酸化的ストレスによる細胞死と消化管がん抑制機構におけるMUTYHの働き

• Project/Area Number: 18013038
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: 中別府 雄作 Kyushu University, 生体防御医学研究所, 教授 (30180350)
• Co-Investigator(Kenkyū-buntansha): 中津 可道 九州大学, 医学研究院, 准教授 (00207820)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥12,800,000 (Direct Cost: ¥12,800,000); Fiscal Year 2007: ¥6,500,000 (Direct Cost: ¥6,500,000); Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
• Keywords: 酸化ストレス / 8-オキソグアニン / 大腸腺腫症 / 発がん抑制 / 細胞死 / 核ゲノム / ミトコンドリアゲノム

Research Abstract

自然突然変異の主要な原因の1つである酸化塩基8-オキソグアニンがゲノムDNAに蓄積すると複製に伴い鋳型DNA鎖中の8-オキソクアニンに対してシンとアデニンが同程度に取り込まれる。我々は,核あるいはミトコンドリアゲノムDNA中に一定量の8-オキソグアニン:アデニン対合が蓄積するとアデニンDNAグリコシラーセ活性を有するMUTYHが開始する塩基除去修復の過程デゲノム中にDNA一本鎖切断が蓄積し、結果として以下の異なる2つの経路で細胞死誘発されることを明らかにした。核ゲノムに8-オキソグアニン:アデニン対合が蓄積するとMUTYHにより開始される塩基除去修復の過程で蓄積したDNA一本鎖切断はポリ(ADP-リボース)ポリメラーゼ(PARP)により認識され、その結果活性化されたPARPに依存してApoptosis-inducing factorの核移行を伴う細胞死が誘発された。一方、ミトコンドリアゲノムに8-オキソグアニン:アデニン対合蓄積するとMUTYHに依存してミトコンドリアDNAが分解された。ミトコンドリアDNAの枯渇はミトコンドリア機能異常、すなわちATPの枯渇を引き起こし、ミトコンドリア膜の透過性の上昇をきたした。その結果、ミトコンドリアCaイオンが細胞質へ流出し、Ca依存性プロアーゼのカルパインの活性化に依存した細胞死誘発された。
MUTYH欠損マウスでは自然および酸化ストレス誘導性の突然変異率ともに野生型より顕著に上昇しており、さらに消化管腫瘍も多発することを明らかにした。また、APC遺伝子変異陰性の家族性大腸腺腫症家系におけるMUTYH変異のスクリrニングを行い、一例の家系においてMUTYHの磯能喪矢を引き起す劣性変異を国内で始めて同定した。
以上より、酸化ストレス下でゲノムDNAに蓄積した8-オキソグアニン:アデニン対合は突然変異を高頻度に生じるだけでなく,細胞死を誘発することが明らかになった.MUTYHは8-オキソグアニン:アデニン対合の蓄積を感知して細胞死のプログラムを起動させることでこのような突然変異を引き起こしやすい細胞を生体内から排除し、結果として発がんおよびがんの進展を抑制することが明らかになった。

Research Products

• [Journal Article] Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. (2008)
  • Author(s): Ichikawa, J, et. al.
  • Journal Title: DNA Repair 7(3) Pages: 418-430
  • Peer Reviewed
• [Journal Article] Two distinct pathways of cell death triggered by oxdative damage to nuclear and mitochondrial DNAs. (2008)
  • Author(s): Oka, S, et. al.
  • Journal Title: EMBO J. 27(2) Pages: 421-432
  • Peer Reviewed
• [Journal Article] Oxidative damage in nucleic acids and Pakinson's disease. (2007)
  • Author(s): Nakabeppu, Y, et. al.
  • Journal Title: J Neurosci Res. 85(5) Pages: 919-934
  • Peer Reviewed
• [Journal Article] Accumulation of 8-oxo-deoxyguanosine in cardiovascular tissues with the development of hypertension. (2007)
  • Author(s): Ohtsubo, T., et. al.
  • Journal Title: DNA Repair 6(6) Pages: 760-769
  • Peer Reviewed
• [Journal Article] RNA polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS. (2007)
  • Author(s): Kuraoka, I., et. al.
  • Journal Title: DNA Repair 6(6) Pages: 841-851
  • Peer Reviewed
• [Journal Article] Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. (2007)
  • Author(s): Tsuzuki, T., et. al.
  • Journal Title: Cancer Sci. 98(4) Pages: 465-470
  • Peer Reviewed
• [Journal Article] MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intstinal tumorigensis. (2007)
  • Author(s): Sakamoto, K., et. al.
