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HIFトランザクティベーションドメインのアスパラジンヒドロキシル化が,ヒポキシスイッチスイッチである
David Lando1, Daniel J Peet, Dean A Whelan
1Department of Molecular Biosciences (Biochemistry), Adelaide University, SA 5005, Australia.
Science (New York, N.Y.)
|February 2, 2002
まとめ
低酸素誘導因子 (HIF) は,低酸素状態で安定性と効力を獲得します. この研究では,プロリンヒドロキシル化と並行してアスパラジンヒドロキシル化を阻害することで,p300との相互作用を可能にすることで,HIFを完全に活性化することが明らかになりました.
科学分野:
- 分子生物学は分子生物学である.
- 細胞のストレス反応は,
- 遺伝子規制 遺伝子規制
背景:
- 低酸素誘導因子 (HIF) は,低酸素状態への細胞適応を調節する重要な転写因子です.
- HIFの安定性と活性性は,主にノルモキシア下でVHL-ウビキチンリガゼ複合体経由でHIFを分解するプロリン水酸化を標的として,厳密に制御されています.
研究 の 目的:
- HIFのCOOH端末トランザクティベーション領域 (CAD) の低酸素誘導のメカニズムを調査する.
- HIF CAD内のアスパラジン水酸化が転写活動の調節における役割を決定する.
主な方法:
- アスパラジンの水酸化を阻害するために,Fe (II) -および2オキシグルタラート依存型ダイオキシゲナーゼの阻害剤を使用した.
- HIF CAD.で保存されたアスパラジン (Asn) をアラニン (Ala) で置き換え,部位指向型変異を生成した.
- HIF CADとp300トランスクリプションコアクティベーターの相互作用を評価した.
主要な成果:
- HIF CADの低酸素誘導は,アスパラジン水酸化の廃止によって媒介されます.
- ダイオキシゲナーゼを標的とする阻害剤はAsnの水酸化を阻害し,p300とのCAD相互作用を促進した.
- 構成的なp300相互作用と強力な転写活性は,Asn to Ala置換で観察されました.
結論:
- HIF-1αとHIF-2αの完全な誘導には,プロリンとアスパラジンの両方の水酸化を同時に廃止する必要があります.
- プロリン・ヒドロキスライゼーションはHIFの分解を調節し,アスパラジン・ヒドロキスライゼーションはノルモキシア下でトランザクティベーションドメインの活動を制御する.
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