ミトゲン活性化タンパク質キナーゼによるリン酸化によるエストロゲン受容体の活性化
1Department of Agricultural Chemistry, Tokyo University of Agriculture, Japan.
まとめ
エストロゲン受容体 (ER) Ser118のMAPKによるリン酸化は,ER活性化機能1 (AF-1) の活性化に不可欠である. Ras-MAPKのような成長因子シグナル伝達経路は,Ser118リン酸化経由でER活性を調節する.
科学分野:
- エンドクリノロジー エンドクリノロジー
- 分子生物学は分子生物学である.
- 細胞シグナル伝達 細胞信号伝達
背景:
- 人間のエストロゲン受容体 (ER) は,細胞プロセスにおいて重要な役割を果たします.
- 活性化機能1 (AF-1) は,ERの転写活動に不可欠である.
- リン酸化などの翻訳後の改変は,タンパク質の機能を調節する.
研究 の 目的:
- ERの活性におけるERセリン残留118 (Ser118) のリン酸化の役割を調査する.
- Ser118のリン酸化に責任を負うキナーゼを特定する.
- ER Ser118のリン酸化に関与するシグナル伝達経路とその転写活動への影響を解明する.
主な方法:
- インビトロおよびインビボのリン酸化測定法.
- サイト・ダイレクト・ミュータゲネシスにより,ER変異体 (Ser118からアラニン) が作られる.
- レポーター遺伝子解析は,転写活動の測定を目的としています.
- 信号経路の成分 (MAPKK, Ras) の過剰表現.
主要な成果:
- ER Ser118のリン酸化は,AF-1の完全な活性化に不可欠である.
- ミトゲン活性化タンパク質キナーゼ (MAPK) は,ER Ser118をインビトロおよびインビボでリン酸化する.
- 皮膚表皮成長因子 (EGF) とインスリン類似成長因子 (IGF) は,Ser118のリン酸化を刺激する.
- Ras-MAPK経路の活性化により,エストロゲンおよびタモキシフェン誘発のER転写活性が強化されます.
- Ser118でのアラニンを持つ変異性ERは,活性の強化を示さなかった.
結論:
- MAPKによるER Ser118のリン酸化は,ER AF-1の活性に対する重要な規制メカニズムである.
- 成長因子シグナル伝達経路,特にRas-MAPKカスケードは,Ser118リン酸化を通じてER活性を調節する.
- Ras-MAPK経路を標的にすることは,ER媒介遺伝子発現に影響を与える可能性があります.
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