Clarification of the mechanism of germline mutation occurrence that causes familial tumor

• Project/Area Number: 15H04298
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Kyushu University
• Principal Investigator: SAKUMI KUNIHIKO 九州大学, 生体防御医学研究所, 准教授 (50211933)
• Co-Investigator(Renkei-kenkyūsha): OKA Sugako 九州大学, 生体防御医学研究所, 特任助教 (80467894)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 生殖細胞突然変異 / がんと遺伝 / ミューテーターマウス / エクソーム解析 / 8-オキソグアニン / MTH1 / OGG1 / MUTYH / 遺伝性腫瘍 / 酸化ストレス / DNA修復

Outline of Final Research Achievements

To clarify the mechanism of germline mutation occurrence that causes familial tumor, we analyzed Mth1/Ogg1/Mutyh triple KO (TOY-KO) mice, which feature a mutator phenotype. At first we screened the causative gene of familial tumor observed in the TOY-KO mouse pedigree by whole exome sequence analysis, and determined a candidate gene. We established and cryopreserved a new TOY-KO mouse line. In addition to the TOY-KO mouse, we established TO-, OY-, TY-, T-, O- and Y-KO mice in the same genetic back ground. Using new TOY-KO mice, spontaneous tumorigenesis experiment has performed (continues). In these mice, we observed accumulation of mutations in nuclear genome, but not in the mitochondrial genome.

