透明細胞腎臓細胞がんにおける腫瘍発生因子としてのVHL基板転写因子ZHX2
Jing Zhang1,2, Tao Wu3, Jeremy Simon1,4
1Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Science (New York, N.Y.)
|July 21, 2018
まとめ
フォン・ヒッペル・リンダウ (VHL) タンパク質の喪失は,クリアセル腎臓細胞癌 (ccRCC) を誘発する. 研究者は,ZHX2をVHL標的として特定し,ZHX2をccRCCの潜在的な治療標的として明らかにした.
科学分野:
- 腫瘍学
- 分子生物学
- 生物化学
背景:
- フォン・ヒッペル・リンダウ (VHL) E3ユビキチンリガゼの不活性化は,クリアセル腎臓細胞癌 (ccRCC) の病原性における重要な出来事である.
- VHLの喪失によって影響を受ける下流経路を理解することは,効果的なccRCC治療法の開発に不可欠です.
研究 の 目的:
- 水酸化時にVHLと相互作用するタンパク質を特定する.
- 特定されたVHL目標の ccRCCの開発と進歩における役割を調査する.
- ccRCCの潜在的な治療標的としてZHX2を調査する.
主な方法:
- VHL結合タンパク質を特定するための全ゲノムインビトロ発現スクリーニング.
- VHLによるZHX2タンパク質の安定性調節の評価
- ccRCC患者の腫瘍におけるZHX2の豊富性と局所性の分析.
- ZHX2の枯渇を伴うインビトロおよびインビボ機能検査
- 統合されたクロマチンの免疫降水配列とマイクロアレイ分析により,分子メカニズムが解明される.
主要な成果:
- 亜鉛指とホメオボックス2 (ZHX2) はVHL標的として特定され,その水酸化によりVHL媒介のタンパク質安定性調節が可能になった.
- VHL変異を有するccRCC腫瘍細胞において,ZHX2の多量化と核の局所化が観察された.
- ZHX2の枯渇は,VHL欠乏性CCRCC細胞の成長をインビトロとインビボの両方で有意に抑制しました.
- ZHX2は核因子 κB (NF-κB) の活性化を促進することが判明した.
結論:
- ZHX2は,ccRCCに関与する新しいVHL標的タンパク質です.
- ZHX2は,ccRCC細胞の成長とNF-κBの活性化を促進する上で重要な役割を果たします.
- ZHX2は,ccRCC治療の有望な治療目標です.
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