Elucidation of balancing mechanisms of death receptor signaling mediated by STK11

• Project/Area Number: 18K06622
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Noguchi Takuya 東北大学, 薬学研究科, 准教授 (20431893)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アポトーシス / STK11 / キナーゼ / Fas / シグナル伝達 / Fasリガンド / カスパーゼ / RNAiスクリーニング / プロテインキナーゼ / TNF受容体 / FAS

Outline of Final Research Achievements

Fas-induced apoptosis is mediated by tow pathways, "internal pathway" and "external pathway", depending on whether or not mitochondrial outer membrane permeation is required. This study revealed that STK11 activates the external pathway by promoting the degradation of the anti-apoptotic factor XIAP. In addition, under the condition that the signal of the internal pathway is sufficiently transmitted, STK11 promotes PARP-dependent nuclear translocation of AIF and induces programmed cell death called parthanatos to enhance the activation of the internal pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果明、細胞死促進因子として我々が独自に同定したSTK11が、状況依存的に別々の機構を活性化することでFas誘導性アポトーシスの感受性を亢進させていることが明らかとなった。癌抑制遺伝子としてのSTK11の新たな腫瘍抑制機構
の発見は、癌研究領域での学術的意義が高い。また、STK11を介したアポトーシスシグナルSTK11によるFasシグナル制御機構を明らかにすることは、癌抑制遺伝子として注目されているSTK11を標的とした治療薬の有効性を担保する強力な科学的裏付けとなり、その治療薬開発に具体性と確実性をもたらす。

Research Products

• [Int'l Joint Research] University of Lausanne(スイス)
• [Int'l Joint Research] Department of Biochemistry/University of Lausanne(スイス)
• [Int'l Joint Research] University of Lausanne(スイス)
• [Journal Article] Gefitinib initiates sterile inflammation by pomoting IL-1β and HMGB1 release via two distinct mechanisms (2021)
  • Author(s): Takuya Noguchi, Yuto Sekiguchi, Yuki Kudoh, Rio Naganuma, Tomohiro Kagi, Akiko Nishidate, Kazuhiro Maeda, Chizuru Ishii, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa
  • Journal Title: Cell Death. Dis. Volume: 12 Issue: 1 Pages: 49-49
  • DOI: 10.1038/s41419-020-03335-7
  • Peer Reviewed / Open Access
• [Journal Article] The Antibiotic Cefotaxime Works as Both an Activator of Nrf2 and an Inducer of HSP70 in Mammalian Cells (2020)
  • Author(s): Yamada Mayuka、Suzuki Midori、Noguchi Takuya、Yokosawa Takumi、Sekiguchi Yuto、Mutoh Natsumi、Toyama Takashi、Hirata Yusuke、Hwang Gi-Wook、Matsuzawa Atsushi
  • Journal Title: BPB Reports Volume: 3 Issue: 1 Pages: 16-21
  • DOI: 10.1248/bpbreports.3.1_16
  • NAID: 130007944896
  • ISSN: 2434-432X
  • Peer Reviewed / Open Access
• [Journal Article] Pro-apoptotic functions of TRAF2 in p53-mediated apoptosis induced by cisplatin (2020)
  • Author(s): Tsuchida, M., Yokozawa, T., Noguchi, T., Shimada, T., Yamada, M., Sekiguchi, Y., Hirata, Y., Matsuzawa, A.
  • Journal Title: The Journal of Toxicological Sciences Volume: 45 Issue: 4 Pages: 219-226
  • DOI: 10.2131/jts.45.219
  • NAID: 130007825449
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms. (2020)
  • Author(s): Midori Suzuki, Yukino Asai, Tomohiro Kagi, Takuya Noguchi, Mayuka Yamada, Yusuke Hirata, Atsushi Matsuzawa
  • Journal Title: Int. J. Mol. Sci. Volume: 21 Issue: 24 Pages: 9497-9497
  • DOI: 10.3390/ijms21249497
  • Peer Reviewed / Open Access
• [Journal Article] trans-Fatty acids facilitate DNA damage-induced apoptosis through the mitochondrial JNK-Sab-ROS positive feedback loop (2020)
  • Author(s): Yusuke Hirata, Aya Inoue, Saki Suzuki, Miki Takahashi, Ryosuke Matsui, Nozomu Kono, Takuya Noguchi, Atsushi Matsuzawa
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-16
  • DOI: 10.1038/s41598-020-59636-6
  • Peer Reviewed / Open Access
• [Journal Article] The Antibiotic Cefotaxime Works as Both an Activator of Nrf2 and an Inducer of HSP70 in Mammalian Cells (2020)
  • Author(s): Mayuka Yamada, Midori Suzuki, Takuya Noguchi, Takumi Yokosawa, Yuto Sekiguchi, Natsumi Mutoh, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa
  • Journal Title: BPB reports Volume: 3 Pages: 16-21
  • NAID: 130007944896
  • Peer Reviewed / Open Access
• [Journal Article] Pro-caspase-3 protects cells from polymyxin B-induced cytotoxicity by preventing ROS accumulation (2020)
  • Author(s): T Yokosawa, M Yamada, T Noguchi, S Suzuki, Y Hirata, A Matsuzawa
  • Journal Title: The Journal of antibiotics Volume: 72 Issue: 11 Pages: 848-852
  • DOI: 10.1038/s41429-019-0216-6
  • Peer Reviewed / Open Access
• [Journal Article] The anti-cancer drug gefitinib accelerates Fas-mediated apoptosis by enhancing caspase-8 activation in cancer cells (2019)
  • Author(s): Yuto Sekiguchi, Mayuka Yamada, Takuya Noguchi, Chise Noomote, Mei Tsuchida, Yuki Kudoh, Yusuke Hirata, Atsushi Matsuzawa
  • Journal Title: The Journal of Toxicological Sciences Volume: 44 Issue: 6 Pages: 435-440
  • DOI: 10.2131/jts.44.435
  • NAID: 130007659535
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Nuclear-accumulated SQSTM1/p62-based ALIS act as microdomains sensing cellular stresses and triggering oxidative stress-induced parthanatos (2018)
  • Author(s): Noguchi Takuya、Suzuki Midori、Mutoh Natsumi、Hirata Yusuke、Tsuchida Mei、Miyagawa Sayoko、Hwang Gi-Wook、Aoki Junken、Matsuzawa Atsushi
  • Journal Title: Cell Death & Disease Volume: 9 Issue: 12 Pages: 1193-1193
  • DOI: 10.1038/s41419-018-1245-y
  • Peer Reviewed / Open Access