発がんに関与する活性酸素生成型NADPHオキシダーゼ活性化の分子機構

• Project/Area Number: 18012037
• 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: 住本 英樹 Kyushu University, 生体防御医学研究所, 教授 (30179303)
• Co-Investigator(Kenkyū-buntansha): 武谷 立 九州大学, 生体防御医学研究所, 助教 (50335981) ; 鎌倉 幸子 九州大学, 生体防御医学研究所, 助教 (80398081)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥10,200,000 (Direct Cost: ¥10,200,000); Fiscal Year 2007: ¥5,200,000 (Direct Cost: ¥5,200,000); Fiscal Year 2006: ¥5,000,000 (Direct Cost: ¥5,000,000)
• Keywords: 癌 / 酵素 / シグナル伝達 / 脂質 / 蛋白質

Research Abstract

活性酸素は、DNA損傷を引き起こすこと等で発がんに関与すると考えられる。活性酸素のソースの1つであるNADPHオキシダーゼ(Nox:ヒトではNox1〜Nox5の5種が知られるがマウス等はNox5を欠く)は、p47^<phox>, p67^<phox>, Noxo1(p47^<phox>のホモログ),Noxa1(p67^<phox>のホモログ),p40^<phox>などのSH3ドメインをもつNox制御蛋白質や低分子量G蛋白質Racにより活性化を制御されている。私達はオキシダーゼの活性化機構を研究し、平成19年度は以下のような成果を得た。
(1)Nox1活性化に必要なNoxo1は、細胞非刺激時は分子内結合により不活性型であるが、細胞刺激時には翻訳後修飾によるコンフォメーション変化うけ活性化されること、これがNox1活性化に重要であることを示した。また、RacはNox1活性化に関与するが、Racのinsert regionはNox1活性化に不要であることを明らかにした。
(2)Nox2はNADPHから電子を受け取り、その電子を伝達して最終的に酸素分子に渡しスーパーオキシドを生成する。この電子伝達に必要なアミノ酸残基の同定に成功した。また、p67^<phox>のN末のSH3ドメインは、Nox2の活性化を増強する働きがあることを示した
(3)Rac1がNox3の活性化にも関与することを明らかにし、特に、p67^<phox>存在下でのNox3活性化に重要な役割を果たすことを示すとともに、Rac1の作用はp67^<phox>の膜移行を誘導することによるものであることを明らかにした。

