Radiation-induced long-lived radicals causing mutation and carcinogenesis

• Project/Area Number: 16101002
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Kyoto University
• Principal Investigator: WATANABE Masami Kyoto University, 原子炉実験所, 教授 (20111768)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Keiji 長崎大学, 大学院・医歯薬学総合研究科, 准教授 (00196809) ; KODAMA Seiji 大阪府立大学, 産学官連携機構, 教授 (00195744) ; KUMAGAI Jun 名古屋大学, 大学院・工学研究科, 准教授 (20303662) ; SHIMADA Yoshiya 放射線医学総合研究所, プロジェクトリーダー (10201550)
• Project Period (FY): 2004 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥101,270,000 (Direct Cost: ¥77,900,000、Indirect Cost: ¥23,370,000); Fiscal Year 2008: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2007: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2006: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2005: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2004: ¥26,390,000 (Direct Cost: ¥20,300,000、Indirect Cost: ¥6,090,000)
• Keywords: 放射線 / 突然変異 / 細胞がん化 / 長寿命ラジカル / 放射線発がん / 自然発がん / 染色体異数化 / ミトコンドリア / バイスタンダー効果 / ビタミンC / 細胞内酸化ラジカル / 染色体三倍体 / 細胞老化 / セミキセノンラジカル / 遺伝的不安定性 / 遅延型影響 / 情報伝達因子 / ESR解析 / システインラジカル / エピガロカテキン / X線 / 遠紫外線(UV-B) / 照射後処理

Research Abstract

放射線を照射された細胞に複数の長寿命ラジカル(LLR^*)が誘導されることがわかった。その代表的なものが、システイン残基を持つタンパク質に生じたスルフィニルラジカル(R-CH2-SO・)およびセミキセノンラジカルである。これらは、放射線被ばく後、1時間~10時間の間にミトコンドリアで誘導され、細胞内の高分子タンパクをゆっくりラジカル化することによって、細胞の様々な高度機能障害を生じさせることが明らかとなった。

Research Products

• [Journal Article] Introduction of a normal human chromosome 8 corrects abnormal phenotypes of Werner syndrome cells immortalized by expressing an hTERT gene (2009)
  • Author(s): Ariyoshi K, Suzuki K, Goto M, Oshimura M, Ishizaki K, Watanabe M, Kodama S
  • Journal Title: J. Radiat. Res. (in press)
  • NAID: 10025911840
• [Journal Article] Evaluation of the potential of hexamethylenetetramineas a combined agent with gamma-ray irradiation and cisplatin treatment in vivo, compared with tirapazamine (2009)
  • Author(s): Masunaga S, Tano K, Watanabe M, Kashino G, Suzuki M, Kinashi Y, Ono K, Nakamura J
  • Journal Title: British J Radiol Jan 19(Epub ahead of print)
• [Journal Article] Induction of DNA double-strand breaks and cellular migration through bystander effects in cells irradiated with the slit-type microplanar beam of the SPring-8 synchrotron (2009)
  • Author(s): Kashino G, Kondoh T, Nariyama N, Umetani K, Ohigashi T, Shinohara K, Kurihara A, Fukumoto M, Tanaka H, Maruhashi A, Suzuki S, Kinashi Y, Liu Yong, Masunaga S,Watanabe M, Ono K
  • Journal Title: Intern J Radiat Oncol Biol Phys (in press)
• [Journal Article] Usefulness of hexamethylenetetramine in combination with chemotherapy using free and pegylated liposomal doxorubicin in vivo, referring to the effect on quiescent cells (2009)
  • Author(s): Masunaga S, Kono K, Nakamura J, Tano K, Yoshida Y, Watanabe M, Kashino G, Suzuki M, Kinashi Y, and Ono K
  • Journal Title: Oncology Report 21 Pages: 1307-1312
• [Journal Article] The contribution of radiation-induced large deletion of the genome to chromosomal instability (2009)
  • Author(s): Toyokuni H, Maruo A, Suzuki K, Watanabe M
  • Journal Title: Radiat Res 171 Pages: 198-203
• [Journal Article] Intervention of oxygen-control ability to radiation sensitivity, cell aging and cell transformation (2009)
  • Author(s): Yoshii H, Watanabe M
  • Journal Title: J RadiatRes (Tokyo) 50 Pages: 127-137
  • NAID: 10025911412
• [Journal Article] Phosphorylated H2AX foci in tumor cells have no correlation with their radiation sensitivities (2009)
  • Author(s): Yoshikawa T, Kashino G, Ono K, Watanabe M
