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Molecular mechanism of regulation of PSM activity by NRF1 O-GlcNAc modification

Research Project

Project/Area Number 17K08618
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General medical chemistry
Research InstitutionTohoku University

Principal Investigator

Sekine Hiroki  東北大学, 加齢医学研究所, 助教 (50506285)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords転写因子 / プロテアソーム / タンパク質恒常性 / 翻訳後修飾 / タンパク質分解 / 転写制御 / 生体分子医学
Outline of Final Research Achievements

Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1). O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model.

Academic Significance and Societal Importance of the Research Achievements

本研究でO-GlcNAc化ががんにおいて、プロテアソーム活性維持に関わることを明らかとした。一方で細胞内のタンパク質の恒常性維持(プロテオスタシス)は、正常な細胞機能にとっても極めて重要であり、その破綻が神経変性疾患、老化現象など多くの疾患の分子基盤となることが明らかにされている。またO-GlcNAc化は細胞の栄養状態によって制御されており、神経機能維持、日周性維持など多くの生命現象に関与する。本研究で明らかとしたO-GlcNAc化-プロテアソーム活性という軸は、これら幅広い生命現象に関わる可能性があり、がんだけでなく他の分野への波及効果は大きいと考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (13 results)

All 2019 2018 2017

All Journal Article (5 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (7 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (1 results)

  • [Journal Article] An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts2019

    • Author(s)
      Sato Koji、Hirano Ikuo、Sekine Hiroki、Miyauchi Kenichiro、Nakai Taku、Kato Koichiro、Ito Sadayoshi、Yamamoto Masayuki、Suzuki Norio
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 11254-11254

    • DOI

      10.1038/s41598-019-47766-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] O-GlcNAcylation Signal Mediates Proteasome Inhibitor Resistance in Cancer Cells by Stabilizing NRF12018

    • Author(s)
      Sekine Hiroki、Okazaki Keito、Kato Koichiro、Alam M. Morshedul、Shima Hiroki、Katsuoka Fumiki、Tsujita Tadayuki、Suzuki Norio、Kobayashi Akira、Igarashi Kazuhiko、Yamamoto Masayuki、Motohashi Hozumi
    • Journal Title

      Molecular and Cellular Biology

      Volume: 38 Issue: 17 Pages: 00252-18

    • DOI

      10.1128/mcb.00252-18

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A2018

    • Author(s)
      Dodo Mina、Kitamura Hiroshi、Shima Hiroki、Saigusa Daisuke、Wati Sisca Meida、Ota Nao、Katsuoka Fumiki、Chiba Hatsune、Okae Hiroaki、Arima Takahiro、Igarashi Kazuhiko、Koseki Takeyoshi、Sekine Hiroki、Motohashi Hozumi
    • Journal Title

      The Journal of Biochemistry

      Volume: 165 Issue: 4 Pages: 323

    • DOI

      10.1093/jb/mvy108

    • NAID

      40021893390

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activatpr NRF22017

    • Author(s)
      Alam MM, Okazaki K, Nguyen LTT, Ota N, Kitamura H, Murakami S, Shima H, Igarashi K, Sekine H, Motohashi H
    • Journal Title

      J Biol Chem

      Volume: 印刷中 Issue: 18 Pages: 7519-7530

    • DOI

      10.1074/jbc.m116.773960

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes2017

    • Author(s)
      Nezu Masahiro、Souma Tomokazu、Yu Lei、Sekine Hiroki、Takahashi Nobuyuki、Wei Andrew Zu-Sern、Ito Sadayoshi、Fukamizu Akiyoshi、Zsengeller Zsuzsanna K.、Nakamura Tomohiro、Hozawa Atsushi、Karumanchi S. Ananth、Suzuki Norio、Yamamoto Masayuki
    • Journal Title

      Sci Signal

      Volume: 10 Issue: 479

    • DOI

      10.1126/scisignal.aam5711

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] グルコース・グルタミンによるヘキソサミン経路を介したタンパク質の分解制御2019

    • Author(s)
      関根弘樹
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 低酸素誘導性因子HIF2aによる転写活性化の分子基盤2019

    • Author(s)
      関根弘樹
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] O-結合型糖鎖修飾によるがん細胞のプロテアソーム阻害剤の分子機構2018

    • Author(s)
      関根弘樹
    • Organizer
      第6回がんと代謝研究会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] O-GlcNAcylation signal confers resistance to proteasome inhibitors on cancer cells by increasing NRF1 stability.2018

    • Author(s)
      Hiroki Sekine.
    • Organizer
      The 77th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 翻訳後修飾を介したプロテアソームサブユニット遺伝子発現制御機構2017

    • Author(s)
      関根弘樹
    • Organizer
      第33回がん・エピゲノム研究会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] O-GlcNAcylation signal confers resistance to proteasome inhibitors on cancer cells by increasing NRF1 stability.2017

    • Author(s)
      Hiroki Sekine.
    • Organizer
      未来型医療拠点キックオフ 第二回カロリンスカ研究所・東北大学合同会議
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] O-GlcNAcylation signal confers resistance to proteasome inhibitors on cancer cells by increasing NRF1 stability.2017

    • Author(s)
      Hiroki Sekine, Keito Okazaki, Md. Morshedul Alam, Hozumi Motohashi.
    • Organizer
      第12回研究所ネットワーク国際シンポジウム
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Book] がん細胞の代謝とCNC転写因子MRF1, NRF2.医学のあゆみ2019

    • Author(s)
      関根弘樹、本橋ほづみ
    • Total Pages
      7
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2023-12-25  

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