Exploring the molecular mechanism of GTP-driven stress response system

• Project/Area Number: 20H03165
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 42030:Animal life science-related
• Research Institution: Keio University
• Principal Investigator: Sasaki Atsuo 慶應義塾大学, 政策・メディア研究科(藤沢), 特任教授 (80620385)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: エネルギー代謝 / シグナル伝達 / イノシトールリン脂質 / PI5P4K / GTP / 恒常性 / ストレス応答 / がん / 代謝 / がん代謝 / p53 / トランスクリプトーム / プロテオーム

Outline of Research at the Start

生体の恒常性は、合成と分解のバランスにより保たれている。がん細胞のように増殖の盛んな細胞では、合成が亢進し分解が抑制することが広く知られている。分解には、活性を失ったタンパク質や、細胞内の小器官ミトコンドリアなどを除去し恒常性を保つ役割、栄養飢餓状態において、余剰のタンパク質などを分解し、再利用に用いたり、またエネルギーを取り出す重要な役割がある。そのため増殖細胞は、機能不全タンパクや細胞内小器官の蓄積が起こり、また栄養飢餓に陥りやすくなる。本研究では、合成亢進にともなうストレスを細胞がどのように克服しているのかを、独自に見出したGTPエネルギーを起点にしたシステムから解明を目指す。

Outline of Final Research Achievements

The research focused on PI5P4Kβ, a protein that senses the energy needed for cell growth. To elucidate how this protein regulates intracellular signals, biochemical analysis and data analysis were conducted to discover a new mechanism for how cells grow under stress. Furthermore, these results provide clues to how cells respond to the various stress conditions they encounter.

Academic Significance and Societal Importance of the Research Achievements

ストレス条件下において、細胞の成長やエネルギー管理に重要な役割を果たすたんぱく質「PI5P4Kβ」の働きを理解することに貢献した。これにより、がん細胞の成長を制御する新たな治療方法の開発につながる可能性がもたらされた。細胞のエネルギー感知機能についての知見は、がん治療だけでなく、一般的な病気の理解にも応用できるため、広範な社会的意義が期待される。

