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Dissecting the physiological roles of CNOT4 ubiquitin ligase for prevention of fetal growth restriction.

Research Project

Project/Area Number 18K15038
Research Category

Grant-in-Aid for Early-Career Scientists

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

Principal Investigator

Yamaguchi Tomokazu  秋田大学, 医学系研究科, 助教 (30749940)

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: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsCNOT4 / 胚発生 / ユビキチン転移酵素 / 細胞増殖 / RNA結合タンパク質 / 胎児発育不全 / CCR4-NOT複合体
Outline of Final Research Achievements

In this study, we analyzed the molecular functions of CNOT4 ubiquitin ligase to dissect its physiological roles in mammalian tissues. Although CNOT4 RING mutant mice show prenatal growth retardation and high postnatal lethality, mutant embryo developed with wild type placenta made by aggregation chimaera also showed developmental deficiency, indicating that occurrence of those phenotypes were independent of placental formation. For further analysis, we generated CNOT4 floxed mice and depleted CNOT4 in MEFs. As a result, significant decrease of cell proliferation rate and increased cell death CNOT4-depleted MEFs were observed. In addition, RNA-seq analysis of CNOT4 knockdown HEK293T cells suggested that CNOT4 positively regulate mRNA expression that contribute to embryonic organ development.

Academic Significance and Societal Importance of the Research Achievements

ユビキチン転移酵素であるCNOT4の哺乳類組織における役割を報告した例はいまだない。本研究では、変異型CNOT4を発現するマウスは胎児期の発育不全と出生後の高い致死率を示すことから、胎児の発育にCNOT4が必須の役割を果たすことがわかり、培養細胞においてはCNOT4が発現しない条件下では発生に必要な種々の遺伝子の発現が有意に低下してしまうことが明らかとなった。以上の発見は、胚発生期におけるユビキチン化修飾と遺伝子発現制御との連携に焦点を当てた新たなパラダイムの構築に繋がり、将来的には胎児発育不全やそれに付随する種々の疾病の解明と新たな治療技法の確立のための重要な基礎情報になると期待している。

Report

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

    (17 results)

All 2020 2019 2018

All Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction2020

    • Author(s)
      Minato T, Nirasawa S, Sato T, Yamaguchi T, Hoshizaki M, Inagaki T, Nakahara K, Yoshihashi T, Ozawa R, Yokota S, Natsui M, Koyota S, Yoshiya T, Yoshizawa-Kumagaye K, Motoyama S, Gotoh T, Nakaoka Y, Penninger JM, Watanabe H, Imai Y, Takahashi S, Kuba K
    • Journal Title

      Nature Communications

      Volume: 11(1) Issue: 1 Pages: 1058-1058

    • DOI

      10.1038/s41467-020-14867-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential functions of the CNOT7/8 catalytic subunits of the CCR4-NOT complex in mRNA regulation and cell viability2020

    • Author(s)
      Mostafa Dina、Takahashi Akinori、Yanagiya Akiko、Yamaguchi Tomokazu、Abe Takaya、Kureha Taku、Kuba Keiji、Kanegae Yumi、Furuta Yasuhide、Yamamoto Tadashi、Suzuki Toru
    • Journal Title

      RNA Biology

      Volume: 17 Issue: 3 Pages: 403-416

    • DOI

      10.1080/15476286.2019.1709747

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The CCR4-NOT deadenylase complex maintains adipocyte identity2019

    • Author(s)
      Takahashi A., Takaoka S., Kobori S., Yamaguchi T., Ferwati S., Kuba K., Yamamoto T., and Suzuki T.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 Issue: 21 Pages: 5274-5274

    • DOI

      10.3390/ijms20215274

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome‐Scale CRISPR/Cas9 Screening Reveals Squalene Epoxidase as a Susceptibility Factor for Cytotoxicity of Malformin A12019

    • Author(s)
      Koizumi Yukio、Fukushima Jun、Kobayashi Yayoi、Kadowaki Ayumi、Natsui Miyuki、Yamaguchi Tomokazu、Imai Yumiko、Sugiyama Toshihiro、Kuba Keiji
    • Journal Title

      ChemBioChem

      Volume: 20 Issue: 12 Pages: 1-7

    • DOI

      10.1002/cbic.201800769

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology.2018

    • Author(s)
      Kuba K, Sato T, Imai Y, Yamaguchi T
    • Journal Title

      Peptides.

      Volume: in press Pages: 62-70

    • DOI

      10.1016/j.peptides.2018.04.011

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 圧負荷心不全におけるCNOT6L脱アデニル化因子の抗線維化作用の解明2020

    • Author(s)
      山口智和、佐藤輝紀、湊隆文、安健博、星崎みどり、渡邊博之、今井由美子、山本雅、久場敬司
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 心不全病態モデルマウスにおけるmRNA poly(A)制御、翻訳制御の生理機能の解明2019

    • Author(s)
      山口智和、佐藤輝紀、中岡慎治、久場敬司
    • Organizer
      2019年度「先進ゲノム支援」拡大班会議
    • Related Report
      2019 Annual Research Report
  • [Presentation] Protective roles of CNOT6L deadenylase in pressure overload-induced cardiac remodeling2019

    • Author(s)
      Tomokazu Yamaguchi, Teruki Sato, Takafumi Minato, Jianbo An, Midori Hoshizaki, Hiroyuki Watanabe, Yumiko Imai, Tadashi Yamamoto, Keiji Kuba
    • Organizer
      The 50th NIPS International Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CCR4-NOT脱アデニル化因子による心臓リモデリング抑制作用の解析2019

    • Author(s)
      山口智和、佐藤輝紀、湊隆文、安健博、星崎みどり、渡邊博之、今井由美子、山本雅、久場敬司
    • Organizer
      第29回日本循環薬理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肥満組織におけるCNOT4ユビキチンリガーゼの生理機能解析2019

    • Author(s)
      山口智和、佐藤輝紀、夏井美幸、星崎みどり、山本雅、今井由美子、久場敬司
    • Organizer
      第92回生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 細胞増殖制御におけるユビキチン転移酵素CNOT4の機能解析2019

    • Author(s)
      山口智和
    • Organizer
      第7回CCR4-NOT研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CCR4-NOT 複合体によるAtg7 依存性細胞死の阻害と心臓の恒常性維持2019

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第83回 日本生化学会 東北支部例会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CNOT4ユビキチンリガーゼによるRNA制御機構の解析2018

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第6回CCR4NOT研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] Atg7依存性細胞死を阻害するCCR4-NOT脱アデニル化酵素 複合体の心機能制御機構の解明2018

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第20回 日本RNA学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] CCR4-NOT脱アデニル化酵素複合体による心機能制御機構の解明2018

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第69回 日本薬理学会北部会
    • Related Report
      2018 Research-status Report
  • [Presentation] CCR4-NOT脱アデニル化酵素複合体によるAtg7依存性細胞死の阻害と心機能改善作用2018

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 細胞恒常性維持におけるCCR4-NOT複合体を介した mRNA制御メカニズムの包括的解析2018

    • Author(s)
      山口智和、鈴木享、佐藤輝紀、高橋明格、山本雅、今井由美子、久場敬司
    • Organizer
      2018年度「先進ゲノム支援」拡大班会
    • Related Report
      2018 Research-status Report

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

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