  • Journal Title: J Radiat Res(Tokyo) 50 Pages: 151-160
  • NAID: 10025911507
• [Journal Article] Intervention of oxygen-control ability to radiation sensitivity, cell aging and cell transformation. (2009)
  • Author(s): Yoshii H, Watanabe M
  • Journal Title: J Radiat Res (Tokyo) 50 Pages: 127-137
  • NAID: 10025911412
  • Peer Reviewed
• [Journal Article] Different involvement of radical species in irradiated and bystander cells. (2009)
  • Author(s): Harada T, Kashino G, Suzuki K, Matsuda N, Kodama S, Watanabe M
  • Journal Title: Int J Radiat Biol 379 Pages: 809-814
  • Peer Reviewed
• [Journal Article] Phosphorylated H2AX foci in tumor cells have no correlation with their radiation sensitivities. (2009)
  • Author(s): Yoshikawa T, Kashino G, Ono K, Watanabe M
  • Journal Title: J Radiat Res(Tokyo) 50 Pages: 151-160
  • NAID: 10025911507
  • Peer Reviewed
• [Journal Article] The contribution of radiation-induced large deletion of the genome to chromosomal instability. (2009)
  • Author(s): Hamamoto T, Suzuki K, Yamauchi M, Kodama S, Sasaki H, Watanabe M
  • Journal Title: Int J Hyperthermia 24 Pages: 415-425
  • Peer Reviewed
• [Journal Article] Introduction of a normal human chromosome 8 corrects abnormal phenotypes of Werner syndrome cells immortalized by expressing (2009)
  • Author(s): Ariyoshi K, Suzuki K, Goto M, Oshimura M, Ishizaki K, Watanabe M
  • Journal Title: J Radiat Res(Tokyo) (in press)
  • Peer Reviewed
• [Journal Article] The contribution of radiation-induced large deletion of the genome to chromosomal instability. (2009)
  • Author(s): Kashino G, Kondoh T, Watanabe M, ほか3名
  • Journal Title: Intern J Radiat Oncol Biol Phys (in press)
  • Peer Reviewed
• [Journal Article] Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling. (2009)
  • Author(s): Yamauchi M, Oka Y, Kodama S, Watanabe M, Suzuki K, ほか5名
  • Journal Title: DNA Repair(Amst) 7 Pages: 405-417
  • NAID: 120006983929
  • Peer Reviewed
• [Journal Article] Establishment of ponasterone A-inducible the wild-type p53 protein-expressing clones from HSC-1 cells, cell growth suppression by p53 expression and the suppression mechanism (2008)
  • Author(s): Hori M, Suzuki K, Udono MU, Yamauchi M,Mine M, Watanabe M, Kondo S, Hozumi Y
  • Journal Title: Arch Dermatol Res Nov 14
• [Journal Article] p53 status-dependent sensitization of humantumour cells to hyperthermia by plant flavonol (2008)
  • Author(s): Hamamoto T, Suzuki K, Yamauchi M,Kodama S, Sasaki H, Watanabe M
  • Journal Title: Int J Hyperthermia 24 Pages: 415-425
• [Journal Article] Growth of persistent foci of DNA damage checkpoint factors is essential for amplification of G1 checkpoint signaling (2008)
  • Author(s): Yamauchi M, Oka Y, Yamamoto M, Niimura K, Uchida M, Kodama S, Watanabe M, Sekine I, Yamashita S, Suzuki K
  • Journal Title: DNA Repair(Amst) 7 Pages: 405-417
  • NAID: 120006983929
• [Journal Article] Different involvement of radical species in irradiated and bystander cells (2008)
  • Author(s): Harada T, Kashino G, Suzuki K, Matsuda N, Kodama S, Watanabe M
  • Journal Title: Int J Radiat Biol 84 Pages: 809-814
• [Journal Article] Generation and characterization of cells that can be conditionally depleted of mitochondrial SOD2 (2008)
  • Author(s): Takada S, Inoue E, Tano K, Yoshii H, Abe T, Yoshimura A, Akita M, Tada S, Watanabe M, Seki M, Enomoto T
  • Journal Title: Biochem Biophys Res Commun 379 Pages: 233-238
• [Journal Article] Alteration of p53-binding protein 1 expression during skin carcinogenesis : association with genomic instaibility (2008)