  • Journal Title: Cancer Res. 67(14) Pages: 6599-6604
  • Peer Reviewed
• [Journal Article] Narrow-band UVB induces more carcinogenic skin tumors than broad-band UVB through the formation of cyclobutane pyrimidine dimer. (2007)
  • Author(s): Kunisada, M, et. al.
  • Journal Title: J Invest Dermatol. 127(12) Pages: 2865-2871
  • Peer Reviewed
• [Journal Article] APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. (2007)
  • Author(s): Guikema, J. E., et. al.
  • Journal Title: J Exp Med. 204(12) Pages: 3017-3026
  • Peer Reviewed
• [Journal Article] RNA Polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS. (2007)
  • Author(s): Kuraoka, I., Suzuki, K., Ito, S., Hayashida, M., Seah, J., Kwei, M., Ikegami, T., Handa, H., Nakabeppu, Y., Tanaka, K
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Accumulation of 8-oxo-deoxyguanosine in Cardiovascular Tissues with the Development of Hypertension. (2007)
  • Author(s): Ohtsubo, T., Ohya, Y., Nakamura, Y., Kansui, Y., Furuichi, M., Matsumura, K., Fujii, K., Iida, M., Nakabeppu, Y.
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. (2007)
  • Author(s): Tsuzuki, T., Nakatsu, Y., Nakabeppu, Y.
  • Journal Title: Cancer Sci. (印刷中)
• [Journal Article] Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A. (2007)
  • Author(s): Miyata, K., Yasukawa, T., Fukuda, M., Takeuchi, T., Yamazaki, K., Sakumi, K., Tamamori-Adachi, M., Ohnishi, Y., Ohtsuki, Y., Nakabeppu, Y., Kitajima, S., Onishi, S., Aso, T.
  • Journal Title: Cell Death Differ. 14・4 Pages: 716-726
• [Journal Article] Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein. (2006)
  • Author(s): Kamiya, H., Cadena-Amaro, C., Dugue, L., Yakushiji, H., Minakawa, N., Matsuda, A., Pochet, S., Nakabeppu, Y., Harashima, H.
  • Journal Title: J. Biochem. 140・6 Pages: 843-849
• [Journal Article] Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP. (2006)
  • Author(s): Nakamura, T., Kitaguchi, Y., Miyazawa, M., Kamiya, H., Toma, S., Ikemizu, S., Shirakawa, M., Nakabeppu, Y., Yamagata, Y.
  • Journal Title: Acta Crystallograph. Sect. F. Struct. Biol. Cryst. Commun. 62・12 Pages: 1283-1285
• [Journal Article] Angiotensin I-converting enzyme gene polymorphism modifies the smoking-cancer association : the Hisayama Study. (2006)
  • Author(s): Arima, H., Kiyohara, Y., Tanizaki, Y., Nakabeppu, Y., Kubo, M., Kato, I., Sueishi, K., Tsuneyoshi, M., Fujishima, M., Iida, M.
  • Journal Title: Eur. J. Cancer Prev. 15・3 Pages: 196-201
• [Journal Article] A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. (2006)
  • Author(s): Ohno, M., Miura, T., Furuichi, M., Tominaga, Y., Tsuchimoto, D., Sakumi, K., Nakabeppu, Y.
  • Journal Title: Genome Res. 16・5 Pages: 567-575
• [Journal Article] Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-like Protein(s) In the Rodent Neocortex. (2006)
  • Author(s): Powell, K.J., Binder, T.L., Hori, S., Nakabeppu, Y., R., D., Weinberger, Lipska, B.K., Robertson, G.S.
  • Journal Title: Neuropsychopharmacology 31・4 Pages: 700-711
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (2006)
  • Author(s): Yamaguchi, H., Kajitani, K., Dan, Y., Furuichi, M., Ohno, M., Sakumi, K., Kang, D., Nakabeppu, Y.
  • Journal Title: Cell Death Differ. 13・4 Pages: 551-563
• [Journal Article] Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. (2006)
  • Author(s): Nakabeppu, Y., Sakumi, K., Sakamoto, K., Tsuchimoto, D., Tsuzuki, T., Nakatsu, Y.
  • Journal Title: Biol. Chem. 387・4 Pages: 373-379
• [Journal Article] The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice. (2006)
  • Author(s): Arima, T., Yamasaki, K., John, R.M., Kato, K., Sakumi, K., Nakabeppu, Y., Wake, N., Kono, T.
