低線量・低線量率放射線による細胞応答の発現機構

2002 Fiscal Year Annual Research Report

• Project/Area Number: 12358010
• Research Institution: Nara Medical University
• Principal Investigator: 大西 武雄 奈良県立医科大学, 医学部, 教授 (60094554)
• Co-Investigator(Kenkyū-buntansha): 小松 賢志 京都大学, 放射線生物研究センター, 教授 (80124577) ; 丹羽 太貫 京都大学, 放射線生物研究センター, 教授 (80093293) ; 内海 博司 京都大学, 原子炉実験所, 教授 (20025646) ; 渡邉 正己 長崎大学, 薬学部, 教授 (20111768) ; 法村 俊之 産業医科大学, 医学部, 教授 (20039530)
• Keywords: 低線量・低線量率放射線 / p53 / 情報伝達 / 適応 / アポトーシス / 細胞周期 / 突然変異誘発 / 遺伝的不安定性

Research Abstract

(1)センサー
・緩照射は、NOを介したバイスタンダー効果により蓄積誘導された正常型p53の衰退を促進し、このp53の衰退促進はHdm2による分解促進であることが示唆された。(福井医大・松本)
・低線量放射線照射により誘発されたDNA二重鎖切断の認識は、NBS1がはじめに損傷部位のヒストンを認識してヌクレアーゼを損傷部位にリクルートして、次にヌクレアーゼが損傷DNAに結合する二段階機構が明らかになった。(広大・小松)
(2)情報伝達
・あらかじめの低線量放射線の線量と、次の致死線量の被曝までのインターバルがマウス個体における適応応答に重要であることを明らかにした。(奈良医大・大西)
・極低線量の放射線は細胞核由来の情報伝達経路は活性化せず細胞膜由来のERK1/2を経由する細胞内シグナル伝達系を活性化し、ヒストンH3のリン酸化を起こすことがわかった。(長崎大・渡辺)
(3)適応を含む機能発現
・放射線高感受性のマウス胸腺リンパ腫由来3SB細胞は、低線量照射後短時間の内にアポトーシスで死滅するが、線量率効果が見られなかった。(広大・鈴木)
・低線量率照射での生存率上昇は、KU70欠損では観察されず、RAD54及びATM欠損細胞では観察され、低線量率照射回復は相同組換えではなく非相同組換えが主要な経路であることを明らかにした。(京大・内海)
・p53依存性アポトーシスを介した組織修復機構がDNA修復機構と協調して働けば、低線量(率)放射線による少々の遺伝子損傷は効率的に排除され、その蓄積は起こらないことを明らかにした。(産業医大・法村)
・低線量放射線により誘発される突然変異の質は、生殖腺細胞では欠失型変異の誘発が少なく、体細胞組織とは異なるDNA修復機構をもっていることが示唆された。(東北大・小野)
・低線量放射線照射した精子のDNA損傷は遅延的に体細胞突然変異を誘発した。(京大・丹羽)

