Functional analysis of GCN1L1 in mitochondrial stress response

• Project/Area Number: 18K06910
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Hirosaki University
• Principal Investigator: Kasai Shuya 弘前大学, 医学研究科, 助教 (20609664)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Gcn1 / アミノ酸飢餓応答 / 統合的ストレス応答 / タモキシフェン / 体重減少 / Gcn2 / Tamoxifen / Cre/loxP / Body weight loss / Amino acid starvation / GCN1L1 / ミトコンドリアストレス / GCN2 / eIF2α / ATF4

Outline of Final Research Achievements

Gcn1 is ribosome binding protein which mediates translational attenuation and amino acid synthesis in response to amino acid starvation. Since Gcn1 knockout mice show embryonic growth retardation and lethality, current study analyzed the phenotype of conditional Gcn1 knockout (CKO) mice employing tamoxifen-inducible Cre and Gcn1 flox mice. Gcn1 CKO mice generated by tamoxifen administration showed decrease in the body weight and accompanying decreases in blood glucose, liver weight and lipid content, and white adipose tissue weight. These data implicates Gcn1 is involved in resistance to tamoxifen toxicity and metabolic homeostasis.

Academic Significance and Societal Importance of the Research Achievements

哺乳類におけるGcn1はアミノ酸飢餓応答だけでなく、非飢餓状態においても細胞周期の進行や胎児期での成長にも関わることを明らかにしたが、その分子機構は不明である。本研究では成獣マウスにおけるGcn1のノックアウトにより、Gcn1がタモキシフェン毒性による異化代謝亢進を抑制している可能性が示唆された。近年、ミトコンドリア脱共役剤であるBAM15によっても同様の現象が報告されており、Gcn1がミトコンドリア機能維持に関わる可能性が考えられる。

Research Products

• [Journal Article] Nrf2とATF4の相互作用を基盤にした未病気における疾患予防法の開発 (2021)
  • Author(s): 葛西秋宅、多田羅洋太、三村純正、伊東健
  • Journal Title: BIO Clinica Volume: 36 Pages: 80-84
• [Journal Article] ストレス応答性転写因子Nrf2とATF4の相互作用を基盤にした疾患予防・アンチエイジング法の開発 (2020)
  • Author(s): 葛西秋宅、清水直、多田羅洋太、三村純正、伊東健
  • Journal Title: BIO Clinica Volume: 35 Pages: 60-64
• [Journal Article] Ribosome binding protein GNC1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice (2020)
  • Author(s): Yamazaki H,Kasai S,Mimura J,Ye P,Inose-Maruyama A,Tanji K,Wakabayashi K,Mizuno S,Sugiyama F,Takahashi S,Sato T,Ozaki T,Cavener DR,Yamamoto M,Itoh K
  • Journal Title: PloS Genet. Volume: 16 Issue: 4 Pages: e1008693-e1008693
  • DOI: 10.1371/journal.pgen.1008693
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Ribosome binding protein Gcn1 knockout mice exhibit embryonic lethality with growth retardation (2020)
  • Author(s): 葛西 秋宅、劉 君、山嵜 博未、三村 純正、伊東 健
  • Organizer: 第93回日本生化学会大会
• [Presentation] Ribosome binding protein GCN1L1 knockout mice exhibit embryonic lethality with growth retardation and reduced cell proliferation (2019)
  • Author(s): Shuya Kasai, Hiromi Yamazaki, Junsei Mimura, Peng Ye, Atsushi Inose-Maruyama, Ken Itoh
  • Organizer: 9th Biennial Meeting for the Society for Free Radical Research Asia
  • Int'l Joint Research
• [Presentation] Body weight loss in postnatal GCN1L1 knockout mice (2019)
  • Author(s): Jun Liu, Shuya Kasai, Hiromi Yamazaki, Junsei Mimura, Ken Itoh
  • Organizer: 第1回弘前メディカルサイエンスフォーラム
• [Presentation] Involvement of GCN1L1-GCN2 in mitochondrial dysfunction-induced ATF4 activation (2019)
  • Author(s): Shuya Kasai, Ken Itoh
  • Organizer: Keystone symposia, Mitochondrial Biology in Heart and Skeletal Muscle
  • Int'l Joint Research
• [Presentation] ミトコンドリアストレスによるATF4活性化とGCN1L1-GCN2経路の関与 (2018)
  • Author(s): 葛西秋宅、山嵜博未、三村純正、伊東健
  • Organizer: 第92回日本生化学会大会
• [Presentation] ATF4を介したミトコンドリアストレス応答経路におけるGCN1L1-GCN2経路の関与 (2018)
  • Author(s): 葛西秋宅、山嵜博未、三村純正、伊東健
  • Organizer: 第71回日本酸化ストレス学会、第18回日本NO学会 合同学術集会