Physiological roles of the transcription factor Nrf1 on the lipid metabolism

• Project/Area Number: 19590268
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Doshisha University (2008); Tohoku University (2007)
• Principal Investigator: KOBAYASHI Akira Doshisha University, 生命医科学部, 准教授 (50292214)
• Co-Investigator(Kenkyū-buntansha): TSUCHIYA Yoshiki 同志社大学, 生命医科学部, 助教 (30456777)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脂質代謝 / 転写制御 / タンパク質分解 / 酸化ストレス / センサー / タンパク質構造 / ユビキチン / ストレス / 遺伝子破壊マウス / 遺伝子発現制

Research Abstract

本研究の目的は, 社会的な問題に発展しているメタボリックシンドロームに対する新たな治療標的として転写因子Nrf1に着目し, その脂質代謝にかかわる遺伝子発現制御ネットワークを解明する点にある。Nrf1の肝臓特異的遺伝子破壊マウスは, 肝臓に脂肪が蓄積して, 脂肪肝を経て最終的に肝ガンを発症する。 このマウスの症状は, ヒトの非アルコール性脂肪肝(NASH)の症状ときわめて酷似しているため, 疾患モデルマウスとなることが期待されている。本研究では, Nrf1の欠失による遺伝子発現制御ネットワークの破綻がもたらす脂質代謝異常について, その発症の分子機構を解析することを目標した。
まずNrf1の標的遺伝子を同定するために, Nrf1遺伝子破壊マウスの肝臓を用いてマイクロアレー解析を行った。Nrf1は転写活性化因子のため, 遺伝子破壊によって発現が減少している遺伝子に着目したが, 脂質代謝に関わる遺伝子は見いだせなかった。このことは, Nrf1は脂質代謝に対して直接は機能せず, 本来の生理機能が破綻したことによって間接的に脂質代謝へ影響をもたらした可能性が示唆された。次に, Nrfの生理機能をもたらす分子基盤として, Nrf1の細胞内局在とタンパク質機能制御について検討した。Nrf1は, 通常細胞質の小胞体(ER)に局在し, プロテアソーム依存的なタンパク質分解を受けていることを見いだした。すなわちNrf1の機能発現には, この小胞体局在とタンパク質分解による機能抑制を解除する活性化シグナル・ストレスが存在することを見いだした。そこで, Nrf1タンパク質の分解機構を解明する目的で, Nrf1結合タンパク質を検索した結果, ユビキチン結合酵素のアダプターを同定した。したがって, Nrf1は, ユビキチンープロテアソーム依存的にタンパク質分解を受けている可能性が高いことが分かった。

