANCA were not responsible. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), mimicked the priming irradiation in that the inhibitor alone rendered the cells resistant against the induction of chromosome aberrations and apoptosis by the subsequent X-ray irradiation. The adaptive response, whether it was afforded by low-dose X-rays or wortmannin, occurred in parallel with the reduction of apoptotic cell death by challenging doses. The inhibitor of p38MAPK which blocks the adaptive response did not suppress apoptosis. These observations indicate that the adaptive response and apoptotic cell death constitute a complementary defense system via life-or-death decisions. The p53 has a pivotal role in channeling the radiation-induced DNA double-strand breaks (DSBs) into an adaptive legitimate repair pathway, where the signals are integrated into p53 by a circuitous PKC-p38MAPK-PLC damage sensing pathway, and hence turning off the signals to an alternative pathway to illegitimate repair and apoptosis. A possible molecular mechanism of adaptive response to low-dose ionizing irradiation has been discussed in relation to the repair of DSBs and implicated to the current controversial observations on the expression of adaptive response.
authors.affiliation: Radiation Biology Center, Kyoto University, Yoshida-konoecho, Sakyo-ku, Kyoto, Japan. msasaki@emp.mbox.media.kyoto-u.ac.jp
authors.forename: Masao S
authors.initials: MS
authors.lastname: Sasaki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ejima
authors.forename: Akira
authors.initials: A
authors.lastname: Tachibana
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamada
authors.forename: Kanji
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Taisei
authors.initials: T
authors.lastname: Nomura
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000528:radiation effects*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D052217:Fanconi Anemia Complementation Group A Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases