2022 Fiscal Year Final Research Report

Elucidation of new non-genomic mechanisms of action of retinoic acid and their applications

Research Project

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Project/Area Number	20K07021
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	Hoshi University
Principal Investigator	Takahashi Noriko 星薬科大学, 薬学部, 教授 (50277696)
Co-Investigator(Kenkyū-buntansha)	今井正彦星薬科大学, 薬学部, 講師 (40507670) 長谷川晋也星薬科大学, 薬学部, 講師 (60386349)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	レチノイン酸 / レチノイル化 / タンパク質修飾 / シグナル伝達 / プロテインキナーゼA
Outline of Final Research Achievements	Retinoic acid (RA) is an essential bodily nutrient that is attracting increasing attention for its potential value in the prevention and treatment of cancer and lifestyle-related diseases. Using human leukemia cells, we investigated retinoylation (protein modification by RA), which is a non-genomic mechanism of RA action that differs from its nuclear receptor-mediated actions. We elucidated physiological roles of retinoylation of the actin-binding protein α-actinin and the regulatory subunit of protein kinase A (PKA). We found that retinoylation stabilizes and changes the localization of each protein and that nuclear retinoylated PKA phosphorylates splicing regulatory factors and histones. These nuclear proteins are important for gene expression regulation, and promoting cell differentiation and suppression of proliferation. Our results support non-genomic actions of RA.
Free Research Field	生化学
Academic Significance and Societal Importance of the Research Achievements	レチノイル化は、RAとタンパク質が共有結合することでタンパク質の構造変化を引き起こすRA修飾であり、安定性・局在性・酵素活性等に変化を与えることから、RA受容体とは異なる新しい情報伝達機構である。本研究で、レチノイル化が細胞骨格関連タンパク質α-アクチニンの安定性と局在性に変化を与えることを示す。また、核内レチノイル化PKAによりリン酸化される基質としてスプライシング調節因子SF2を同定し、細胞分化・増殖抑制経路を実証する。さらに、核レチノイル化ヒストンによるエピジェネティクス制御の提案は、RA受容体経路の補完という学術的意義を与える。この新経路を基にした抗がん剤開発は大きな社会的意義を持つ。