  • Journal Title: Genomics 88・5 Pages: 650-658
• [Journal Article] Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. (2006)
  • Author(s): Thijssen, V.L., Postel, R., Brandwijk, R.J., Dings, R.P., Nesmelova, I., Satijn, S., Verhofstad, N., Nakabeppu, Y., Baum, L.G., Bakkers, J., Mayo, K.H., Poirier, F., Griffioen, A.W.
  • Journal Title: Proc. Natl. Acad. Sci. U. S. A. 103・43 Pages: 15975-15980
• [Journal Article] Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis. (2006)
  • Author(s): Akatsuka, S., Aung, T.T., Dutta, K.K., Jiang, L., Lee, W.H., Liu, Y.T., Onuki, J., Shirase, T., Yamasaki, K., Ochi, H., Naito, Y., Yoshikawa, T., Kasai, H., Tominaga, Y., Sakumi, K., Nakabeppu, Y., Kawai, Y., Uchida, K., Yamasaki, A., Tsuruyama, T., Yamada, Y., Toyokuni, S.
  • Journal Title: Am. J. Pathol. 169・4 Pages: 1328-1342
• [Journal Article] Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease. (2006)
  • Author(s): Arai, T., Fukae, J., Hatano, T., Kubo, S., Ohtsubo, T., Nakabeppu, Y., Mori, H., Mizuno, Y., Hattori, N.
  • Journal Title: Acta Neuropathol. 112・2 Pages: 139-145
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Sakai, Y., Oda, H., Yoshimura, D., Furuichi, M., Kang, D., Iwai, S., Hara, T., Nakabeppu, Y.
  • Journal Title: J. Mol. Med. 84・8 Pages: 660-670
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. (2006)
  • Author(s): Nakabeppu, Y., Kajitani, K., Sakamoto, K., Yamaguchi, H., Tsuchimoto, D.
  • Journal Title: DNA Repair 5・7 Pages: 761-772
• [Presentation] Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. (2008)
  • Author(s): Oka, S., et. al.
  • Organizer: The Joint Symposium of the 3rdInternational Symposium of Institutes Network and Hot Spring Harbor-Global COE Symposium
  • Place of Presentation: 別府
  • Year and Date: 2008-02-01
• [Presentation] Oxdative stress-induced intestinal tumorigenesis in mice with a targeted disruption of the Mutyh gene. (2007)
  • Author(s): 中津可道, ら、
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] Nitric oxide induces cell death through oxidation of mitochondrial deoxynucleotide pools. (2007)
  • Author(s): Ichikawa, J, et. al.
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-14
• [Presentation] ゲノムに蓄積した8-オキソグアニンは染色体組換えを誘発する。 (2007)
  • Author(s): 大野みずき, ら、
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] ITP結合タンパク質ITPBP1の生化学的特性の解析 (2007)
  • Author(s): 野中麻里, ら、
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] 哺乳動物細胞における2-OH-ATPの生物学的影響 (2007)
  • Author(s): 太田詠子, ら、
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-13
• [Presentation] ITPA-deficient mouse embryonic fibroblasts exhibit chromosomal aberrations. (2007)
  • Author(s): Abolhassani, N, et. al.
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-12
• [Presentation] 核とミトコンドリアゲノムに蓄積した8-オキソグアニンは異なる2つの経路による細胞死を誘導する (2007)
  • Author(s): 岡素雅子, ら、
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] Oxidative stress-induced tumorigenesis in the small intestine of Mutyh-deficient mice. (2007)
  • Author(s): Tsuzuki, T, et. al.
  • Organizer: 日本環境変異学会・第36回大会
  • Place of Presentation: 北九州
  • Year and Date: 2007-11-29
• [Presentation] Msh2欠損マウスにおける酸化ストレス誘発消化管発癌 (2007)
  • Author(s): 朴晶淑, ら、
  • Organizer: 日本放射線影響学会・第50回大会
  • Place of Presentation: 千葉
  • Year and Date: 2007-11-15
• [Presentation] Mutyh遺伝子欠損マウスにおける酸化ストヒス誘発消化管腫瘍の解析 (2007)
  • Author(s): 續輝久, ら、
  • Organizer: 日本放射線影響学会・第50回大会
  • Place of Presentation: 千葉
  • Year and Date: 2007-11-15
• [Presentation] Disruption of Defence Mechanisms Against Oxidative Damage in Nucleic Acids and the Affect of Polyphenols. (2007)
  • Author(s): Nalaneppu, Y, et. al.