Research Products

• [Journal Article] Nrf1 and Nrf2 Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes. (2008)
  • Author(s): Ohtsuji, M., Katsuoka, F., Kobayashi, A., Aburatani, H., Hayes, J. D. and Yamamoto, M.
  • Journal Title: J. Biol. Chem 283 Pages: 33554-33562
  • Peer Reviewed
• [Journal Article] Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in Basal and oxidative environments (2008)
  • Author(s): Mamiya, T., Katsuoka, F., Hirayama, A., Nakajima, O., Kobayashi, A., Maher, J. M., Matsui, H., Hyodo, I. and Yamamoto M, and Hosoya, T.
  • Journal Title: Tohoku J Exp Med 216 Pages: 331-339
  • NAID: 10025104347
  • Peer Reviewed
• [Journal Article] Keap1 regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells (2008)
  • Author(s): Kusano, Y., Horie, S., Shibata, T., Satsu, H., Shimizu, M., Hitomi, E., Nishida, M., Kurose, H., Itoh, K., Kobayashi, A., Yamamoto, M. and Uchida, K.
  • Journal Title: Biochemistry 47 Pages: 6169-6177
  • Peer Reviewed
• [Journal Article] Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1 (2008)
  • Author(s): Padmanabhan, B., Tong, KI., Kobayashi, A., Yamamoto, M., and Yokoyama S.
  • Journal Title: J Synchrotron Radiat 15(Pt 3) Pages: 273-276
  • Peer Reviewed
• [Journal Article] Loss of Keap1 function activates Nrf2 and provides advantages for lungcancer cell growth. (2008)
  • Author(s): Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., Shibata, T., Yamamoto, M., Hirohashi, S.
  • Journal Title: Cancer Res 68 Pages: 1303-1309
  • Peer Reviewed
• [Journal Article] Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity (2008)
  • Author(s): Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J., Motohashi, H., and Yamamoto, M.
  • Journal Title: Mol. Cell. Biol 28 Pages: 2758-2770
  • Peer Reviewed
• [Journal Article] Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1 (2008)
  • Author(s): Satoh, T., Kosaka, K., Itoh, K., Kobayashi, A., Yamamoto, M., Shimojo, Y., Kitajima, C., Cui, J., Kamins, J., Okamoto, S., Izumi, M., Shirasawa, T. and Lipton, SA.
  • Journal Title: J. Neurochem 104 Pages: 1116-1131
  • Peer Reviewed
• [Journal Article] Down-regulation of the PI3-kinase/Akt pathway by ERK MAP kinase in growth factor signaling (2008)
  • Author(s): Hayashi H, Tsuchiya Y, Nakayama K, Satoh T, Nishida E.
  • Journal Title: Genes Cells 13 Pages: 941-947
  • Peer Reviewed
• [Journal Article] Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nri2 pathway via S-alkylation of targeted cysteines on Keapl. (2008)
  • Author(s): Satoh, T., et al.
  • Journal Title: J. Neurochem. 104 Pages: 1116-1131
  • Peer Reviewed
• [Journal Article] Physiological Significance of Reactive Cysteine Residues of Keapl in Determining Nrf2 Activity. (2008)
  • Author(s): Yamamoto, T., et al.
  • Journal Title: Mol. Cell. Biol. 28 Pages: 2758-2770
  • Peer Reviewed
• [Journal Article] Loss of Keapl function activates Nrf2 and provides advantages for lung cancer cell growth. (2008)
  • Author(s): Ohta, T., et al.
  • Journal Title: Cancer Res. 68 Pages: 1303-1309
  • Peer Reviewed
• [Journal Article] Structural insights into the similar modes of Nrf2 transcription factor recognition by the cytoplasmic repressor Keap1 (2008)
  • Author(s): Padmanabhan, B., et al.
  • Journal Title: J Synchrotron Radiat. 15(Pt3) Pages: 273-276
  • Peer Reviewed
• [Journal Article] Keapl regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells. (2008)
  • Author(s): Kusano, Y., et al.
  • Journal Title: Biochemistry 47 Pages: 6169-6177
  • Peer Reviewed
• [Journal Article] Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in Basal and oxidative environments. (2008)
  • Author(s): Mamiya, T., et al.
  • Journal Title: Tohoku J Exp Med. 216 Pages: 331-339
  • Peer Reviewed