Research Products

• [Journal Article] Homogeneous luminescent quantitation of cellular guanosine and adenosine triphosphates (GTP and ATP) using QT-LucGTP&ATP assay (2023)
  • Author(s): Kopra Kari、Mahran Randa、Yli-Hollo Titta、Tabata Sho、Vuorinen Emmiliisa、Fujii Yuki、Vuorinen Iida、Ogawa-Iio Aki、Hirayama Akiyoshi、Soga Tomoyoshi、Sasaki Atsuo T.、H?rm? Harri
  • Journal Title: Analytical and Bioanalytical Chemistry Volume: 415 Issue: 27 Pages: 6689-6700
  • DOI: 10.1007/s00216-023-04944-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells (2023)
  • Author(s): Ikeda Yoshiki、Davis Mindy I.、Sumita Kazutaka、Zheng Yuxiang、Kofuji Satoshi、Sasaki Mika、Hirota Yoshihisa、Pragani Rajan、Shen Min、Boxer Matthew B.、Takeuchi Koh、Senda Toshiya、Simeonov Anton、Sasaki Atsuo T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 679 Pages: 116-121
  • DOI: 10.1016/j.bbrc.2023.08.050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional molecular evolution of a <scp>GTP</scp> sensing kinase: <scp>PI5P4Kβ</scp> (2023)
  • Author(s): Takeuchi Koh、Senda Miki、Ikeda Yoshiki、Okuwaki Koji、Fukuzawa Kaori、Nakagawa So、Sasaki Mika、Sasaki Atsuo T.、Senda Toshiya
  • Journal Title: The FEBS Journal Volume: 290 Issue: 18 Pages: 4419-4428
  • DOI: 10.1111/febs.16763
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity (2022)
  • Author(s): Takeuchi Koh、Ikeda Yoshiki、Senda Miki、Harada Ayaka、Okuwaki Koji、Fukuzawa Kaori、Nakagawa So、Yu Hong Yang、Nagase Lisa、Imai Misaki、Sasaki Mika、Lo Yu-Hua、Ito Doshun、Osaka Natsuki、Fujii Yuki、Sasaki Atsuo T.、Senda Toshiya
  • Journal Title: Structure Volume: 30 Issue: 6 Pages: 886-899.e4
  • DOI: 10.1016/j.str.2022.04.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Beyond Warburg: LDHA activates RAC for tumour growth (2022)
  • Author(s): Osaka Natsuski、Sasaki Atsuo T.
  • Journal Title: Nature Metabolism Volume: 4 Issue: 12 Pages: 1623-1625
  • DOI: 10.1038/s42255-022-00709-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification (2021)
  • Author(s): Osaka Natsuki、Hirota Yoshihisa、Ito Doshun、Ikeda Yoshiki、Kamata Ryo、Fujii Yuki、Chirasani Venkat R.、Campbell Sharon L.、Takeuchi Koh、Senda Toshiya、Sasaki Atsuo T.
  • Journal Title: Frontiers in Molecular Biosciences Volume: 8 Pages: 1-12
  • DOI: 10.3389/fmolb.2021.707439
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SI-MOIRAI: a new method to identify and quantify the metabolic fate of nucleotides (2021)
  • Author(s): Ikeda Yoshiki、Hirayama Akiyoshi、Kofuji Satoshi、Hirota Yoshihisa、Kamata Ryo、Osaka Natsuki、Fujii Yuki、Sasaki Mika、Ikeda Satsuki、Smith Eric P、Bachoo Robert、Soga Tomoyoshi、Sasaki Atsuo T
  • Journal Title: The Journal of Biochemistry Volume: 170 Issue: 6 Pages: 699-711
  • DOI: 10.1093/jb/mvab077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting Energy Metabolism to Overcome Therapeutic Resistance of Glioblastoma and Tumor-associated Edema (2021)
  • Author(s): Dasgupta Biplab、Hirota Yoshihisa、Fujii Yuki、Osaka Natsuki、Ito Doshun、Plas David R.、Sasaki Atsuo T.
  • Journal Title: Gliomas Volume: 1 Pages: 121-138
  • DOI: 10.36255/exonpublications.gliomas.2021.chapter7
  • ISBN: 9780645001747
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emerging Roles of Wild-type and Mutant IDH1 in Growth, Metabolism and Therapeutics of Glioma (2021)
  • Author(s): Garrett Matthew、Fujii Yuki、Osaka Natsuki、Ito Doshun、Hirota Yoshihisa、Sasaki Atsuo T.
  • Journal Title: Gliomas Volume: 1 Pages: 61-78
  • DOI: 10.36255/exonpublications.gliomas.2021.chapter4
  • ISBN: 9780645001747
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis. (Posters). (2024)
  • Author(s): Aki Ogawa-Iio.(Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (Posters). (2024)
  • Author(s): Fujii Yuki. (Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] Identification of DNA damage response-related genes as biomarkers for castrationresistant prostate cancer. (Posters). (2024)
  • Author(s): Oshima Masashi. (Mentor: Atsuo Sasaki).
  • Organizer: 13TH ANNUAL RESEARCH SYMPOSIUM DEPARTMENT OF INTERNAL MEDICINE
  • Int'l Joint Research
• [Presentation] GTP-sensor PI5P4Kβ counteracts anabolic stresses by lysosomal acidification.(Poster). (2024)