  • Author(s): Naruke Y, Nakashima M, Suzuki K, Matsuu-Matsuyama M, Shichijo K, Kondo H, Sekine I
  • Journal Title: Cancer Sci 99(5) Pages: 946-951
• [Journal Article] Foci formation of p53-binding protein 1 in thyroid tumors:activation of genomic instaibility duringthyroid carcinogenesis (2008)
  • Author(s): Nakashima M, Suzuki K, Meirmanov S, Naruke Y, Matsuu-Matsuyama M, Shichijo K, Saenko V, Kondo H, Hayashi T, Ito M,Yamashita S, Sekine I
  • Journal Title: Int J Cancer 122(5) Pages: 1082-1088
• [Journal Article] Generation and characterization of cells that can be conditionally depleted of mitochondrial S0D2. (2008)
  • Author(s): Takada S, Inoue E, Tano K, Watanabe M, Enomoto T, ほか6名
  • Journal Title: Biochem Biophys Res Commun 379 Pages: 233-238
  • Peer Reviewed
• [Journal Article] Transmission of Genomic Instability from a Single Irradiated Human Chromosome to the Progeny of Unirradiated Cells. (2007)
  • Author(s): Mukaida N, Kodama S, Suzuki K, Oshimura M, Watanabe M
  • Journal Title: Radiation Res 167 Pages: 675-681
  • Peer Reviewed
• [Journal Article] Correlation of malignant phenotypes of human tumour cell lines with augmented expression of HSP72 protein measured by laser scanning cytometry. (2007)
  • Author(s): Hamamoto, T, Suzuki, K, Kodama S, Sasaki, H, Abe, K, Hayashi, T, Watanabe, M
  • Journal Title: Int J Hyper 23 Pages: 363-370
  • Peer Reviewed
• [Journal Article] Effective suppression of bystander effects by DMSO treatment of irradiated CHO cells. (2007)
  • Author(s): Kashino G, Prise KM, Suzuki K, Matsuda N, Kodama S, Suzuki M, Nagata K, Kinashi Y, Masunaga S, Ono K, Watanabe M
  • Journal Title: J Radiat Res 48 Pages: 327-333
  • NAID: 110006343945
  • Peer Reviewed
• [Journal Article] Radiation induced bystander sugnals are independent of DNA damage and DNA repair capacity of the irradiated cells. (2007)
  • Author(s): Kashino G, Suzuki K, Matsuda N, Kodama S, Ono K, Watanabe M, Rrise KM
  • Journal Title: Mutat. Res. (in press)
• [Journal Article] Transmission of Genomic Instability from a Single Irradiated Human Chromosome to the Progeny of Unirradiated Cells (2007)
  • Author(s): Mukaida N, Kodama S, Suzuki K, Oshimura M, Watanabe M
  • Journal Title: Radiat. Res. (in press)
• [Journal Article] Histone H2AX phosphorylation in normal human cells irradiated with focused ultrasoft X rays : evidence for chromatin movement during repair (2006)
  • Author(s): Hamada N, Schettino G, Kashino G, Vaid M, Suzuki K, Kodama S, Vojnovic B, Folkard M, Watanabe M, Michael BD, Prise KM
  • Journal Title: Radiat. Res. 166 Pages: 31-38
• [Journal Article] Phosphorylated histone H2AX foci persist on rejoined mitotic chromosomes in normal human diploid cells exposed to ionizing radiation (2006)
  • Author(s): Suzuki M, Suzuki K, Kodama S, Watanabe M
  • Journal Title: Radiat. Res. 165(3) Pages: 265-276
• [Journal Article] Delayed activation of DNA damage checkpoint and radiation-induced genomic instability (2006)
  • Author(s): Suzuki K, Ojima M, Kodama S, Watanabe M
  • Journal Title: Mutat. Res. 597 Pages: 73-77
• [Journal Article] Interstitial chromatin alteration causes persistent p53 activation involved in the radiation-induced senescence-like growth arrest (2006)
  • Author(s): Suzuki M, Suzuki K, Kodama S, Watanabe M
  • Journal Title: Biochem. Biophys. Res. Commun. 340(1) Pages: 145-150
• [Journal Article] The higher lethality of UVB radiation to cultured human cells is associated with the specific activation of a DNA damage-independent signaling pathway. (2006)
  • Author(s): Horikawa-Miura, M., Yoshida, M., Okumura, Y., Mori, T., Watanabe, M.