Research Products

• [Journal Article] Co-regulation of Cxcl1 and versican in the inflammatory response to UVB induced reactive oxygen species in skin photo-tumorigenesis. (2017)
  • Author(s): Takemori C, Kunisada M, Yogianti F, Oka S, Sakumi K, Ono R, Nakabeppu Y, Nishigori C.
  • Journal Title: J Dermatol Sci Volume: 85 Issue: 2 Pages: 140-143
  • DOI: 10.1016/j.jdermsci.2016.10.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. (2017)
  • Author(s): Li GH, Akatsuka S, Chew SH, Jiang L, Nishiyama T, Sakamoto A, Takahashi T, Futakuchi M, Suzuki H, Sakumi K, Nakabeppu Y, Toyokuni S.
  • Journal Title: Pathol Int. Volume: 67 Issue: 11 Pages: 564-574
  • DOI: 10.1111/pin.12598
  • NAID: 120006382249
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 生殖細胞突然変異 (2017)
  • Author(s): 作見 邦彦
  • Journal Title: BIO Clinica Volume: 32 Pages: 90-96
  • Acknowledgement Compliant
• [Journal Article] 生殖細胞突然変異 (2017)
  • Author(s): 作見 邦彦
  • Journal Title: 地域ケアリング Volume: 19 Pages: 89-95
  • Acknowledgement Compliant
• [Journal Article] Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells. (2016)
  • Author(s): Y. Yoneshima, N. Abolhassani, T. Iyama, K. Sakumi, N. Shiomi, M. Mori, T. Shiomi, T. Noda, D. Tsuchimoto, and Y. Nakabeppu
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 32849-32849
  • DOI: 10.1038/srep32849
  • Peer Reviewed / Open Access
• [Journal Article] PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E-deficient mice. (2016)
  • Author(s): K. Torisu, X. Zhang, M. Nonaka, T. Kaji, D. Tsuchimoto, K. Kajitani, K. Sakumi, T. Torisu, K. Chida, K. Sueishi, M. Kubo, J. Hata, T. Kitazono, Y. Kiyohara, and Y. Nakabeppu
  • Journal Title: Genes Cells Volume: 21 Issue: 10 Pages: 1030-1048
  • DOI: 10.1111/gtc.12402
  • Peer Reviewed / Open Access
• [Journal Article] Galectin-1 and galectin-3 as key molecules for peripheral nerve degeneration and regeneration. (2016)
  • Author(s): K. Sango, S. Takaku, N. Niimi, T. Kadoya, H. Yako, M. Tsukamoto, K. Sakumi, Y. Nakabeppu, and H. Horie
  • Journal Title: AIMS Molecular Science Volume: 3 Issue: 3 Pages: 325-337
  • DOI: 10.3934/molsci.2016.3.325
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer's disease. (2016)
  • Author(s): S. Oka, J. Leon, K. Sakumi, T. Ide, D. Kang, F.M. LaFerla, and Y. Nakabeppu
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 37889-37889
  • DOI: 10.1038/srep37889
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nucleotide excision repair of oxidised genomic DNA is not a source of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (2016)
  • Author(s): Evans, M. D., Misty, V., Singh, R., Gackowski, D., Rozalski, R., Siomek, A., Phillips, D. H., Zuo, J., Mullenders, L., Pines, A., Nakabeppu, Y., Sakumi, K., Sekiguchi, M., Tsuzuki, T., Bignami, M., Farmer, P. B., Oliski, R., Cooke, M. S.
  • Journal Title: Free Radic. Biol. Med. Volume: 99 Pages: 385-391
  • DOI: 10.1016/j.freeradbiomed.2016.08.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions (2016)
  • Author(s): Julio, Leon, Sakumi Kunihiko, Castillo Erika, Sheng Zijing, Oka Sugako, Nakabeppu Yusaku.
  • Journal Title: Scientific Reports Volume: 25 Issue: 1 Pages: 22086-22086
  • DOI: 10.1038/srep22086
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] イノシン三リン酸分解酵素ITPA欠損症のモデルマウス作製と解析 (2017)
  • Author(s): 土本 大介, 古賀 祐一郎, 米嶋 康臣, 浅田 真司, 作見 邦彦, 中別府 雄作
  • Organizer: 平成28年度「先端モデル動物支援プラットフォーム成果発表会」
  • Place of Presentation: 大津
  • Year and Date: 2017-02-06
• [Presentation] Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH-deficient mice (2017)
  • Author(s): 赤塚 慎也, 李 光華, 作見 邦彦, 中別府 雄作, 二口 充, 鈴木 拓, 豊國 伸哉
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Somatic mutation analysis of oxodative stress-induced colon cancer model (2017)
  • Author(s): 大野 みずき, 鷹野 典子, 高野 京子, 作見 邦彦, 中別府 雄作, 中津 可道, 續 輝久
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 遺伝性大腸がんモデルマウスにおける酸化ストレス誘発発がんと体細胞突然変異の解析 (2017)
  • Author(s): 大野 みずき, 鷹野 典子, 佐々木 史子, 作見 邦彦, 中別府 雄作, 中津 可道, 續 輝久
  • Organizer: 日本放射線影響学会 第60回大会
• [Presentation] 遺伝性疾患自然発症モデル動物としてのmutator mouse (2017)
  • Author(s): 作見 邦彦, 大野 みずき, 中別府 雄作
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] マウス脳におけるFOSBアイソフォームによる遺伝子発現調節機構の解析 (2016)
  • Author(s): 加藤木 敦央, 大西 克典, 作見 邦彦, 中別府 雄作
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] アルツハイマー病進展における核あるいはミトコンドリアDNA中に蓄積した8-oxoguanineの役割 (2016)
  • Author(s): 岡 素雅子, 盛 子敬, フリオ レオン, 土本 大介, 作見 邦彦, 中別府 雄作
