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Anti-aging drugs by targeting PTEN

Research Project

Project/Area Number 20K20661
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Studies on the Super-Aging Society
Research InstitutionKobe University

Principal Investigator

Suzuki Akira  神戸大学, 医学研究科, 教授 (10311565)

Project Period (FY) 2020-07-30 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsPTEN / 長寿薬 / がん抑制遺伝子 / 長寿
Outline of Research at the Start

健康的に長寿を迎えたいという欲求は、古来からの人間の根源的な欲望である。
近年、線虫やショウジョウバエにおいて、寿命を制御する遺伝子がいくつか判明し、抗糖尿病薬メトフォルミンを投与した正常マウスが長寿になること等も示されて、人類が古来から夢見ていた長寿薬の探索が現実となってきた。
今回我々はPTENの不安定化分子を標的とする長寿薬のハイスループットスクリーニングを行い、健康的寿命の延長と国民福祉の向上を目指す。

Outline of Final Research Achievements

Two E3 SUMOylating enzymes (X, Y) and the deubiquitinating enzyme Z were identified as PTEN binding and destabilising molecules. Knockdown of X and Y increased PTEN, decreased phosphorylated AKT and reduced cell proliferation, whereas knockdown of Z resulted in nuclear localisation of PTEN and increased PTEN protein. X and Y homozygous deletion mice have been generated and their longevity is currently being investigated.
On the other hand, we found that WWP2, one of the 5 PTEN E3 ligases, has the highest PTEN destabilising effect, so a PTEN-WWP2 binding visualisation system was established and chemical compounds were screened. Six compounds were positive, but no PTEN increase was obtained. We are currently screening for unpublished small molecules.

Academic Significance and Societal Importance of the Research Achievements

長寿薬の開発は古来からの人類の夢であり、その開発が待たれる。近年PTENを軽度増加せると寿命が延長することが示された。一方PTENは代表的な癌抑制ドライバー分子であるために、その制御機構の解明は癌治療につながる。本研究によって癌の発症抑制をも兼ねそなえた、PTENタンパク質安定性亢進を標的とする長寿薬の開発によって、健康寿命の延長と国民福祉の向上を狙うことが可能となる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (38 results)

All 2022 2021 2020 Other

All Int'l Joint Research (3 results) Journal Article (8 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 8 results,  Open Access: 7 results) Presentation (26 results) (of which Int'l Joint Research: 6 results,  Invited: 2 results) Book (1 results)

  • [Int'l Joint Research] トロント大学(カナダ)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] Toronto University(カナダ)

    • Related Report
      2021 Research-status Report
  • [Int'l Joint Research] Toronto University/University of British Columbia(カナダ)

    • Related Report
      2020 Research-status Report
  • [Journal Article] A mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their diseaseassociated regulation.2022

    • Author(s)
      Morioka S, Nakanishi H, Yamamoto T, Hasegawa J, Tokuda E, Hikita T, Sakihara T, Kugii Y, Oneyama C, Yamazaki M, Suzuki A, Sasaki J, Sasaki T.
    • Journal Title

      Nature Communications

      Volume: 13(1) Issue: 1 Pages: 83-83

    • DOI

      10.1038/s41467-021-27648-z

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.2021

    • Author(s)
      Nakatani K, Maehama T, Nishio M, Otani J, Yamaguchi K, Fukumoto M, Hikasa H, Hagiwara S, Nishina H, Mak TW, Honma T, Kondoh Y, Osada H, Yoshida M, Suzuki A
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 10 Pages: 4303-4316

    • DOI

      10.1111/cas.15079

    • NAID

      120007159906

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands.2021

    • Author(s)
      Miyachi Y, Nishio M, Otani J, Matsumoto S, Kikuchi A, Mak TW, Maehama T, Suzuki A.
    • Journal Title

      Genes Cells.

      Volume: 26(9) Issue: 9 Pages: 714-726

    • DOI

      10.1111/gtc.12879

    • NAID

      120007148944

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hepatocyte MKK7 Contributes to Restoration of the Liver Parenchyma Following Injury2020

    • Author(s)
      Ooshio Takako、Yamamoto Masahiro、Fujii Kiyonaga、Xin Bing、Watanabe Kenji、Goto Masanori、Okada Yoko、Suzuki Akira、Penninger Josef M.、Nishina Hiroshi、Nishikawa Yuji
    • Journal Title

      Hepatology

      Volume: online Issue: 6 Pages: 31565-31565

    • DOI

      10.1002/hep.31565

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] YAP1 is a potent driver of the onset and progression of oral squamous cell carcinoma2020

    • Author(s)
      Omori Hirofumi、Nishio Miki、Masuda Muneyuki、Miyachi Yosuke、Ueda Fumihito、Nakano Takafumi、Sato Kuniaki、Mimori Koshi、Taguchi Kenichi、Hikasa Hiroki、Nishina Hiroshi、Tashiro Hironori、Kiyono Tohru、Mak Tak Wah、Nakao Kazuwa、Nakagawa Takashi、Maehama Tomohiko、Suzuki Akira
    • Journal Title

      Science Advances

      Volume: 6 Issue: 12 Pages: 3324-3324

    • DOI

      10.1126/sciadv.aay3324

    • NAID

      120006818745

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition.2020

    • Author(s)
      Ishihara E, Nagaoka Y, Okuno T, Kofuji S, Ishigami-Yuasa M, Kagechika H, Kamimura K, Terai S, Yokomizo T, Sugimoto Y, Fujita Y, Suzuki A, Nishina H.
    • Journal Title

      Genes Cells.

      Volume: 25(3) Issue: 3 Pages: 197-214

    • DOI

      10.1111/gtc.12750

    • NAID

      120006873037

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.2020

    • Author(s)
      Miki Nishio , Yoko To , Tomohiko Maehama , Yukari Aono , Junji Otani , Hiroki Hikasa , Akihiro Kitagawa , Koshi Mimori , Takehiko Sasaki , Hiroshi Nishina , Shinya Toyokuni , John P Lydon , Kazuwa Nakao , Tak Wah Mak , Tohru Kiyono , Hidetaka Katabuchi , Hironori Tashiro , Akira Suzuki
    • Journal Title

      Cancer science

      Volume: 111 Issue: 10 Pages: 3576-3578

    • DOI

      10.1111/cas.14581

    • NAID

      120006892076

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The role of Hippo-YAP signaling in squamous cell carcinomas.2020

    • Author(s)
      Tomohiko Maehama , Miki Nishio , Junji Otani , Tak Wah Mak , Akira Suzuki
    • Journal Title

      Cancer science

      Volume: 112 Issue: 1 Pages: 51-60

    • DOI

      10.1111/cas.14725

    • NAID

      120006950333

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] がん抑制因子PTENの制御に関わる新たな因子の同定2022

    • Author(s)
      池末信太郎、前濱朝彦、西尾美希、大谷淳二、鈴木聡
    • Organizer
      第19回生命科学研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] がん抑制因子PTENの制御に関わる新たな因子の同定2022

    • Author(s)
      前濱朝彦、池末信太郎、西尾美希、大谷淳二、鈴木聡
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Hippo-YAP signaling pathway in squamous cell carcinoma onset and progression2021

    • Author(s)
      Tomohiko Maehama, Miki Nishio, Junji Otani, Akira Suzuki
    • Organizer
      The 39th Sapporo International Cancer Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hippo-YAP signaling pathway in squamous cell carcinoma onset and progression2021

    • Author(s)
      Tomohiko Maehama, Miki Nishio, Junji Otani, Akira Suzuki
    • Organizer
      The 5th UW-KU International Joint Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] The role of Hippo-TAZ pathway in basal like breast cancer2021

    • Author(s)
      曽山弘敏、西尾美希、増田隆明、三森功士、原重雄、前濱朝彦、福本巧、鈴木聡
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] A carbazole compound affects Hippo signaling pathway and represses bladder cancer cell proliferation2021

    • Author(s)
      白石祐介, 前濱朝彦, 西尾美希, 藤沢正人, 鈴木聡
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hippoシグナルによるがんの発症進展制御2021

    • Author(s)
      西尾美希、前濱朝彦、大谷淳二、曽山弘敏、鈴木聡
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Hippoシグナルによる舌がんの発症および進展の制御2021

    • Author(s)
      前濱朝彦、大森裕文、西尾美希、鈴木聡
    • Organizer
      第66回公益社団法人日本口腔外科学会総会・学術大会
    • Related Report
      2021 Research-status Report
  • [Presentation] PICT1を基点とした核小体ストレス応答の分子機構2021

    • Author(s)
      前濱朝彦、西尾美希、鈴木聡
    • Organizer
      第44回分子生物学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] PTENの安定性を制御する新たな因子の同定2021

    • Author(s)
      池末信太郎、前濱朝彦、西尾美希、大谷淳二、鈴木聡
    • Organizer
      第10回日本プロテインホスファターゼ研究会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 乳腺の腫瘍化におけるHippoキナーゼ経路の機能解析2021