  • Journal Title: Radiat.Res. (in press)
• [Journal Article] Cellular and molecular effects for mutation induction in normal human cells irradiated with accelerated neon ions. (2006)
  • Author(s): Suzuki M, Tsuruoka C, Kanai T, Kato T, Yatagai F, Watanabe, M.
  • Journal Title: Mutat Res. 594 Pages: 86-92
• [Journal Article] Histone H2AX phosphorylation in normal human cells irradiated with focused ultrasoft X-rays : Evidence for chromatin movement during repair. (2006)
  • Author(s): Hamada, N., Schettino, G., Kashino, G., Vaid, M., Suzuki, K., Kodoma, S., Vojnovic, B., Folkard, M., Watanabe, M., Michael B.
  • Journal Title: Radiat.Res. (In press)
• [Journal Article] Qualitative and quantitative analysis of phosphorylated ATM foci induced by low dose ionizing radiation. (2006)
  • Author(s): Suzuki, K., Okada, Yamauchi, M., Oka, Y., Kodama, S., Watanabe, M.
  • Journal Title: Radiat.Res. (In press)
• [Journal Article] Phosphorylated histone H2AX foci persist on rejoined mitotic chromosomes in normal human diploid cells exposed to ionizing radiation (2006)
  • Author(s): Suzuki, M., Suzuki, K., Kodama, S., Watanabe, M.
  • Journal Title: Radiat.Res. 165・3 Pages: 269-276
• [Journal Article] Evidence for induction of DNA double strand breaks in the bystander response to targeted soft X-rays in CHO cells. (2005)
  • Author(s): Kashino G, Prise KM, Schettino G, Folkard M, Vojnovic B., Michael BD, Suzuki K, Kodama S, Watanabe M.
  • Journal Title: Mutat.Res. 556・1-2 Pages: 209-215
  • NAID: 130005443043
• [Journal Article] Interstitial chromatin alteration causes persistent p53 activation involved in the radiation-induced senescence-like growth arrest. (2005)
  • Author(s): Suzuki, M., Suzuki, K., Kodama, S., Watanabe, M.
  • Journal Title: Biochem.Biophys.Res.Commun. 340・1 Pages: 145-150
• [Journal Article] Exogenous expression of exonuclease domain-deleted WRN interferes with the repair of radiation-induced DNA damages (2005)
  • Author(s): Kashino, G, Kodama, S., Suzuki, K., Matsumoto, T., Watanabe, M.
  • Journal Title: J.Radiat.Res. 46・6 Pages: 407-414
  • NAID: 110004061516
• [Journal Article] Post-stress metabolism involves umbelliferone production in anthocyanin-producing and nonproducing cells of Glehnia littoralis suspension cultures. (2005)
  • Author(s): Ishikawa, A., Kitamura, Y., Ozeki, Y., Itoh, Y., Yamada, A., Watanabe, M.B.
  • Journal Title: J.Plant.Physiol. 162・6 Pages: 703-710
• [Journal Article] Differences in Effects of Oncogenes on Sensitivity to Anticancer Drugs (2005)
  • Author(s): Hamamoto, T., Suzuki, K., Sasaki, H., Ichikawa, M., Kodama, S., Watanabe, M.
