Identification and functional analysis of regulators of senescence

• Project/Area Number: 16H06148
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Johmura Yoshikazu 東京大学, 医科学研究所, 助教 (40616322)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000); Fiscal Year 2018: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2017: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2016: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
• Keywords: 老化 / 細胞周期 / 代謝 / がん / ゲノムワイド / 癌 / シグナル伝達 / p53 / ゲノムワイド解析

Outline of Final Research Achievements

Senolytic removal of senescent cells (senolysis) has been proposed to be beneficial for improving various age-associated pathologies, but effective compounds as well as the molecular pathways for their senolytic activity have not yet emerged. In the present study, genome-wide shRNA screening identified GLS1 as an essential gene for survival of senescent cells. The intracellular pH in senescent cells was lowered by excess protein synthesis-mediated lysosomal membrane damage, and this lowered intracellular pH induced KGA-type GLS1 expression. Enhanced glutaminolysis then caused the production of ammonia which neutralized the lowered pH and improved survival of the senescent cells. GLS1 inhibitor treatment of aged mice eliminated senescent cells and ameliorated age-associated kidney dysfunction. Our results suggest that cells in a senescent state require glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.

Academic Significance and Societal Importance of the Research Achievements

最近の研究により、加齢に伴う老化細胞の蓄積が老化・老年病発症の大きな要因の一つであることも分かりつつあり、老化細胞除去薬の開発が世界的に注目されている。本研究により、グルタミナーゼ阻害剤により老化細胞を選択的に除去することが可能となった。今後、より臨床に即した形でグルタミナーゼ阻害剤の研究を進めることで、動脈硬化症、腎障害、さらにはがんなどの加齢性疾病の治療・予防の新たな方法論の開発に大きく貢献できるものと考えられる。

Research Products

• [Journal Article] Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase. (2019)
  • Author(s): Nishimura K, Johmura Y, Deguchi K, Jiang Z, Uchida KSK, Suzuki N, Shimada M, Chiba Y, Hirota T, Yoshimura SH, Kono K, Nakanishi M.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41467-019-08957-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isozyme-Specific Role of SAD-A in Neuronal Migration During Development of Cerebral Cortex (2018)
  • Author(s): Nakanishi Keiko、Niida Hiroyuki、Tabata Hidenori、Ito Tsuyoshi、Hori Yuki、Hattori Madoka、Johmura Yoshikazu、Yamada Chisato、Ueda Takashi、Takeuchi Kosei、Yamada Kenichiro、Nagata Koh-ichi、Wakamatsu Nobuaki、Kishi Masashi、Pan Y Albert、Ugawa Shinya、Shimada Shoichi、Sanes Joshua R、Higashi Yujiro、Nakanishi Makoto
  • Journal Title: Cerebral Cortex Volume: 160 Issue: 9 Pages: 721-721
  • DOI: 10.1093/cercor/bhy253
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. (2018)
  • Author(s): Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 12 Pages: 5603-5619
  • DOI: 10.1172/jci121679
  • Peer Reviewed / Open Access
• [Journal Article] The G2 checkpoint inhibitor CBP-93872 increases the sensitivity of colorectal and pancreatic cancer cells to chemotherapy. (2017)
  • Author(s): Iwata T, Uchino T, Koyama A, Johmura Y, Koyama K, Saito T, Ishiguro S, Arikawa T, Komatsu S, Miyachi M, Sano T, Nakanishi M, Shimada M.
  • Journal Title: Plos one Volume: 12 Issue: 5 Pages: 1-13
  • DOI: 10.1371/journal.pone.0178221
  • Peer Reviewed / Open Access
• [Journal Article] Usp7-dependent histone H3 deubiquitylation regulates maintenance of DNA methylation. (2017)
  • Author(s): Yamaguchi L, Nishiyama A, Misaki T, Johmura Y, Ueda J, Arita K, Nagao K, Obuse C, Nakanishi M
  • Journal Title: Scientific reports Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-017-00136-5
  • Peer Reviewed / Open Access
• [Journal Article] A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. (2017)
  • Author(s): Negishi Y, Miya F, Hattori A, Johmura Y, Nakagawa M, Ando N, Hori I, Togawa T, Aoyama K, Ohashi K, Fukumura S, Mizuno S, Umemura A, Kishimoto Y, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Nakanishi M, Saitoh S.
  • Journal Title: BMC Med Genet. Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12881-016-0363-6
  • Peer Reviewed / Open Access
• [Journal Article] HP1 regulates the localization of FANCJ at sites of DNA double-strand breaks. (2016)
  • Author(s): Wu W, Togashi Y, Johmura Y, Miyoshi Y, Nobuoka S, Nakanishi M, Ohta T.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 10 Pages: 1406-1415
  • DOI: 10.1111/cas.13008
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple facets of p53 in senescence induction and maintenance. (2016)
  • Author(s): Johmura Y, Nakanishi M.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 11 Pages: 1550-1555
  • DOI: 10.1111/cas.13060
  • Peer Reviewed / Open Access
• [Journal Article] Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. (2016)
  • Author(s): Johmura Y, Yamashita E, Shimada M, Nakanishi K, Nakanishi M.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 31194-31194
  • DOI: 10.1038/srep31194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization. (2016)
  • Author(s): Kato K, Satouh Y, Nishimasu H, Kurabayashi A, Morita J, Fujihara Y, Oji A, Ishitani R, Ikawa M, Nureki O.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 12198-12198
  • DOI: 10.1038/ncomms12059
  • NAID: 120006957420
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Challenging boundaries in healthspan: Mechanisms of cellular senescence induction and maintenance (2019)
  • Author(s): Yoshikazu Johmura
  • Organizer: 6th Symposium of the Smart-Aging Research Center
  • Invited
• [Book] アンチ・エイジング医学 (2018)
  • Author(s): 城村由和、中西真.
  • Total Pages: 7
  • Publisher: ディカルレビュー社
  • ISBN: 9784779221606
• [Book] 実験医学 (2017)
  • Author(s): 城村由和、中西真
  • Total Pages: 6
  • Publisher: 羊土社
  • ISBN: 9784758101677