  • Organizer: 3rdInternational Conference on Polyphenol and Health
  • Place of Presentation: Kyoto
  • Year and Date: 2007-10-25
• [Presentation] Defenses against damage in nucleotide pools and suppression ofcarcinogenesis, neurodegeneration and heart failure. (2007)
  • Author(s): Nakabeppu Y, et. al.
  • Organizer: 38thAnnual Meeting of the Environmental Mutagen Society
  • Place of Presentation: Atlanta, GA, USA
  • Year and Date: 2007-10-22
• [Presentation] Oxidative stress-induced tumorigenesis in the small intestine of Mutyh-deficient mice (2007)
  • Author(s): Tsuzuki, T, et. al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Oxidative stress-induced tumorigenesis in the small intestine of Mutyh-deficient mice. (2007)
  • Author(s): Piao, J, et. al.
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] 8-オキソグアニンのゲノム蓄積は染色体組換えを促進する。 (2007)
  • Author(s): 大野みずき, ら、
  • Organizer: 第79回日本遺伝学会大会
  • Place of Presentation: 岡山
  • Year and Date: 2007-09-20
• [Presentation] Mutyh遺伝子欠損マウスにおける酸化ストヒス誘発腫瘍における癌関連遺伝子の突然変異解析 (2007)
  • Author(s): 中津可道, ら、
  • Organizer: 第79回日本遺伝学会大会
  • Place of Presentation: 岡山
  • Year and Date: 2007-09-20
• [Presentation] Oxidative damage in nucleic acids in Huntington's disease model (2007)
  • Author(s): Sheng, Z, et. al.
  • Organizer: 第30回日本神経科学大会・第50回日本神経化学会大会・第17回日本神経回路学会大会 合同学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] 8-オキソグアニンのゲZム蓄積は相同染色体組換えを促進し遺伝附多様性を生み出す原動力となる。 (2007)
  • Author(s): 大野みずき, ら、
  • Organizer: 第9回日本進化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2007-09-01
• [Presentation] Oxidative stress-induced intestinal tumorgenesis in mice with a targeted disruption of the Mutyh gene (2007)
  • Author(s): Tsuzuki, T, et. al.
  • Organizer: The 13thInternational Congress of Radiation Research
  • Place of Presentation: San Franxisco, CA, USA
  • Year and Date: 2007-07-10
• [Presentation] Celldeath caused by 8-oxoguanine (2007)
  • Author(s): Nakabeppu, Y
  • Organizer: 3rdJapan-US DNA Repair Meeting
  • Place of Presentation: Akiu, Sendai,
  • Year and Date: 2007-05-08
• [Presentation] Two distince pathways of cell death triggered by oxidative damge to nuclear and mitochondrial DNAs. (2007)
  • Author(s): Oka, S., et. al.
  • Organizer: Nordic Region Workshop on Mitochondria(Scandomit 07)
  • Place of Presentation: Mirikka, Finland
• [Book] 遺伝子変異の機構 図説 分子病態学 4版(一瀬白帝, 鈴木宏治 編集) (2008)
  • Author(s): 中別府雄作
  • Publisher: 中外医学社
• [Book] Prvention of the mutagenecity and cytotoxicity of oxidized pruine nucleotides. In Evands, M.D. and Cooke, M.S.(eds), Oxidative Damage to Nucleic Acids. (2007)
  • Author(s): Nakabeppu, Y., et. al.
  • Publisher: Springer, Austin, TX
• [Book] DNA Replication and Transcription: In Meyrers RA(eds), Genomics and Genetics: From Molecular Details to Analysis and Techniques. (2007)
  • Author(s): Nakabeppu, Y., et. al.
  • Publisher: Wiley-VCH Verlag GmbH and Co., Weinheim, Germany
• [Book] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides, In Oxidative Damage to Nucleic Acids (2007)
  • Author(s): Nakabeppu, Y., Behmanesh, M., Yamaguchi, H., Yoshimura, D., Sakumi, K
  • Total Pages: 14
  • Publisher: Landes Bioscience/Eurekah, Georgetown, TX. USA
• [Book] DNA Replication and Transcription. (From Molecular Details to Analysis and Techniques)(In : Meyers RA, editor. Genomics and Genetics) (2007)
  • Author(s): Nakabeppu Y, Maki H, Sekiguchi. M
  • Total Pages: 27
  • Publisher: Wiley-VCH Verlag GmbH ＆ Co., Weinheim, Germany
• [Remarks]
  • URL: http://www.bioreg.kyushu-u.ac.jp/nfg/index.html