  • Journal Title: J.Radiat.Res. 46・2 Pages: 197-203
  • NAID: 110004041116
• [Journal Article] Induction of Micronuclei in CHO Cells by Bleomycin but not by X-irradiation is Decreased by Treatment with HMG-CoA Reductase Inhibitors. (2005)
  • Author(s): Iwashita, J., Kodama, S., Nakashima, M., Sasaki, H., Taniyama, K., M.Watanabe
  • Journal Title: J.Radiat.Res. 46・2 Pages: 191-195
  • NAID: 110004041115
• [Journal Article] Abnormal stability of wild-type p53 protein in a human lung carcinoma cell line. (2005)
  • Author(s): Yamauchi, M., Suzuki, K., Kodama, S., Watanabe, M.
  • Journal Title: Biochem.Biophys.Res.Commun. 330・2 Pages: 483-488
• [Journal Article] Radiation-induced DNA damage and delayed induced genomic instability (2004)
  • Author(s): Suzuki K, Ojima M, Kodama S, Watanabe
  • Journal Title: Oncogene 22 Pages: 6988-6993
• [Journal Article] Involvement of telomere dysfunction in the induction of genomic instability by radiation in scid mouse cells (2004)
  • Author(s): Urushibara A, Kodama S, Suzuki K, Desa M.B., Suzuki F, Tsutsui T, Watanabe M.
  • Journal Title: Biochem Biophys Res Commun. 313 Pages: 1037-1043
• [Journal Article] Involvement of reactive oxygen species (ROS) in the induction of genetic instability by radiation (2004)
  • Author(s): Tominaga, H., Kodama S, Matsuda, N., Suzuki, K., Watanabe, M.
  • Journal Title: Journal of Radiation Research 45 Pages: 181-188
  • NAID: 110002334513
• [Journal Article] Delayed induction of telomere instability in normal human fibroblast cells by ionizing radiation (2004)
  • Author(s): Ojima, M., Hamano, H., Suzuki, M., Suzuki, K., Kodama, S., Watanabe, M.
  • Journal Title: Journal of Radiation Research 45 Pages: 105-110
  • NAID: 110004040999
• [Journal Article] X-ray-induced telomeric instability in Atm-deficient mouse cells (2004)
  • Author(s): Undarmaa, B., Kodama, S., Suzuki, K., Niwa, O., Watanabe, M.
  • Journal Title: Biochem Biophys Res Commun. 315 Pages: 51-58
• [Journal Article] Evidence for induction of DNA double strand breaks in the bystander response to targeted soft X-rays in CHO cells. (2004)
  • Author(s): Kashino G, Prise KM, Schettino G, Folkard M, Vojnovic B, Michael BD, Suzuki K, Kodama S, Watanabe M.
  • Journal Title: Mutation Res. 556 Pages: 209-215
  • NAID: 130005443043
• [Presentation] The main route of radiation-induced carcinogenesis is the same as that of natural carcinogenesis. (2009)
  • Author(s): Watanabe M, Yoshii H, Watanabe K
  • Organizer: The 54th Annual Meeting of the Radiation Research
  • Place of Presentation: Boston, USA
• [Presentation] Is there a non-targeted route in radiation carcinogenesis? Is There a Non-targeted Route in Radiation Carcinogenesis Process? -Candidate Playing an Important Role (2008)
  • Author(s): Watanabe M
  • Organizer: In an International Symposium of Kyoto University RRI
  • Place of Presentation: Kumatori, Japan(Invited)
  • Year and Date: 2008-12-18
• [Presentation] How to set Ikaros up as the villain in radiation lymphoma-genesis (2008)
  • Author(s): Simada Y
  • Organizer: In an International Symposium of Kyoto University RRI
  • Place of Presentation: Kumatori, Japan(Invited)
  • Year and Date: 2008-12-18
• [Presentation] Amplification of intranuclear DNA damaging signal reduces genome reorganization involved in radiation-induced carcinogenesis (2008)
  • Author(s): Suzuki K
