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TGF-βは,RASエフェクターRREB1を介して,繊維性および発達性EMTをオーケストラする

Jie Su¹, Sophie M Morgani^2,3, Charles J David^1,4

¹Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

|January 10, 2020

まとめ

RAS反応性要素結合タンパク質1 (REB1) は,RASと成長因子β (TGF-β) 経路を結合し,上皮からメゼンキマへの移行 (EMT) を制御する. この発見により EMTが発育,線維症,がんの進行を促す仕組みが明らかになりました

科学分野:

細胞生物学
分子生物学
発達生物学

背景:

エピテリアからメゼンキマへの移行 (EMT) は,発育,傷の治癒,線維症,癌に不可欠です.
成長因子β (TGF-β) 信号伝達とRASとMAPK経路は,EMTを駆動しています.
調節不良のTGF-βシグナル伝達とEMTは,様々な線維性疾患と癌に関与しています.

研究の目的:

EMT誘導におけるRASとTGF-β経路を調整する分子メカニズムを解明する.
これらのシグナリングカスケードを統合するキーレギュレータを特定する.
発達過程と病理学的状態の両方でこれらの統合された経路の役割を理解する.

主な方法:

RAS反応性要素結合タンパク質1 (RREB1) とTGF-β活性化SMAD転写因子の相互作用を調査した.
MAPKで活性化されたRREB1によるSNAIL転写因子へのSMAD因子の徴集を分析した.
EMT中に遺伝子発現を調節する文脈依存のクロマチンのアクセシビリティを調べた.

主要な成果:

EMTにおけるSMAD転写因子の重要なパートナーとしてRREB1を特定した.
MAPKで活性化されたRREB1がSNAILに SMAD因子を誘発することを証明した.
RREB1とSMADは,クロマチンのアクセシビリティに基づいて特定の遺伝子を活性化し,がんにおける線維性EMTまたは発達中のメゼンドームの分化を誘導することを示した.

結論:

RREB1はRASとTGF-β経路の間の分子ブリッジとして機能し,EMTを調整します.
このメカニズムは開発と病気における EMTの二重の役割を説明します.
発見は,上皮の可塑性や癌や線維症におけるその役割の理解を深める.

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