Development of degron system for cancer therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03171
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Kyoto University
• Principal Investigator: Naruse Chie 京都大学, 医学研究科, 准教授 (30372486)
• Co-Investigator(Kenkyū-buntansha): 杉原 一司 京都大学, 医学研究科, 技術職員 (10377418) ; 浅野 雅秀 京都大学, 医学研究科, 教授 (50251450)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: マウス / デグロン / プロテインノックダウン / PD-1

Outline of Final Research Achievements

We established a system that can degrade PD-1 in a time-specific manner in cultured cells and mice using SMASh degron system. PD-1-SMASh fusion protein in Jurkat cells and CD3+ splenocytes was reduced by 1 day after administration of Asunaprevir (ASV) or Grazoprevir (GRV) that are NS3/4A protease inhibitors. Growth of MC-38 adenocarcinoma cells inoculated in PD-1-mCherry-SMASh knockin (KI) mice with ASV was repressed compared to wild-type (WT) and untreated KI mice. Moreover, the WT mice transplanted with KI bone marrow cells after being irradiated with lethal radiation could reject MC-38 cells with GRV. KI mice appeared healthy and showed no signs of autoimmune disease. We suggest that use of the degron system in living organisms is expected to advance not only various biological studies but the treatment of diseases.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

動物個体での内在性タンパク質に対するプロテインノックダウンシステムは，タグが致死的であることや，発現量の制御等の困難により，未だに困難である。本研究は、必要な時だけ特定のタンパク質を分解して減らすことのできるデグロンシステムによって、マウス生体内の内在性タンパク質を機能阻害できることを示した最初の例の１つであり、様々な生物現象や病気の治療法の研究などに応用することが期待できる。