p53のMdm2媒介のNEDD8結合は,p53の転写活動を抑制する

Dimitris P Xirodimas¹, Mark K Saville, Jean-Christophe Bourdon

¹University of Dundee, Ninewells Hospital and Medical School, Department of Surgery and Molecular Oncology, Dundee DD1 9SY, UK.

Cell

|July 10, 2004

まとめ

Mdm2 E3リガゼは,p53腫瘍抑制剤をNEDD8で修正し,その転写活動を抑制する. これはMdm2を明らかにします.

科学分野:

分子生物学は分子生物学である.
がん研究がん研究
ウビキチン生物学

背景:

NEDD8結合経路は,主にSCFのユビキチンリガゼ複合体を調節する.
E3リガゼMdm2は,p53のユビキチン化と分解における役割で知られている.
SCF以外の基板におけるNEDD8改変の機能は,ほとんど未調査のままである.

研究の目的:

NEDD8結合におけるMdm2の役割を調査する.
Mdm2媒介のNEDD8改変がp53活動に与える影響を判断する.
UbiquitinとNEDD8の両方の結合経路におけるMdm2の関与を探求する.

主な方法:

温度に敏感なNEDD8結合変異細胞系 (TS-41) を利用した.
NEDDylation (3NKR) に抵抗するp53変異体を使用した.
p53のMdm2-依存のNEDD8変異と,そのトランスクリプション活動への影響が評価されました.

主要な成果:

Mdm2がp53腫瘍抑制体のNEDD8変異を媒介することを示した.
Mdm2自体がNEDD8の修正を受けていることを示しました.
Mdm2に依存したp53のNEDDylationがp53の転写活動を抑制することを確認しました.

結論:

Mdm2は,ユビキチンとNEDD8の両方の結合経路でE3リガゼとして機能します.
Mdm2によるp53のNEDD8改変は,p53の機能を制御する規制メカニズムとして機能します.
これは,基板タンパク質の調節におけるE3リガゼの既知の役割を拡大する.

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