  • Organizer: in an International Symposium of Kyoto University RRI
  • Place of Presentation: Kumatori, Japan(Invited)
  • Year and Date: 2008-12-18
• [Presentation] A Role of Chromosomal Instability in Carcinogenesis and Cellular Senescence (2008)
  • Author(s): Kodama S
  • Organizer: in an International Symposium of Kyoto University RRI
  • Place of Presentation: Kumatori, Japan(Invited)
  • Year and Date: 2008-12-18
• [Presentation] Main route of radiation-carcinogenesis is DNA damage-independent pathways (2008)
  • Author(s): Watanabe M, Yoshii H, Watanabe K, Suzuki K, Kodama S, Kumagai J
  • Organizer: International congress of Radiation Research
  • Place of Presentation: San Fransisco
  • Year and Date: 2008-08-24
• [Presentation] Mitchondria and cell transformation, In an International Symposim on "The participation of the energy metabolic system in radiation carcinogenesis process" (2008)
  • Author(s): Yoshi H, Watanabe M
  • Organizer: The 51th Annual Meeting of Japanese Radiation Research Society
  • Place of Presentation: Kokura(Invited)
• [Presentation] Mutagenic slow releasing long-lived radicals are produced from dysfunctional mitochondria (2008)
  • Author(s): Kumagai J, Miura K, Kashino, Watanabe M
  • Organizer: In an International Symposim on "The participation of the energy metabolic systemin radiation carcinogenesis process",The 51thAnnual Meeting of Japanese RadiationResearch Society
  • Place of Presentation: (Invited)
• [Presentation] The mainroute of radiation-induced carcinogenesis isthe same as that of natural carcinogenesis (2008)
  • Author(s): Watanabe M, Yoshii H, Watanabe K
  • Organizer: The 54th Annual Meeting of the Radiation Research Society
  • Place of Presentation: Boston, USA(Invited)
• [Presentation] Target of radiation carcinogenesis is protein (2008)
  • Author(s): Watanabe M
  • Organizer: The First InternationalSymposium on the Establishment of a NewDiscipline" Medical Care for Hibakusha"
  • Place of Presentation: Nagasaki(Invited)
• [Presentation] 特別講演 ; 放射線発がんの新しい機構-DNA損傷を起源としない経路の (2008)
  • Author(s): 渡邊正己
  • Organizer: 第14回放射線癌治療増感研究会(招待講演)
  • Place of Presentation: 鈴鹿
• [Presentation] 細胞がん化には倍数化より異数化が深く関与する (2008)
  • Author(s): 渡漫正己, 吉居華子
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] ミトコンドリア機能と細胞がん化 (2008)
  • Author(s): 渡洛正己, 吉居華子
  • Organizer: 第8回日本ミトコンドリア学会
  • Place of Presentation: 東京
• [Presentation] Plenary Lecture I, The mainroute of radiation carcinogenesis-The firsttarget of radiation-induced carcinogenesis isnot DNA (2007)
  • Author(s): Watanabe M
  • Organizer: International Symposium of Korea University Brain Korea 21 Program for Biomedical Sciences
  • Place of Presentation: Seoul(Invited)
  • Year and Date: 2007-01-23
• [Presentation] Main route of radiation-carcinogenesis is DNA damage- independentpathway. (2007)
  • Author(s): Watanabe M, Yoshii H, Watanabe K, Suzuki K, Kodama S, Kumagai J
  • Organizer: 13th International Congress of Radiation Research
  • Place of Presentation: San Francisco(Invited)
• [Book] 突然変異は放射線発がんの主因ではない、モデルが拓く放射線防護研究の新たな展開-第一回放射線防護研究センターシンポジウム(根井充編)(64-70) (2007)
  • Author(s): 渡辺正己
  • Publisher: 放射線医学総合研究所
• [Book] 放射線発がんの主たる標的はDNAではない可能性が高い(25(5)) (2007)
  • Author(s): 渡辺正己
  • Publisher: ESI-NEWS
• [Remarks]
  • URL: http://www.rri.kyoto-u.ac.jp/rb-rri/
• [Remarks]
  • URL: http://www.rri.kyoto-u.ac.jp/rb-rri/
• [Remarks]
  • URL: http://www.rri.kyoto-u.ac.jp/rb-rri/