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] イノシン三リン酸分解酵素ITPA欠損の哺乳動物細胞およびマウス中枢神経系への影響の解析 (2016)
  • Author(s): 土本 大介, 米嶋 康臣, 古賀 祐一郎, Nona Abolhassani, 猪山 輝昭, 浅田 真司, 作見 邦彦, 塩見 尚子, 森 雅彦, 塩見 忠博, 野田 哲生, 中別府 雄作
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Regulation of base substitution mutagenesis and chromosome recombination induced by 8-oxoguanine accumulated in the genome (2016)
  • Author(s): Ohno Mizuki, Kunihiko Sakumi, Yusaku Nakabeppu
  • Organizer: The 39th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Impaired hippocampal neurogenesis in App-knock-in model mice of Alzheimer’s disease (2016)
  • Author(s): Guianfranco Mazzei, Erika Castillo, Kunihiko Sakumi, Takashi Saito, Takaomi Saido, Yusaku Nakabeppu
  • Organizer: The 39th Annual Meeting of the Molecular Biology Society of Japan
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Comparative gene expression profiling of triple-transgenic 3xTg-AD and APP-knock-in model mice of Alzheimer’s disease (2016)
  • Author(s): Erika Castillo, Julio Leon, Nona Abolhassani, Guianfranco Mazzei, Kunihiko Sakumi, Takashi Saito, Takaomi Saido, Yusaku Nakabeppu
  • Organizer: The 46th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Cell death induced by MUTYH-initiated base excision repair plays a role in p53-mediated tumor suppression (2016)
  • Author(s): 岡 素雅子、フリオ レオン、土本 大介、作見 邦彦、中別府 雄作
  • Organizer: 平成 27 年度「個体レベルでのがん研究支援活動」 ワークショップ
  • Place of Presentation: 大津
  • Year and Date: 2016-02-03
• [Presentation] 8-オキソグアニンに起因する生殖細胞突然変異と家族性腫瘍 (2016)
  • Author(s): 作見 邦彦
  • Organizer: 平成 27 年度「個体レベルでのがん研究支援活動」 ワークショップ
  • Place of Presentation: 大津
  • Year and Date: 2016-02-03
• [Presentation] 生殖細胞自然突然変異の新規発生と変異アリールの伝達 (2015)
  • Author(s): 作見 邦彦, 大野 みずき, 古市 正人, 續 輝久, 中別府 雄作
  • Organizer: 第44回 日本環境変異学会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-27
• [Presentation] MUTYHによる塩基除去修復過程に依存して誘導される細胞死はp53の発がん抑制機構の１つとして機能する (2015)
  • Author(s): 岡 素雅子, フリオ レオン, 土本 大介, 作見 邦彦, 中別府 雄作
  • Organizer: 第44回 日本環境変異学会
  • Place of Presentation: 福岡
  • Year and Date: 2015-11-27
• [Presentation] 8-Oxoguanine accumulated in mitochondrial DNA disturbs neuritic regeneration of cultured adult mouse cortical neurons under conditions of oxidative stress (2015)
  • Author(s): Julio Leon, Kunihiko Sakumi, Sugako Oka, Erika Castillo, Yusaku Nakabeppu
  • Organizer: 45th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] 8-oxoguanine causes spontaneous de novo germline mutations in mice (2015)
  • Author(s): Kunihiko Sakumi, Mizuki Ohno, Masato Furuichi, Teruhisa Tsuzuki, Yusaku Nakabeppu
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 活性酸素によるDNA損傷が引起こすさまざまな生命現象： 突然変異から神経変性まで (2015)
  • Author(s): 中別府 雄作, 岡 素雅子, 盛 子敬, 大野 みずき, 土本 大介, 作見 邦彦
  • Organizer: 第17回 日本進化学会年大会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-20
  • Invited
• [Presentation] The role of MUTYH in the oxidative stress-induced mutagenesis and tumorigenesis in the mouse intestine (2015)
  • Author(s): Mizuki Ohno, Noriko Takano, Kunihiko Sakumi, Ryutaro Fukumura, Yuki Iwasaki, Toshimichi Ikemura, Yoichi Gondo, Yusaku Nakabeppu, Yoshimichi Nakatsu, Teruhisa Tsuzuki
  • Organizer: The Zing conference on “Genomic Integrity"
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2015-08-01
  • Int'l Joint Research / Invited
• [Presentation] Cortical neurons isolated from adult Mth1/Ogg1-double-knockout mouse exhibit impaired neurite regeneration under conditions of oxidative stress (2015)
  • Author(s): Julio Jesusu Leon Incio, Kunihiko Sakumi, Sugako Oka, Erika Castillo, Yusaku Nakabeppu
  • Organizer: The 38th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] MUTYH-dependent programmed cell death triggered by 8-oxoguanine and its implication in tumor suppression and neurodegeneration (2015)
  • Author(s): Yusaku Nakabeppu, Sugako Oka, Zijing Sheng, Kunihiko Sakumi
  • Organizer: 15th International Congress of Radition Research: ICRR2015
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2015-05-25
  • Int'l Joint Research / Invited
• [Presentation] Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs (2015)
  • Author(s): Sugako Oka, Ohno Mizuki, Daisuke Tsuchimoto, Kunihiko Sakumi, Yusaku Nakabeppu
  • Organizer: BIT’ 8th, Annual World Cancer Congress-2015
  • Place of Presentation: Beijing, China
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Remarks] 九州大学生体防御医学研究所脳機能制御学分野
  • URL: http://www.bioreg.kyushu-u.ac.jp/nfg/index.html