    • Author(s)
      曽山弘敏、西尾美希、大谷淳二、福本巧、前濱朝彦、鈴木聡
    • Organizer
      第10回日本プロテインホスファターゼ研究会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 膀胱癌の増殖を抑制するHippo経路を標的とした低分子化合物の開発2021

    • Author(s)
      白石祐介、前濱朝彦、西尾美希、鈴木聡
    • Organizer
      第10回日本プロテインホスファターゼ研究会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] トリプルネガティブ乳癌発症進展の鍵となる Hippo-TAZ 経路2021

    • Author(s)
      曽山弘敏, 前濱朝彦, 西尾美希, 鈴木聡
    • Organizer
      第五回徳島大学研究クラスター合同会議
    • Related Report
      2021 Research-status Report
  • [Presentation] Hippo経路による扁平上皮癌の制御2020

    • Author(s)
      前濱朝彦、西尾美希、大森裕文、田代浩徳、中尾一和、鈴木聡
    • Organizer
      第57回日本臨床分子医学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Asymmetric distribution of cadherin-catenin complex drives cell intercalations in nectin-dependent mosaic cellular pattern formation2020

    • Author(s)
      Shuhei Kuno, Sayaka Katsunuma, Akira Suzuki, and Hideru Togashi.
    • Organizer
      53rd Annual meeting of the Japanese Society of Developmental Biologists
    • Related Report
      2020 Research-status Report
  • [Presentation] 核小体オルガネラゾーンにおけるストレス制御と癌の発症進展機構2020

    • Author(s)
      前濱朝彦、大谷淳二、鈴木 聡
    • Organizer
      オルガネラゾーン領域会議
    • Related Report
      2020 Research-status Report
  • [Presentation] Hippo経路分子MOB1による肥満の制御2020

    • Author(s)
      山口慶子、西尾美希、鈴木聡
    • Organizer
      【先端モデル動物支援プラットフォーム】若手支援技術講習会
    • Related Report
      2020 Research-status Report
  • [Presentation] YAPの多段階活性化による扁平上皮癌の発症・進展の制御2020

    • Author(s)
      前濱朝彦、西尾美希、大森裕文、鈴木聡
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] "Asymmetric distribution of cadherin-catenin complex drives cell intercalations in nectin-dependent mosaic cellular pattern formation"2020

    • Author(s)
      久野 舟平、勝沼 紗矢香、鈴木 聡、富樫 英
    • Organizer
      JSDB Online Trial Meeting 2020 (日本発生生物学会)
    • Related Report
      2020 Research-status Report
  • [Presentation] YAPの多段階活性化による扁平上皮癌の発症・進展の制御2020

    • Author(s)
      前濱朝彦、西尾美希、大森裕文、鈴木聡
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] YAP1/TAZ阻害による抗腫瘍作用を示す天然物の同定2020

    • Author(s)
      西尾美希、中谷圭佑、大谷淳二、日笠弘基、前濱朝彦、鈴木聡
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] がん抑制遺伝子の機能解析2020

    • Author(s)
      鈴木 聡、西尾美希、藤 庸子、大森博文、田代浩徳、前濱朝彦
    • Organizer
      第19回日本産婦人科がん分子標的研究会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Squamous cell carcinoma onset and progression driven by multistep YAP activation2020

    • Author(s)
      Tomohiko Maehama, Miki Nishio, Hirofumi Omori, Akira Suzuki
    • Organizer
      The 14th International Conference on Protein Phosphatase
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] A natural product Alantolactone is a potent YAP1/TAZ inhibitor via ROS production2020

    • Author(s)
      Junji Otani, Keisuke Nakatani, Tomohiko Maehama, Miki Nishio, Akira Suzuki
    • Organizer
      The 14th International Conference on Protein Phosphatase
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hippo-YAP/TAZ経路による肥満の制御2020

    • Author(s)
      山口慶子、西尾美希、大谷淳二、前濱朝彦、鈴木聡
    • Organizer
      オルガネラゾーン若手の会
    • Related Report
      2020 Research-status Report
  • [Presentation] Hippo-YAP1経路異常と扁平上皮癌2020

    • Author(s)
      鈴木 聡
    • Organizer
      2020年度東京医科歯科大学難治疾患共同研究拠点シンポジウム
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] 医学のあゆみ2020

    • Author(s)
      前濱 朝彦、西尾 美希、鈴木 聡
    • Total Pages
      5
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2020 Research-status Report

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Published: 2020-08-03   Modified: 2024-01-30  

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