Research Products

• [Journal Article] Structure and function of the PB1 domain, a protein-interaction module conserved in animals, fungi, amoebas, and plants. (2008)
  • Author(s): Sumimoto, H.・Kamakura, S.・Ito, T.
  • Journal Title: Sci. STKE 2007. re6(in press)
  • Peer Reviewed
• [Journal Article] Characterization of teleost phatocyte NADPH oxedase: molecular cloning and expression analysis of carp(Cyprinus carpio) phatocyte NADPH oxidase. (2008)
  • Author(s): Miyumi, M.・Takeda, Y.・Hoshiko, M.・Serada, K.・Murata, M.・Moritomo, T.・Takizawa, F.・Kobayashi, I.・Araki, K.・Nakanishi, T.・Sumimoto, H.
  • Journal Title: Mol. Immunol. 45 Pages: 1720-1731
  • Peer Reviewed
• [Journal Article] The mammalian formin FHOD1 is activated via phosphorylation by ROCK and mediates thrombin-induced stress gibre formation in ednothelial cells. (2008)
  • Author(s): Takeya, R.・Taniguchi, K.・Narumiya, S.・Sumimoto, H.
  • Journal Title: EMBO J. 27 Pages: 618-628
  • Peer Reviewed
• [Journal Article] Enhanced expression of NAPDH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival. (2008)
  • Author(s): Shono, T.・Yokoyama, N.・Uesaka, T.・Kuroda, J.・Takeya, R.・Yamasaki, T.・Amano, T.・Mizoguchi, M・Suzuki, S. O.・Niiro, H.・Miyamoto, K.・Akashi, K.・Iwaki, T.・Sumimoto, H.・Sasaki, T.
  • Journal Title: Int. J. Cancer. (in press)
  • Peer Reviewed
• [Journal Article] Nox ファミリーの活性調節機構. (2008)
  • Author(s): 前原 優一, 宮野 佳, 住本英樹
  • Journal Title: G. I. Research 16(印刷中)
  • Peer Reviewed
• [Journal Article] Interaction between the SH3 domains and C-terminal proline-rich region in NADPH oxdase organizer 1(Noxo 1). (2007)
  • Author(s): Yamamoto, A.・Kami, K.・Takeya, R.・Sumimoto, H.
  • Journal Title: Biochem. Biophy. Res. Commun. 352 Pages: 560-565
  • Peer Reviewed
• [Journal Article] Full-length p40^<phox> structure suggests a basis for regulation mechanims of its membrane binding. (2007)
  • Author(s): Honbou, K.・Minakami, R.・Yuzawa, S.・Takeya, R.・Suzuki, N. N.・Kamakura, S.・Sumimoto, H.・Inagaki, F.
  • Journal Title: EMBO J. 26 Pages: 1176-1186
  • Peer Reviewed
• [Journal Article] Transient receptor potential(TRP) protein 7 acts as a G protein-activated Ca^<2+> channel mediating angiotensin II-induced myocardial apoptosis. (2007)
  • Author(s): Satoh, S.・Tanaka, H.・Ueda, Y.・Oyama, J. I.・Sugano, M.・Sumimoto, H.・Mori, Y.・Makino, N.
  • Journal Title: Cell. Biochem. 294 Pages: 205-215
  • Peer Reviewed
• [Journal Article] A regulated adaptor function of p40^<phox>: distinct p67^<phox> membrane targeting by p40^<phox> and by p47^<phox>. (2007)
  • Author(s): Ueyama, T.・Tatsuno, T.・Kawasaki, T.・Tsujibe, S.・Shirai, Y.・Sumimoto, H.・Leto, T. L.・Saito, N.
  • Journal Title: Mol. Biol. Cell. 18 Pages: 441-454
  • Peer Reviewed
• [Journal Article] Nox 1 redox-signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulationg Rho. (2007)
  • Author(s): Shinohara, M.・Shang, W. H.・Kubodera, M.・Harada, S.・Mitsushita, J.・Kato, M.・Miyazaki, H.・Suminoto, H.・Kamata, T.
  • Journal Title: J. Biol. Chem. 282 Pages: 17640-17648
  • Peer Reviewed
• [Journal Article] Pitavastain ameliorates albuminuria and renal mesangial expansion via down-regulation of NOX4 in db/db mice. (2007)
  • Author(s): Fujii, M.・Inoguchi, T.・Maeda, Y.・Sasaki, S.・Sawada, F.・Saito, R.・Kobayashi, K.・Sumimoto, H.・Takayanagi, R.
  • Journal Title: Kidney Int. 72 Pages: 473-480
  • Peer Reviewed
• [Journal Article] Role of the small GTPase Rac in p22^<phox>-dependent NADPH oxidases. (2007)
  • Author(s): Miyano, K.・Sumimoto, H.
  • Journal Title: Biochimie. 89 Pages: 1133-1144
  • Peer Reviewed
• [Journal Article] Nox ファミリーの調節機構. (2007)
  • Author(s): 宮野佳, 水上令子, 住本英樹
  • Journal Title: 臨床検査 51 Pages: 1111-1115
  • Peer Reviewed
• [Journal Article] Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca^<2+> channel mediating angiotensin II-induced myocardial apoptosis. (2007)
  • Author(s): Satoh, S., Tanaka, H., Ueda, Y., Oyama, J.I., Sugano, M., Sumimoto, H., Mori, Y., Makino, N.
  • Journal Title: Mol. Cell. Biochem. 294 Pages: 205-215
• [Journal Article] Interaction between the SH3 domains and C-terminal proline-rich region in NADPH oxidase organizer 1 (Noxo1). (2007)
  • Author(s): Yamamoto, A., Kami, K., Takeya, R., Sumimoto, H.
  • Journal Title: Biochem. Biophys. Res Commun. 352 Pages: 560-565
• [Journal Article] A regulated adaptor function of p40^<phox> : distinct p67^<phox> membrane targeting by p40^<phox> and by p47^<phox>. (2007)
  • Author(s): Ueyama, T., Tatsuno, T., Kawasaki, T., Tsujibe, S., Shirai, Y., Sumimoto, H., Leto, T.L., Saito.N.
  • Journal Title: Mol. Biol. Cell 18 Pages: 441-454
• [Journal Article] Full-length p40^<phox> structure suggests a basis for regulation mechanism of its membrane binding. (2007)
  • Author(s): Honbou, K., Minakami, R., Yuzawa, S., Takeya, R., Suzuki, N.N., Kamakura, S., Sumimoto, H., Inagaki, F.
