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Elucidation of glutathione-independent cell survival mechanism

Research Project

Project/Area Number 18K15039
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionYamagata University

Principal Investigator

Kobayashi Sho  山形大学, 大学院医学系研究科, 助教 (10779490)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsフェロトーシス / グルタチオン代謝 / システイン再利用系 / メタボロミクス解析 / プロテオミクス解析 / グルタチオン / シスチントランスポーター / マクロファージ / メタボローム / プロテオーム
Outline of Final Research Achievements

The research conducted during this period and its results are as follow. 1) We established a method using LC-MS for simultaneous measurement of γ-glutamyl peptides (γGluPeps) which are produced by glutathione (GSH) metabolism, and found γGluPeps has a characteristic distribution in tissues and some of γGluPeps were increased by GSH synthesis system in cell death caused by GSH deprivation (ferroptosis). 2)Using proteomics analysis, we identified CNDP2 as suppressor gene of GSH deprivation induced-ferroptosis, and it was suggested that CNDP2 suppress ferroptosis by reusing efficiently cysteine through GSH degradation.

Academic Significance and Societal Importance of the Research Achievements

本研究により確立したγGluPeps類の測定法を用いて、それらをバイオマーカーとして利用することで癌の診断に役立つものと考えられる。また、CNDP2のGSH分解を介したシステイン再利用系による細胞の生存機構を解明することは、化学療法の際に問題となる薬剤耐性を持つ癌を標的とする新たな治療薬の開発にもつながると考えている。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (27 results)

All 2020 2019 2018 Other

All Journal Article (11 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 3 results) Presentation (14 results) (of which Int'l Joint Research: 6 results) Book (1 results) Remarks (1 results)

  • [Journal Article] γ-Glutamylcysteine synthetase and γ-glutamyl transferase as differential enzymatic sources of γ-glutamylpeptides in mice.2020

    • Author(s)
      Kobayashi Sho, Ikeda Yoshitaka, Shigeno Yuhei, Konno Hiroyuki, Fujii Junichi
    • Journal Title

      Amino Acids

      Volume: - Issue: 4 Pages: 555-566

    • DOI

      10.1007/s00726-020-02835-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterozygous SOD1 deficiency in mice with an NZW background causes male infertility and an aberrant immune phenotype2019

    • Author(s)
      Homma Takujiro、Takeda Yuji、Sakahara Satoshi、Ishii Naoki、Kobayashi Sho、Abe Hiroyuki、Asao Hironobu、Fujii Junichi
    • Journal Title

      Free Radical Research

      Volume: 53 Issue: 11-12 Pages: 1060-1072

    • DOI

      10.1080/10715762.2019.1677901

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro2019

    • Author(s)
      Homma Takujiro、Kobayashi Sho、Sato Hideyo、Fujii Junichi
    • Journal Title

      Experimental Cell Research

      Volume: 384 Issue: 1 Pages: 111592-111592

    • DOI

      10.1016/j.yexcr.2019.111592

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Induction of ferroptosis by singlet oxygen generated from naphthalene endoperoxide2019

    • Author(s)
      Homma Takujiro、Kobayashi Sho、Fujii Junichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 518 Issue: 3 Pages: 519-525

    • DOI

      10.1016/j.bbrc.2019.08.073

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ascorbic acid insufficiency impairs spatial memory formation in juvenile AKR1A-knockout mice2019

    • Author(s)
      Kurihara Kazuki、Homma Takujiro、Kobayashi Sho、Shichiri Mototada、Fujiwara Hiroki、Fujii Satoshi、Yamada Ken-ichi、Nakane Masaki、Kawamae Kaneyuki、Fujii Junichi
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 65 Issue: 3 Pages: 209-216

    • DOI

      10.3164/jcbn.19-41

    • NAID

      130007740759

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative analysis of γ-glutamylpeptides by liquid chromatography-mass spectrometry and application for γ-glutamyltransferase assays2019

