ユビキチンリガゼSCFFbw7は,アポプトティックJNKシグナル伝達に敵対する
Abdolrahman S Nateri1, Lluís Riera-Sans, Clive Da Costa
1Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Science (New York, N.Y.)
|January 24, 2004
まとめ
E3リガゼSCF (Fbw7) はc-Junの安定性を制御し,神経毒性を防止する. リン酸化c-Junを分解することによって,SCF (Fbw7) はニューロンをJun N-端末キナーゼ (JNK) 誘発のアポトーシスから保護する.
科学分野:
- 神経科学は神経科学である.
- 分子生物学は分子生物学である.
- セルラー・シグナリング
背景:
- Jun N-末端キナーゼ (JNKs) は,マイクロチューブルの組立とアポトーシスを含むニューロンプロセスにおいて重要な役割を果たします.
- JNK媒介の神経毒性は,転写因子c-Jun.のリン酸化と関連している.
- c-Junの安定性を調節する正確なメカニズムと神経毒性におけるその役割は完全に理解されていません.
研究 の 目的:
- 神経細胞におけるリン酸化c-Junの安定性を調節するE3リガスの役割を調査する.
- SCF (((Fbw7) がニューロンのアポトーシスに関与するJNKシグナル伝達経路にどのように影響するかを決定する.
- JNK誘発性神経毒性に対するニューロンの保護メカニズムを解明する.
主な方法:
- タンパク質の安定性と分解経路を研究するために神経細胞モデルを使用した.
- c-Junのリン酸化とユビキチネーションを評価するために,ウエスタン・ブロッティングや免疫プレシピテーションなどのテクニックを使用した.
- Fbw7減少がAP1転写因子活動とニューロンアポトーシスに与える影響を調査した.
主要な成果:
- E3結合酵素SCF ((Fbw7) を,神経細胞におけるリン酸化c-Jun安定性の主要な調節体として特定した.
- SCF ((Fbw7) が, fosforylated c-Jun を ubiquitinates で,分解をターゲットにすることを示した.
- Fbw7の枯渇はc-Junの蓄積,AP1の活性化,そして神経細胞の滅の増大につながることを示した.
結論:
- SCF ((Fbw7) は,JNKシグナル伝達の下流のc-Jun依存アポプトシス経路の重要な負の調節体として作用する.
- この調節メカニズムは,ニューロンが潜在的に神経毒性の高いJNK活動レベルに対する耐性を維持することを可能にします.
- SCF ((Fbw7) -c-Jun軸をターゲットにすると,JNK経路の調節障害を含む神経変性疾患の治療戦略を提供することができる.
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