FBXW7は,mTORの分解を標的とし,PTENと協力して腫瘍抑制を行う

Jian-Hua Mao¹, Il-Jin Kim, Di Wu

¹Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, CA 94143, USA.

Science (New York, N.Y.)

|September 13, 2008

まとめ

腫瘍抑制剤FBXW7は,哺乳類のラパミシン (mTOR) 標的を標的として分解する. 癌細胞におけるFBXW7の喪失は,ラパミシンなどのmTOR経路阻害剤に対する感受性を示している.

科学分野:

バイオケミストリーバイオケミストリー
分子生物学は分子生物学である.
腫瘍学腫瘍学

背景:

ラパミシン (mTOR) 経路の哺乳類の標的は,細胞成長において極めて重要であり,がん治療の重要な標的である.
mTORタンパク質のレベルを調節する仕組みを理解することは,効果的ながん治療の開発に不可欠です.
mTORの活動を制御する腫瘍抑制タンパク質の役割は,ほとんど未知のままです.

研究の目的:

ラパマイシン (mTOR) タンパク質のレベルを哺乳類のターゲットに制御する規制メカニズムを解明する.
癌の文脈でFBXW7とmTORの相互作用を調査する.
mTOR標的治療に対する反応を予測するための潜在的なバイオマーカーを特定する.

主な方法:

ウビキチネーションアッセイは,mTORの修正を検出する.
mTORの安定性を評価するためのタンパク質分解の研究.
FBXW7およびPTEN状態のためのヒト乳がん細胞系と原発腫瘍の分析.
FBXW7変異を有する腫瘍細胞系におけるラパミシン治療を用いた感受性測定.

主要な成果:

腫瘍抑制剤FBXW7は,mTORを直接標的として,ユビキチン化およびその後の分解を図る.
FBXW7の喪失とヒトの乳がんにおけるPTENの欠失/変異の間の相互関係が観察されました.
FBXW7の欠損または変異を有する腫瘍細胞系は,ラパミシンに対する過敏性を高めた.

結論:

FBXW7は,標的の分解を介して,mTORタンパク質レベルの負の調節剤として作用します.
FBXW7の喪失は,しばしばPTENの変異と併発し,mTOR経路阻害に敏感ながんを特定します.
FBXW7の状態は,がん治療におけるラパミシンおよび他のmTOR阻害剤療法に対する予測バイオマーカーとして機能することができます.

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