哺乳類のラパミシン標的による翻訳抑制剤PHAS-Iのリン酸化
G J Brunn1, C C Hudson, A Sekulić
1Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Science (New York, N.Y.)
|July 4, 1997
まとめ
免疫抑制薬ラパミシンは,哺乳類のラパミシン (mTOR) キナーゼの標的をブロックすることによって,細胞サイクル進行を阻害する. この作用は,タンパク質合成の制御に不可欠なタンパク質であるPHAS-Iのリン酸化を防止します.
科学分野:
- 細胞生物学 細胞生物学
- 分子生物学は分子生物学である.
- 薬理学 薬理学とは
背景:
- ラパミシンは免疫抑制剤で,細胞サイクル進行を停止します.
- ラパミシン (mTOR) の哺乳類の標的は,細胞の成長と増殖に関与する重要なシグナル伝達タンパク質です.
- mTORは,細胞刺激とタンパク質合成の調節を結びつける経路における末端キナーゼとして作用する.
研究 の 目的:
- 細胞サイクル進行の調節におけるmTORの役割を明らかにする.
- ラパミシンがG1相進行を阻害するメカニズムを調査する.
- 翻訳制御におけるmTORの機能を定義する.
主な方法:
- リンパ性および他の細胞タイプにおけるG1相進行に対するラパミシンの効果を調査した.
- PHAS-Iリン酸化を調節する信号経路におけるmTORの位置を決定した.
- インスリン刺激細胞におけるPHAS-Iリン酸化のためのラパミシンに敏感なmTORキナーゼ活性度の必要性を調査した.
- mTOR.によるPHAS-Iの in vitro リン酸化アッセイを実施しました.
主要な成果:
- ラパミシンは,mTOR機能を阻害することによって,G1相進行を阻害します.
- mTORは末端キナーゼで,ミトゲン刺激をPHAS-Iリン酸化に結合する.
- mTORキナーゼ活動は,インスリンへの反応としてPHAS-Iリン酸化に不可欠です.
- mTORはセリンおよびセロニン残基のPHAS-Iをリン酸化する.
- mTORによるPHAS-Iリン酸化は,その結合をeukaryotic initiation factor (eIF) -4Eに阻害する.
結論:
- mTORは,翻訳制御において重要な役割を果たします.
- ラパミシンのG1相進行の阻害は,mTORおよびその後の翻訳調節への影響によって媒介されます.
- これらの発見は,細胞サイクル進行に対するラパミシンの作用の分子機構の洞察を提供します.
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