Structural analysis and regulation of transcription factor complexes involved in tumor development and progression.

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H02910
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 38030:Applied biochemistry-related
• Research Institution: Fasmac Co., Ltd. (2022-2023); The University of Tokyo (2020-2021)
• Principal Investigator: Miyazono Kenichi 株式会社ファスマック, バイオ研究支援事業部, 研究員(移行) (90554486)
• Co-Investigator(Kenkyū-buntansha): 栗崎 晃 奈良先端科学技術大学院大学, 先端科学技術研究科, 教授 (60346616)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: TGF-β / 分子間相互作用

Outline of Final Research Achievements

TGF-β regulates cell proliferation, differentiation, and other important biological processes. Therefore, dysregulation of TGF-b signal causes cancer development and malignant transformation. The central players of TGF-β signaling in cells are transcription factors SMAD2/3. SMAD2/3 form a variety of transcription factor complexes with other proteins (SMAD cofactors) to regulate multiple gene expression. In this study, we investigated the structures of the SMAD2/3-cofactor complexes and developed a novel method for the regulation of TGF-β signaling in cells. As a result, we determined the structures of SMAD2/3-transcription factor complexes (SMAD2-CBP, SMAD2-TMEPAI, etc.) by X-ray crystallography and demonstrated that TGF-β signaling can be suppressed through inhibition of transcription factor complex formation.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

TGF-βシグナルを細胞内で伝達する転写因子SMAD2/3は、多様な転写因子複合体を形成することが知られている。本研究では、その多様な複合体形成にかかわる構造基盤を明らかにしたほか、構造を元に設計したペプチド配列を利用することで、タンパク質分子間相互作用の阻害を通じたTGF-βシグナルの抑制を可能とした。TGF-βシグナル伝達系の異常はがんの発生や悪性化に強く関係しており、そのシグナル伝達機構の解明と新規制御法の構築はがんの新規治療法の開発のために重要な知見となる。