Elucidation of the physiological function of iNOS degradation system by generating mice in which the SPSB inhibitor is expressed throughout the body

• Project/Area Number: 23590066
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Okayama University
• Principal Investigator: NISHIYA Tadashi 岡山大学, 医歯(薬)学総合研究科, 准教授 (80399831)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: SPSB / iNOS / CDC14A / FOG-2 / CTTNBP2 / E3 / ユビキチン化 / 蛋白質分解 / ECS(SPSB) / タンパク質分解 / トランスジェニックマウス

Research Abstract

We attempted to generate the mice expressing SPSB inhibitor which blocks the association between SPSB and its substrates. Although several F1 mice in which the SPSB inhibitor-expressing gene was introduced were obtained, SPSB inhibitor was not detected in kidneys and livers from these mice. In parallel to this experiment, we identified CDC14A, CTTNBP2 and FOG-2 as novel substrates for SPSB. These substrates are involved in wide variety of physiological functions such as cell cycle control, development of heart and lung, and the dendritic spine formation. Therefore, the inhibition of the degradation of these substrates might cause serious problems for mouse development.

Research Products

• [Journal Article] NKG2D+ IFN-γ+ CD8+ T cells are responsible for palladium allergy. (2014)
  • Author(s): Kawano M, Nakayama M, Aoshima Y, Nakamura K, Ono M, Nishiya T, Nakamura S, Takeda Y, Dobashi A, Takahashi A, Endo M, Ito A, Ueda K, Sato N, Higuchi S, Kondo T, Hashimoto S, Watanabe M, Watanabe M, Takahashi T, Sasaki K, Nakamura M, Sasazuki T, Narushima T, Suzuki R, Ogasawara K.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: 1-12
  • DOI: 10.1371/journal.pone.0086810
  • Peer Reviewed / Open Access
• [Journal Article] Nicotine- and Tar-Free Cigarette Smoke induces cell damage through reactive oxygen species newly generated by PKC-dependent activation of NADPH oxidase (2012)
  • Author(s): Asano H, Horinouchi T, Mai Y, Sawada O, Fujii S, Nishiya T, Minami M, Katayama T, Iwanaga T, Terada K, Miwa S.
  • Journal Title: J. Phar macol. Sci Volume: 118(2) Pages: 275-287
  • NAID: 10030455160
  • Peer Reviewed
• [Journal Article] Adenylate cyclase-cAMP-protein kinase A signaling pathway inhibits endothelin type A receptor-operated Ca^<2+> entry mediated via TRPC6 channels (2012)
  • Author(s): Horinouchi T, Higa T, Aoyagi H, Nishiya T, Terada K, Miwa S.
  • Journal Title: J. Phar macol. Exp. Ther Volume: 340(1) Pages: 143-151
  • Peer Reviewed
• [Journal Article] Nicotine- and Tar-Free Cigarette Smoke Induces Cell Damage Through Reactive Oxygen Species Newly Generated by PKC-Dependent Activation of NADPH Oxidase (2012)
  • Author(s): Asano H, Horinouchi T, Mai Y, Sawada O, Fujii S, Nishiya T, Minami M, Katayama T, Iwanaga T, Terada K, Miwa S
  • Journal Title: Journal of Pharmacological Sciences Volume: 118 Issue: 2 Pages: 275-287
  • DOI: 10.1254/jphs.11166FP
  • NAID: 10030455160
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Adenylate cyclase-cAMP-protein kinase A signaling pathway inhibits endothelin type A receptor-operated Ca2+ entry mediated via TRPC6 channels (2012)
  • Author(s): Horinouchi T, Higa T, Aoyagi H, Nishiya T, Terada K, Miwa S
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: 340(1) Issue: 1 Pages: 143-151
  • DOI: 10.1124/jpet.111.187500
  • Peer Reviewed
• [Journal Article] Function and regulation of endothelin type A receptor-operated transient receptor potential canonical channels (2011)
  • Author(s): Horinouchi T, Terada K, Higa T, Aoyagi H, Nishiya T, Suzuki H, Miwa S.
  • Journal Title: J . Phar macol. Sci Volume: 117(4) Pages: 295-306
  • NAID: 10030453850
  • Peer Reviewed
• [Journal Article] On-off system for PI3-kinase-Akt signaling through S-nitrosylation of PTEN (2011)
  • Author(s): Numajiri N, Takasawa K, Nishiya T, Tanaka H, Ohno K, Hayakawa W, Asada M, Matsuda H, Azumi K, Kamata H, Nakamura T, Hara H, Minami M, Lipton S, Uehara T.
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. Volume: 108(25)(*Equal contribution) Pages: 10349-10354
  • Peer Reviewed
• [Journal Article] Function and Regulation of Endothelin Type A Receptor-Operated Transient Receptor Potential Canonical Channels (2011)
  • Author(s): Horinouchi T, Terada K, Higa T, Aoyagi H, Nishiya T, Suzuki H, Miwa S