Research Products

• [Publications] Takahashi, A. et al.: "Radiation-induced apoptosis in scid mice spleen after low dose irradiation"Adv. Space Res.. (in press). (2003)
• [Publications] Yasumoto, J. et al.: "Analysis of apoptosis-related gene expression after X-ray irradiation in human tongue squamous cell carcinoma cells harboring wild-type or mutation-type p53 gene"J. Rad. Res.. (in press). (2003)
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• [Publications] Masunaga, S. et al.: "Usefulness of combined treatment with mild hyperthermia and/or tirapazamine in the treatment of solid tumors : its independence of pS3 status"Cancer Sci.. 94. 125-133 (2003)
• [Publications] Takahashi, A. et al.: "p53-Dependent hyperthermic enhancement of tumor growth inhibition by X-ray or carbon-ion beam irradiation"Int. J. Hyperthermia. 19. 145-153 (2003)
• [Publications] Takahashi, A. et al.: "Radiation-induced apoptosis in scid mouse spleen after low dose-rate irradiation"Int. J. Radiat. Biol.. 78. 689-693 (2002)
• [Publications] Masunaga, S. et al.: "Impact of pS3 status of the tumor cells on the effect of reactor neutron beam irradiation with emphasis on the response of intratumor quiescent cells"Jpn. J. Cancer Res.. 93. 1366-1377 (2002)
• [Publications] Asakawa, I. et al.: "Growth inhibition in transplanted human tongue tumors bearing different p53 gene status with X-ray or C-beam irradiation"Anticancer Res.. 22. 2037-2043 (2002)
• [Publications] Ohnishi, K. et al.: "Glycerol as a chemical chaperone enhanced radiation-induced apoptosis in anaplastic thyroid carcinoma cells"Mol. Cancer. 1. 4 (2002)
• [Publications] Ohnishi, T. et al.: "Glycerol restores heat-induced p53-dependent apoptosis of human glioblastoma cells bearing mutant p53"BMC Biotechnol.. 2. 6 (2002)
• [Publications] Ohnishi, K. et al.: "Transfection of mutant p53 gene depresses X-ray-or CDDP-induced apoptosis in a human squamous cell carcinoma of the head and neck"Apoptosis. 7. 367-372 (2002)
• [Publications] Takahashi, A. et al.: "Analysis of death pattern in cancer cells by using different kinds of LET radiation"Nippon Igaku Hoshasen Gakkai Zasshi. 62. 531-534 (2002)
• [Publications] Harima, Y. et al.: "Human papilloma virus (HPV) DNA associated with prognosis of cervical cancer after radiotherapy"Int. J. Radiat. Oncol. Biol. Phys.. 52. 1345-1351 (2002)
• [Publications] Takahashi, S. et al.: "Inhibition of DNA double strand break repair by antimony compounds"Toxicology. 180. 249-256 (2002)
• [Publications] Yoshida, M. et al.: "Roles of DNA-dependent protein kinase and ATM in cell-cycle-dependent radiation sensitivity in human cells"Int. J. Radiat. Biol.. 78. 503-512 (2002)
• [Publications] Ikehata, H., T. Ono: "Mutation induction with UVB in mouse skin epidermis is suppressed in acute high-dose exposure"Mutat. Res.. 508. 41-47 (2002)
• [Publications] Ono a, T. et al.: "Mutation theory of aging, assessed in transgenic mice and knockout mice"Mechanisms Ageing Dev.. 123. 1543-1552 (2002)
• [Publications] Wang, J. et al.: "Dosimetry evaluation of a whole body exposure setup for small animal at 2.45GHz"IEICE Transactions on Communications. E85-B. 2963-2965 (2002)
• [Publications] Jin, Z.H.et al.: "Effects of combined treatment with 40℃ hyperthermia and bleomycin on the accumulation of heat shock protein in murine L cells"Int. J. Oncol.. 20. 137-142 (2002)
• [Publications] Shao, C.L.et al.: "Nitric oxide-mediated bystander effect induced by heavy-ions in human salivary gland tumour cells"Int. J. Radiat. Biol.. 78. 837-844 (2002)
• [Publications] Kashino, G. et al.: "Preferential expression of an intact WRN gene in Werner Syndrome cell lines in which a normal chromosome 8 has been introduced"Biochem. Biophys. Res. Commun.. 289. 111-115 (2002)
• [Publications] Miyakoda, M. et al.: "Activation of ATM by heat shock and phosphorylation of p53"Oncogene. 21. 1090-1096 (2002)
• [Publications] Nakahata, K. et al.: "Heat shock induces centrosomal dysfunction, and causes non-apoptotic catastrophe in human tumor cells"Int. J. Hyperthermia. 18. 332-343 (2002)
• [Publications] Matsuda, N. et al.: "Possible involvement of extracellular signal-regulated kinases 1/2 in mitogenic response of periodontal ligament cells to enamel matrix derivative"Eur. J. Oral. Sci.. 110. 439-444 (2002)