  • Journal Title: EMBO J. 26 Pages: 1176-1186
• [Journal Article] Nox1 redox-signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulating Rho. (2007)
  • Author(s): Shinohara, M., Shang, W.H., Kubodera, M., Harada, S., Mitsushita, J., Kato, M., Miyazaki, H., Sumimoto, H., Kamata, T
  • Journal Title: J. Biol. Chem. 282(in press)
• [Journal Article] Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1. (2006)
  • Author(s): Miyano, K., Ueno, N., Takeya, R., Sumimoto, H.
  • Journal Title: J. Biol. Chem. 281 Pages: 21857-21868
• [Journal Article] Activation of the superoxide-producing phagocyte NADPH oxidase requires co-operation between the tandem SH3 domains of p47^<phox> in recognition of a polyproline type II helix and an adjacent α-helix of p22^<phox>. (2006)
  • Author(s): Nobuhisa, I., Takeya R., Ogura, K., Ueno, N., Kohda, D., Inagaki, F., Sumimoto, H.
  • Journal Title: Biochem. J. 396 Pages: 183-192
• [Journal Article] Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells. (2006)
  • Author(s): Takeya, R., Ueno, N., Sumimoto, H.
  • Journal Title: Methods Enzymol. 406 Pages: 456-468
• [Journal Article] NMR solution structure of the tandem SH3 domains of p47^<phox> complexed with a p22^<phox>-derived proline-rich peptide. (2006)
  • Author(s): Ogura, K., Nobuhisa, I., Yuzawa, S., Takeya, R., Torikai, S., Saikawa, K., Sumimoto, H., Inagaki, F.
  • Journal Title: J. Biol. Chem. 281 Pages: 3660-3668
• [Journal Article] Two forms of human Inscuteable-related protein that links Par3 to the Pins homologues LGN and AGS3. (2006)
  • Author(s): Izaki, T., Kamakura, S., Kohjima, M., Sumimoto, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 341 Pages: 1001-1006
• [Journal Article] Regulation of novel superoxide-producing NAD(P)H oxidases. (2006)
  • Author(s): Takeya, R., Sumimoto, H.
  • Journal Title: Antioxid. Redox Signal. 8 Pages: 1523-1532
• [Journal Article] Expression and function of Noxo1, an alternative splicing form of the NADPH oxidase organizer 1. (2006)
  • Author(s): Takeya, R., Taura M., Yamasaki, T., Naito, S., Sumimoto, H.
  • Journal Title: FEBS J. 273 Pages: 3663-3677
• [Journal Article] Phagocytosis-coupled activation of the superoxide-producing phagocyte oxidase, a member of the NADPH oxidase (Nox) family. (2006)
  • Author(s): Minakami, R., Sumimoto, H.
  • Journal Title: Int. J. Hematol. 84 Pages: 193-198
  • NAID: 10018303702
• [Journal Article] Expression of isoforms of NADPH oxidase components in rat pancreatic islets. (2006)
  • Author(s): Uchizono, U., Takeya, R., Iwase, M., Sasaki, N., Oku, M., Imoto, H., Iida, M., Sumimoto, H.
  • Journal Title: Life Sci. 80 Pages: 133-139
• [Journal Article] Crystallization and preliminary crystallographic analysis of p40^<phox>, a regulatory subunit of NADPH oxidase. (2006)
  • Author(s): Honbou K, Yuzawa S, Suzuki NN, Fujioka Y, Sumimoto H, Inagaki F
  • Journal Title: Acta Crystallograph Sect F Struct Biol Cryst Commun. 62 Pages: 1018-1020
• [Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. (2006)
  • Author(s): Onohara, N., Nishida, M., Inoue, R., Kobayashi, H., Sumimoto, H., Sato, Y., Mori, Y., Nagao, T., Kurose, H.
  • Journal Title: EMBO J. 25 Pages: 5305-5316
• [Journal Article] Increased expression of gp91^<phox> homologues of NAD(P)H oxidase in the aortic media during chronic hypertension; involvement of the rennin-angiotensin system. (2006)
  • Author(s): Akasaki, T., Ohya Y., Kuroda, J., Eto, K., Abe, I., Sumimoto, H., Iida, M.
  • Journal Title: Hypertens. Res. 29 Pages: 813-820
• [Presentation] シンポジウム「生体内ラジカル/活性酸素種による生理応答機構と病態形成」活性酸素生成型NADPHオキシダーゼの活性化の分子機構. (2008)
  • Author(s): 住本 英樹, 宮野 佳, 水上 令子.
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
• [Presentation] シンポジウム「NO/ROS in Cell Signaling」Molecular mechanism for activation of the phagocyte NADPH oxidase. (2007)
  • Author(s): Hideaki, Sumimoto.
  • Organizer: 19thFAOBMB Seoul Conference.
  • Place of Presentation: Seoul, Republic of Korea.
• [Presentation] Mechanism for activation of superoxide-producing NADPH oxidases. (2007)
  • Author(s): Hideaki, Sumimoto.
  • Organizer: The 4th Meeting of International Redox Network.
  • Place of Presentation: Jeju Island, Republic of Korea.
• [Presentation] ワークショップ「酸化ストレスの評価方法と腎障害への応用」活性酸素生成酵素NADPHオキシダーゼ(Nox)ファミリーの機能と調節機構. (2007)
  • Author(s): 住本 英樹.
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 浜松
• [Presentation] ワークショップ「細胞骨格・細胞運動・細胞移動」formin相同タンパク質Fhos1/FHOD1のリン酸化依存的活性化機構. (2007)
  • Author(s): 武谷 立, 住本 英樹.
  • Organizer: 第40回日本発生生物学会 第50回日本細胞生物学会合同大会.
  • Place of Presentation: 福岡
• [Book] 酸化ストレスの医学 (2008)
  • Author(s): 住本 英樹, 前原 優一, 宮野 佳.
  • Publisher: 診断と治療社
• [Book] 生体防御医学事典 (2007)
  • Author(s): 住本 英樹.
  • Total Pages: 6
  • Publisher: 朝倉書店
• [Book] 生体防御医学事典 (2007)
  • Author(s): 住本 英樹(共編者・共著者)
  • Publisher: 朝倉書店(印刷中)