Dissecting the roles of metabolism in the development of cancer by means of the mitochondrial hyperactive model mice

• Project/Area Number: 26640082
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Nagasaki University
• Principal Investigator: YAMAMOTO Kazuo 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (70255123)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ミトコンドリア / トランスジェニックマウス / 白血病 / リンパ腫 / 代謝

Outline of Final Research Achievements

To investigate the roles of metabolism in cancer development, leukemia model mice and mitochondrial hyperactive transgenic mice were analyzed. Mitochondrial hyperactivation resulted in significant extension of the death caused by leukemia. The key protein responsible for this phenomenon was turned out to localize as dots in cytoplasm any other than mitochondria, the Golgi body, endoplasmic reticulum, peroxisome, nor endosome. Transcriptome analysis revealed that a few specific transcription factors governed the unique transcription profile in the cells overexpressing this protein. As the protein synthesis was upregulated in these cells, the effect induced by this protein was analyzed in vivo. The result suggested that the rate of protein synthesis was raised by mitochondrial hyperactivation.

Research Products

• [Int'l Joint Research] キャンベルファミリー癌研究所/トロント大学/マギル大学(カナダ)
• [Journal Article] Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP+/NADPH ratio (2015)
  • Author(s): M Itsumi, S Inoue, AJ Elia, K Murakami, M Sasaki, EF Lind, D Brenner, IS Harris, IIC Chio, S Afzal, RA Cairns, DW Cescon, AR Elford, J Ye, PA Lang, WY Li, A Wakeham, GS Duncan, J Haight, A You-Ten, B Snow, K Yamamoto, PS Ohashi, TW Mak
  • Journal Title: Cell Death & Differentiation Volume: 22 Issue: 11 Pages: 1837-1845
  • DOI: 10.1038/cdd.2015.38
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression (2015)
  • Author(s): Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, Yung KY, Brenner D, Knobbe-Thomsen CB, Cox MA, Elia A, Berger T, Cescon DW, Adeoye A, Brüstle A, Molyneux SD, Mason JM, Li WY, Yamamoto K, Wakeham A, Berman HK, Khokha R, Done SJ, Kavanagh TJ, Lam CW, Mak TW.
  • Journal Title: Cancer Cell Volume: 27 Issue: 2 Pages: 211-222
  • DOI: 10.1016/j.ccell.2014.11.019
  • Peer Reviewed
• [Journal Article] 細胞の大きさを規定する分子基盤 (2015)
  • Author(s): 山本一男
  • Journal Title: 化学と生物 Volume: 53 Pages: 141-142
  • Peer Reviewed
• [Presentation] A mechanism of cell size regulation and its readout governed by Largen (2016)
  • Author(s): Kazuo Yamamoto
  • Organizer: EMBO Workshop
  • Place of Presentation: Joachimsthal, Germany
  • Year and Date: 2016-09-14
  • Int'l Joint Research / Invited
• [Presentation] A molecular basis of mammalian cell size control (2016)
  • Author(s): Kazuo Yamamoto, Masato Sasaki, Ivan Topisirovic, Mitsuhiko Ikura, Nahum Sonenberg, Tak W. Mak
  • Organizer: CDB Symposium 2016
  • Place of Presentation: 理化学研究所多細胞システム形成研究センター（兵庫県・神戸市）
  • Year and Date: 2016-03-28
  • Int'l Joint Research
• [Presentation] 細胞の大きさを制御する遺伝子ネットワークの抽出 (2015)
  • Author(s): 山本一男、Susan McCracken、Tak W. Mak
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県・神戸市）
  • Year and Date: 2015-12-01
• [Book] 実験医学2016年9月増刊号 (2016)
  • Author(s): 山本一男
  • Publisher: 羊土社