  • Author(s): Yoshiki Ikeda, Risa Kawaguchi, Yoshihisa Hirota, Shun Kageyama, Akiyoshi Hirayama, Kazutaka Sumita,Mikako Warren, Yuki Fujii, Mika Sasaki, Kensuke Tateishi, Manabu Natsumeda, Tomoyoshi Soga, Takahisa Nakamura, Diego Perez-Tilve, Koh Takeuchi, Toshiya Senda, Atsuo T. Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis.(Poster) . (2024)
  • Author(s): Aki OGAWA-IIO, Kari Kopra, Harri H, Satoshi Ogasawara, Ryo Kamata, Atsuo T Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] Workshop 2: Metabolic Targets and Vulnerabilities. Fueling the Way-The Role of Localized GTP Synthesis in Renal Cell Carcinoma Metastasis.(Presentation). (2024)
  • Author(s): Aki Ogawa-Iio, Ryo Kamata, Hirofumi Yoshino, Kara Wolfe, Satoshi Kofuji, Harri H, Kari Kopra, Titta Yli-Hollo, Osamu Ogawa, Eijiro Nakamura, Takeshi Kobayashi,Satoshi Ogasawara, Takeshi Murata, Koh Takeuchi, Toshiya Senda, Tomoyoshi Soga, Akiyoshi Hirayama, Laura M Machesky, Atsuo T Sasaki.
  • Organizer: KEYSTONE SYMPOSIA on Molecular and Cellular Biology Tumor Metabolism (B3)
  • Int'l Joint Research
• [Presentation] G-SHINE プローブによる細胞内GTP 局在可視化法とその応用(口頭発表). (2023)
  • Author(s): 飯尾 亜樹、Kari Kopra、Harri H、小笠原 諭、鎌田 諒、佐々木 敦朗.
  • Organizer: 第46回日本分子生物学会
• [Presentation] 時空間マルチスケール分析が照らすGTPエネルギー代謝の未踏領域（口頭発表） (2023)
  • Author(s): 佐々木敦朗
  • Organizer: 第46回日本分子生物学会
  • Invited
• [Presentation] プロドラッグ・ミコフェノール酸モフェチルは非肝臓細胞でも活性化されるのか？(口頭発表) (2023)
  • Author(s): 大田祐誠,佐々木敦朗
  • Organizer: 第46回日本分子生物学会
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (2023)
  • Author(s): Yuki Fujii, Aki Iio (Ogawa), Shun Kageyama, Sho Tabata, Kazutaka Sumita, Mika Sasaki, Ko Takeuchi, Toshiya Senda, Atsuo T. Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research
• [Presentation] At the Front of Cancer Metastasis -A Dynamic Role of Energy Metabolism(Presentations). (2023)
  • Author(s): Atsuo T Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research / Invited
• [Presentation] Fueling the way-The Role of Localized GTP Synthesis in Cancer Metastasis(Presentations). (2023)
  • Author(s): Atsuo T Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research / Invited
• [Presentation] Targeting the GTP sensing kinase PI5P4Kβ to sensitize oxidative and nutrient stresses to suppress the metastatic potential of invasive cancer cells. (Posters). (2023)
  • Author(s): Yuki Fujii, Aki Ogawa-lio, Shun Kageyama, Sho Tabata, Kazutaka Sumita, Mika Sasaki, Ko Takeuchi, Toshiya Senda, Atsuo Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research
• [Presentation] Inosine monophosphate dehydrogenase drives "leadership" in collective cell migration of glioblastoma.(Posters) (2023)
  • Author(s): Aki Ogawa-lio, Satoshi Kofuji, Kari Kopra, Harri H, Satoshi Ogasawara,Atsuo Sasaki.
  • Organizer: CANCER METASTASIS RESEARCH SYMPOSIUM.
  • Int'l Joint Research
• [Presentation] Role of GTP metabolism in human health and diseases (2023)
  • Author(s): Atsuo Sasaki
  • Organizer: Scienc-Ome
  • Int'l Joint Research / Invited
• [Presentation] Role of GTP metabolism in human health and diseases (2022)
  • Author(s): Atsuo Sasaki
  • Organizer: Invited speaker at the Cutting-Edge Biotechnology Laboratory Exploration
  • Invited
• [Presentation] Role of GTP metabolism in human health and diseases (2022)
  • Author(s): Atsuo Sasaki
  • Organizer: Department of Internal Medicine (DOIM) Research Conference
  • Invited
• [Presentation] Role of GTP metabolism in human health and diseases (2022)
  • Author(s): Atsuo Sasaki
  • Organizer: 2022 Cancer Symposium for Sub-Cellular Dynamics, University of Cincinnati Cancer Center
  • Int'l Joint Research / Invited
• [Presentation] GTP Energy Metabolism and Brain Tumors (2021)
  • Author(s): 佐々木 敦朗
  • Organizer: Northwestern University, Basic Research Seminar Series
  • Int'l Joint Research / Invited
• [Presentation] 生命のしなやかさと進化の鍵;GTPレジリエンス研究が拓く未来 (2021)
  • Author(s): 佐々木 敦朗
  • Organizer: 日本分子生物学会年会;GTPワークショップ
  • Int'l Joint Research / Invited
• [Presentation] GTP Energy Metabolism and Cancers (2020)
  • Author(s): 佐々木 敦朗
  • Organizer: WFBCCC-Grand Round Seminar_Wake Forest School of Medicine
  • Invited
• [Presentation] GTPエネルギーによる新たな遺伝子発現と代謝調節メカニズム (2020)
  • Author(s): 佐々木 敦朗
  • Organizer: 第２回鶴岡カンファレンス2020
  • Invited
• [Presentation] GTP代謝研究の夜明け前 (2020)
  • Author(s): 佐々木 敦朗
  • Organizer: 第４３回分子生物学会年会 ワークショップ「細胞のエネルギー制御の進化と多様化」
  • Int'l Joint Research / Invited