• [Journal Article] Nrf1 and Nrf2 Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes. (2008)
  • Author(s): Ohtsuji, M., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 33554-33562
  • Peer Reviewed
• [Journal Article] The Nrf3 transcription factor is a membrane-bound glycoprotein targetedto the endoplasmic reticulum through its N-terminal homology box 1 sequence. (2008)
  • Author(s): Zhang, Y., et al.
  • Journal Title: J. Biol. Chem. 283 Pages: 3195-3210
  • Peer Reviewed
• [Journal Article] Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap 1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1 (2008)
  • Author(s): Satoh T., et. al.
  • Journal Title: J Neurochem. 3 Pages: 1116-1131
  • Peer Reviewed
• [Journal Article] Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. (2007)
  • Author(s): Komatsu M, et. al.
  • Journal Title: Cell 131 Pages: 1149-1163
  • Peer Reviewed
• [Journal Article] Protein S-guanylation by the biological signal 8-nitroguanosine 3',5'-cyclic monophosphate. (2007)
  • Author(s): Sawa T., et. al.
  • Journal Title: Nat Chem Biol. 3 Pages: 725-735
  • Peer Reviewed
• [Journal Article] Subcellular localization and cytoplasmic complex status of endogenous Keap1 (2007)
  • Author(s): Watai y., et. al.
  • Journal Title: Genes to Cells 12 Pages: 1163-1178
  • Peer Reviewed
• [Journal Article] Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response (2007)
  • Author(s): Tong Kl, et. al.
  • Journal Title: Mol Cell Biol. 27 Pages: 7511-7521
  • Peer Reviewed
• [Journal Article] Loss of p62/SQSTM1 Suppresses Cytoplasmic Inclusion Body Formation and Liver Injury in Autophagy-Deficient Mouse.
  • Author(s): Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J., Ezaki, J., Murata, S., Hamazaki, J., Nishito, Y., Iemura, S., Natsume, T., Yanagawa, T., Uwayama, J., Warabi, E., Yoshida, H., Ishii, T., Kobayashi, A., Yamamoto, M., Yue, Z., Uchiyama, Y., Kominami, E. and Tanaka, K.
  • Journal Title: Cell 131 Pages: 1149-1163
  • Peer Reviewed
• [Journal Article] Protein S-guanylation by the biological signal 8-nitroguanosine 3', 5'-cyclic monophosphate
  • Author(s): Sawa, T., Zaki, M.H., Okamoto, T., Akuta, T., Tokutomi, Y., Kim-Mitsuyama, S., Ihara, H. Kobayashi, A., Yamamoto, M., Fujii, S., Arimoto, H. and Akaike, T.
  • Journal Title: Nature Chem. Biol 11 Pages: 727-735
  • NAID: 120002467822
• [Journal Article] Different electrostatic potentials define ETGE and DLG motifs ashinge and latch in oxidative stress response
  • Author(s): Tong, K.I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, H., Yokoyama, S. and Yamamoto, M.
  • Journal Title: Mol. Cell. Biol 21 Pages: 7511-7521
  • Peer Reviewed
• [Journal Article] Subcellular Localization and Cytoplasmic Complex Status of Endogenous Keap1
  • Author(s): Watai, Y., *Kobayashi, A., Nagase, H., Mizukami, M., McEvoy, J., Singer, J.D., Itoh, K., and *Yamamoto, M.
  • Journal Title: Genes to Cells 12 Pages: 1163-1178
  • Peer Reviewed
• [Presentation] 老化をもたらす酸化ストレスに対する生体防御機構 (2008)
  • Author(s): 小林聡
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] 老化をもたらす酸化ストレスに対する生体防御機構 (2008)
  • Author(s): 小林聡
  • Organizer: BMB2008
  • Place of Presentation: 神戸ポートピア
  • Year and Date: 2008-12-09
• [Presentation] Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based Ub E3 liqase to requlate proteasomal deqradation of Nrf2. (2007)
  • Author(s): 小林 聡
  • Organizer: JST-ERATO Yamamoto Environmental Response Project International Symposium
  • Place of Presentation: つくばエポカル
• [Book] 診断と治療社「Keap1-Nrf2システムによる酸化ストレス・親電子性物質応答機構」, 酸化ストレスの医学 (2008)
  • Author(s): 小林聡、山本雅之
• [Book] 酸化ストレスの医学 (2008)
  • Author(s): 小林聡
  • Total Pages: 384
  • Publisher: Keapl-Nrf2システムによる酸化ストレス・親電子性物質応答機構
• [Remarks] 第三回匂坂記念賞受賞
• [Remarks]
  • URL: http://dmbc.med.tohoku.ac.jp/official/index.html