• [Publications] Suzuki, K. et al.: "Delayed reactivation of p53 in the progeny of cells surviving ionaizing radiation"Cancer Res.. 63(in press). (2002)
• [Publications] Sasai, K. et al.: "Suppression of postmitochondrial signaling and delayed response to UV-induced nuclear apoptosis in HeLa cells"Jpn. J. Cancer Res.. 93. 275-283 (2002)
• [Publications] Ota, T.et al.: "Increased mitotic phosphorylation of histon H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability"Cancer Res.. 62. 5168-5177 (2002)
• [Publications] 鈴木文男 他: "放射線誘発アポトーシスにおける細胞種依存的な形質変化とcaspaseの活性化"広島医学. 55. 263-266 (2002)
• [Publications] Kato, F. et al.: "Role of p53 gene in apoptotic repair of genotoxic tissue damage in mice"J. Radiat. Res.. (in press). (2003)
• [Publications] Kunugita, N. et al.: "Micronuclei induced by low dose rate irradiation in early spermatids of p53 null and wild mice"J. Radiat. Res.. (in press). (2003)
• [Publications] Sakai, A. et al.: "Disruption of the p53 gene results in preserved trabecular bone mass and bone formation after mechanical unloading"J. Bone Miner. Res.. 17. 119-127 (2002)
• [Publications] 法村俊之: "放射線損傷の組織修復"Isotope News. 577. 2-6 (2002)
• [Publications] 法村俊之: "アポトーシスによる奇形抑制"小児内科. 34. 1818-1821 (2002)
• [Publications] Wakabayashi, Y. et al.: "Homologous deletions and poit mutations of the Rit1/Ncl11b gene in γ-ray induced mouse thymic lymphomas"Biochem. Biophys. Res. Commu.. 301. 598-603 (2002)
• [Publications] Shimura, T. et al.: "The novel surveilance mechanism of the Trp53-depenent S-phase checkpoint ensures chromosome damage repair and preimplantation-stage development of mouse embryos fertilized with X-irradiated sperm"Radiat. Res.. 158. 735-742 (2002)
• [Publications] Shiraishi, K. et al.: "Persistent induction of somatic reversions of the pink-eyed unstable mutation in F1 mice born to fathers irradiated at the spermatozoa stage"Radiat. Res.. 157. 661-667 (2002)
• [Publications] Shimura, T. et al.: "p53 dependent S phase damage checkpoint and pronuclear crosstalk in mouse zygotes with X-irradiated sperm"Mol. Cell. Biol.. 22. 2220-2228 (2002)
• [Publications] Tauchi, H. et al.: "Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells"Nature. 420. 93-98 (2002)
• [Publications] Kobayashi, J. et al.: "NBS1 localizes to γH2AX foci through interaction with the FHA/BRCT domain"Cuff. Biol.. 12. 1846-1851 (2002)
• [Publications] Tauchi, H. et al.: "Nijmegen breakage syndrome gene, NBS1, and moleculer links to factors for genome stability"Oncogene. 21. 8967-8980 (2002)
• [Publications] Watanabe, H. et al.: "Insulin-like growth factor I receptor is expressed at normal levels in Nijmegen breakage syndrome cells"Biochem. Biophys. Res. Commun.. 296. 62-66 (2002)
• [Publications] Tauchi, H. et al.: "Studies of mutagenesis caused by low dose rate tritium radiation using a novel hyper-sensitive detection system"Fus. Sci. Tech.. 41. 413-416 (2002)
• [Publications] 白石貴博 他: "ファンコニー貧血"遺伝子医学. 6. 62-72 (2002)
• [Publications] 大西 武雄 他: "低線量・低線量率放射線による生物影響発現"アイプリコム. 94 (2003)
• [Publications] 大西 健 他: "集学的癌治療の研究と臨床 (p53遺伝子を先行指標とする放射線・温熱治療のための基礎的研究)"篠原出版. 8(48-56) (2003)
• [Publications] 太田一郎 他: "癌放射線療法2000 (癌関連遺伝子からみたアポトーシス)"篠原出版. 12(203-214) (2002)
• [Publications] Takahashi, A. et al.: "DNA-PK activity acts a role on radioadaptation for radiation-induced apoptosis"Elsevier Science. 6(265-270) (2002)
• [Publications] Matsumoto, H. et al.: "Methods in Enzymology (Intercellular signaling mediated by nitric oxide in glioblastoma cells)"Cadenas, E., Packer, L. (Academic Press). 7(280-286) (2002)
• [Publications] 松本英樹 他: "集学的癌治療の研究と臨床 (集学的症治療における活性窒素種の役割)"加納永一 (篠原出版新社). 7(10-16) (2002)
• [Publications] 金 朝暉 他: "集学的癌治療の研究と臨床 (光力学的治療による制癌:沿革から現状まで)"加納永一 (篠原出版新社). 7(17-23) (2002)
• [Publications] 畑下昌範 他: "集学的癌治療の研究と臨床 (癌関連遺伝子と細胞周期)"加納永一 (篠原出版新社). 7(93-99) (2002)
• [Publications] 林幸子 他: "集学的癌治療の研究と臨床 (細胞および分子レベルにおけるハイパーサーミア)"加納永一 (篠原出版新社). 18(110-117) (2002)
• [Publications] 大坪俊雄 他: "集学的癌治療の研究と臨床 (癌化学療法剤殺細胞効果の温熱による増強)"加納永一 (篠原出版新社). 8(128-135) (2002)
• [Publications] 鈴木文男: "生物薬科学実験講座 (細胞の増殖・分化と成長因子)"井出利憲 編 (廣川書店)(印刷中). (2002)
• [Publications] Norimura, T. et al.: "Radiation and Homeostasis, International Congress Series 1236 (Essential role of p53 gene in apoptotic tissue repair for radiation-induced teratogenic injury)"T. Sugahara, O. Nikaido, O. Niwa (Eds.)(Elsevier Science). 7(423-429) (2002)