  • Journal Title: Journal of Pharmacological Sciences Volume: 117 Issue: 4 Pages: 295-306
  • DOI: 10.1254/jphs.11162FP
  • NAID: 10030453850
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] On-off system for PI3-kinase-Akt signaling through S-nitrosylation of phosphatase with sequence homology to tensin (PTEN) (2011)
  • Author(s): Numajiri N., Takasawa K., Nishiya T., Tanaka H., Ohno K., Hayakawa W., Asada M., Matsuda H., Azumi K., Kamata H., Nakamura T., Hara H., Minami M., Lipton S.A., Uehara T.
  • Journal Title: Proceedings of the National Academy of Sciences, USA Volume: 108 Issue: 25 Pages: 10349-10354
  • DOI: 10.1073/pnas.1103503108
  • Peer Reviewed
• [Journal Article] The ECS (SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase. Biochem (2011)
  • Author(s): Matsumoto, K., Nishiya, T., Maekawa, S., Horinouchi, T., Ogasawara, K., Uehara, T., and Miwa, S
  • Journal Title: Biophys. Res. Commun Volume: 409 Issue: 1 Pages: 46-51
  • DOI: 10.1016/j.bbrc.2011.04.103
  • Peer Reviewed
• [Journal Article] NKG2D^+IFN-^+CD8^+T cells are responsible for palladium allergy
  • Author(s): Kawano M, Nakayama M, Aoshima Y, Nakamura K, Ono M, Nishiya T, Nakamura S, Takeda Y, Dobashi A, Takahashi A, Endo M, Ito A, Ueda K, Sato N, Higuchi S, Kondo T, Hashimoto S, Watanabe M, Watanabe M, Takahashi T, Sasaki K, Nakamura M, Sasazuki T, Narushima T, Suzuki R, Ogasawara K.
  • Journal Title: PLoS One Volume: 9(2)
  • Peer Reviewed
• [Presentation] 新規E3ユビキチンリガーゼECS(SPSB)の基質同定 (2014)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、上原孝
  • Organizer: 第134回日本薬学会年会
  • Place of Presentation: 熊本大学、熊本市
  • Year and Date: 2014-03-30
• [Presentation] E3ユビキチンリガーゼECS(SPSB)の新規基質の網羅的探索 (2014)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、上原孝
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター、仙台市
  • Year and Date: 2014-03-19
• [Presentation] E3ユビキチンリガーゼECS(SPSB)の新規基質の網羅的探索 (2014)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、上原孝
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター
• [Presentation] 新規E3ユビキチンリガーゼECS(SPSB)の基質同定 (2014)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、上原孝
  • Organizer: 第134回日本薬学会年会
  • Place of Presentation: 熊本大学
• [Presentation] E3ユビキチンリガーゼ"ECS(SPSB)"の新規基質の網羅的同定 (2013)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、松本一馬、小笠原康悦、三輪聡一、上原孝
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド、神戸市
  • Year and Date: 2013-12-05
• [Presentation] SPSBファミリー蛋白質を介したCDC14A phosphataseのユビキチン-プロテアソーム依存的分解機構 (2013)
  • Author(s): 西屋禎、丸山拳、松本一馬、小笠原康悦、三輪聡一、上原孝
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡市
  • Year and Date: 2013-03-23
• [Presentation] E3ユビキチンリガーゼ“ECS(SPSB)”の新規基質の網羅的同定 (2013)
  • Author(s): 西屋禎、丸山拳、高澤孔明、浜田恭平、松本一馬、小笠原康悦、三輪聡一、上原孝
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] SPSBファミリー蛋白質を介したCDC14A phosphataseのユビキチン－プロテアソーム依存的分解機構 (2013)
  • Author(s): 西屋 禎 他
  • Organizer: 第86回日本薬理学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] CDC14AはElongin B/C-Cul5-SPSB型E3ユビキチンリガーゼの基質である (2012)
  • Author(s): 西屋禎、松本一馬、小笠原康悦、三輪聡一、上原孝
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場・マリンメッセ福岡、福岡市
  • Year and Date: 2012-12-16
• [Presentation] CDC14AはElongin B/C-Cul5-SPSB型E3ユビキチンリガーゼの基質である (2012)
  • Author(s): 西屋 禎 他
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: マリンメッセ福岡
• [Presentation] 誘導型NO合成酵素のユビキチン・プロテアソーム依存的分解制御機構 (2011)
  • Author(s): 松本一馬、西屋禎、前川聡、堀之内孝広、藤室雅弘、小笠原康悦、上原孝、三輪聡一
  • Organizer: 第25回北海道薬物作用談話会
  • Place of Presentation: 酪農学園大学中央館学生ホール、江別市
  • Year and Date: 2011-07-30
• [Presentation] 誘導型NO合成酵素の分解制御機構 (2011)
  • Author(s): 西屋禎、前川聡、松本一馬、堀之内孝広、藤室雅弘、小笠原康悦、上原孝、三輪聡一
  • Organizer: 第11回日本NO学会
  • Place of Presentation: 昭和薬科大学、東京
• [Presentation] 誘導型NO合成酵素の分解制御機構 (2011)
  • Author(s): 西屋禎
  • Organizer: 第11回日本NO学会
  • Place of Presentation: 昭和薬科大学（東京都）
• [Presentation] 誘導型NO合成酵素のユビキチン・プロテアソーム依存的分解制御機構 (2011)
  • Author(s): 松本一馬
  • Organizer: 第25回北海道薬物作用談話会
  • Place of Presentation: 酪農学園大学（札幌市）
• [Presentation] 新規iNOS分解系の発見とその心血管系への治療標的としての可能性 (2011)
  • Author(s): 西屋禎
  • Organizer: 第21回日本循環薬理学会(招待講演)
  • Place of Presentation: 岡山大学（岡山市）
• [Remarks]
  • URL: http://saibo-yakuri.med.hokudai.ac.jp/seika/seika20110103.html
• [Remarks]
  • URL: http://www.pharm.okayama-u.ac.jp/news/2011/01/noj-biol-chem.html