    • Author(s)
      Kobayashi Sho、Tokairin Yoshinori、Miyakoshi Takeru、Saito Takuya、Nagaoka Keita、Ikeda Yoshitaka、Fujii Junichi、Konno Hiroyuki
    • Journal Title

      Analytical Biochemistry

      Volume: 578 Pages: 13-22

    • DOI

      10.1016/j.ab.2019.04.023

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ferroptosis caused by cysteine insufficiency and oxidative insult2019

    • Author(s)
      Fujii Junichi、Homma Takujiro、Kobayashi Sho
    • Journal Title

      Free Radical Research

      Volume: - Issue: 11-12 Pages: 1-12

    • DOI

      10.1080/10715762.2019.1666983

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Unveiling systemic organ disorders associated with impaired lipid catabolism in fasted SOD1-deficient mice2018

    • Author(s)
      Lee Jaeyong、Homma Takujiro、Kobayashi Sho、Ishii Naoki、Fujii Junichi
    • Journal Title

      Archives of Biochemistry and Biophysics

      Volume: 654 Pages: 163-171

    • DOI

      10.1016/j.abb.2018.07.020

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cystine/glutamate transporter, system x c- , is involved in nitric oxide production in mouse peritoneal macrophages2018

    • Author(s)
      Kobayashi S、Hamashima S、Homma T、Sato M、Kusumi R、Bannai S、Fujii J、Sato H
    • Journal Title

      Nitric Oxide

      Volume: 78 Pages: 32-40

    • DOI

      10.1016/j.niox.2018.05.005

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mice deficient in aldo-keto reductase 1a (Akr1a) are resistant to thioacetamide-induced liver injury.2018

    • Author(s)
      Homma T., Shirato T., Akihara R., Kobayashi S., Lee J., Yamada K., Miyata S., Takahashi M., Fujii J.
    • Journal Title

      Toxicol. Lett.

      Volume: 294 Pages: 37-43

    • DOI

      10.1016/j.toxlet.2018.05.015

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease2018

    • Author(s)
      Fujii Junichi、Homma Takujiro、Kobayashi Sho、Seo Han Geuk
    • Journal Title

      World Journal of Biological Chemistry

      Volume: 9 Issue: 1 Pages: 1-15

    • DOI

      10.4331/wjbc.v9.i1.1

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Oxidative stress aggravates proteasome inhibitor bortezomib-induced proteotoxicity in mice2019

    • Author(s)
      Homma Takujiro、Ishii Naoki、Kobayashi Sho、Fujii Junichi
    • Organizer
      9th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia)、Kyoto
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Carnosine dipeptidase2 (CNDP2) as a potential survival factor for xCT-deficient cells against ferroptosis2019

    • Author(s)
      Kobayashi Sho、Homma Takujiro、Okumura Nobuaki、Takao Toshifumi、Sato Hideyo、Fujii Junichi
    • Organizer
      9th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia)、Kyoto
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Quantiative analysis of γ-glutamylpeptides by LC-MS and application for studying liver injury and γ-glutamyltransferase assay2019

    • Author(s)
      Fujii Junichi、Kobayashi Sho、Tokairin Yoshinori、Miyakoshi Takeru、Saito Takuya、Nagaoka Keita、Ikeda Yoshinori、Konno Hiroyuki
    • Organizer
      9th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia)、Kyoto
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] フリーラジカル消去剤エダラボンによるフェロトーシス抑制作用2019

    • Author(s)
      本間拓二郎、小林翔、佐藤英世、藤井順逸
    • Organizer
      第72回日本酸化ストレス学会学術集会、札幌
    • Related Report
      2019 Annual Research Report
  • [Presentation] LC-MSによるγグルタミルペプチド類の定量解析と生体内でのγグルタミルペプチド類の産生経路に関する研究2019

    • Author(s)
      小林翔、文潔、本間拓二郎、茂野優平、長岡啓太、斎藤拓也、池田義孝、今野博行、藤井順逸
    • Organizer
      第92回日本生化学会大会、横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] Aldehyde reductase (Ak1a)ノックアウトマウスの発育障害ならびに発癌剤感受性に関する検討2019

    • Author(s)
      石井直樹、本間拓二郎、小林翔、藤井順逸
    • Organizer
      第92回日本生化学会大会、横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] エダラボンをはじめとする各種フリーラジカル消去剤によるフェロトーシス抑制作用2019

    • Author(s)
      本間拓二郎、小林翔、佐藤英世、藤井順逸
    • Organizer
      第92回日本生化学会大会、横浜
    • Related Report
      2019 Annual Research Report
  • [Presentation] Hepatocytes are resistant to cysteine deficiency-induced ferroptosis due to recruitment of cysteine by the transsulfuration patyway.2018

    • Author(s)
      Fujii Junichi、 Lee Jaeyong、 Kobayashi Sho、 Homma Takujiro、 Kang Eun Sil、 Sato Hideyo、 Seo Han Geuk
    • Organizer
      International Cell Death Society Meeting, Korea
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Macrophages from xCT-deficient mice survive under high oxidative stress caused by cysteine and glutathione insufficiency.2018

    • Author(s)
      Kobayashi Sho、 Hamashima Shinji、 Homma Takujiro、 Seo Han Geuk、 Sato Hideyo、 Fujii Junichi
    • Organizer
      International Cell Death Society Meeting, Korea
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Oxidative stress causes male infertility by triggering autoimmune response in mice with the NZW background.2018

    • Author(s)
      Homma Takujiro、 Ishii Naoki、 Kobayashi Sho、 Seo Han Geuk、 Fujii Junichi
    • Organizer
      International Cell Death Society Meeting, Korea
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cys取込みによるグルタチオン合成の制御とgamma-グルタミル化ペプチドの生成機構2018

    • Author(s)
      藤井順逸、小林翔、 本間拓二郎、 池田義孝
    • Organizer
      第71回日本酸化ストレス学会, 京都
    • Related Report
      2018 Research-status Report
  • [Presentation] xCT遺伝子欠損マクロファージの生存を可能にする分子機構の解明2018

    • Author(s)
      小林翔、 本間拓二郎、 奥村宣明、 佐藤英世、 高尾敏文、 藤井順逸
    • Organizer
      第91回日本生化学会大会, 京都
    • Related Report
      2018 Research-status Report
  • [Presentation] Oxidative stress triggers systemic organ disorders associated with impaired lipid catabolism in mice during fasting.2018

    • Author(s)
      Takujiro Homma, Jaeyong Lee, Toshihiro Kurahashi, Sho Kobayashi, Naoki Ishii, Junichi Fujii
    • Organizer
      第41回日本分子生物学会大会, 横浜
    • Related Report
      2018 Research-status Report
  • [Presentation] バイオマーカーとしてのγグルタミルペプチド生成経路に関する検討2018

    • Author(s)
      小林翔、 李在勇、 本間拓二郎、 今野博行、 池田義孝、 藤井順逸
    • Organizer
      日本生化学会東北支部第84回例会, 盛岡
    • Related Report
      2018 Research-status Report
  • [Book] Ferroptosis in Health and Disease (Daolin Tang ed)2019

    • Author(s)
      Fujii Junichi、Kobayashi Sho、Homma Takujiro
    • Total Pages
      324
    • Publisher
      Springer Nature
    • Related Report
      2019 Annual Research Report
  • [Remarks] 山形大学大学院 医学系研究科 生命環境医科学専攻 生化学・分子生物学講座

    • URL

      http://www.id.yamagata-u.ac.jp/BiochemII/b2.html

    • Related Report
      2019 Annual Research Report 2018 Research-status Report

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Published: 2018-04-23   Modified: 2021-02-19  

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