Tip60は,オンコゲン誘発のDNA損傷反応に必要なハプロインサフィエンスの腫瘍抑制剤です
Chiara Gorrini1, Massimo Squatrito, Chiara Luise
1Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Milan 20139, Italy.
Nature
|August 31, 2007
まとめ
アセチルトランスファーゼTip60は,Myc誘発リンパマゲネシスに対抗することによって,腫瘍抑制剤として作用します. Tip60のハプロ不足は,早期の腫瘍段階でDNAダメージ応答 (DDR) を低下させ,p53変異と連携します.
科学分野:
- 腫瘍学 腫瘍学
- 分子生物学は分子生物学である.
- 遺伝学 遺伝学とは
背景:
- アセチルトランスフェラーゼであるTip60は,Mycやp53.3のような転写因子を調節することにより,腫瘍形成に影響を与えます.
- Tip60はDNAダメージ応答 (DDR) 信号伝達を調節し,腫瘍遺伝子が誘発すると腫瘍の進行を逆転させることができます.
研究 の 目的:
- ハップロ不足マウスモデルを使用して,Myc誘発リンパ変生におけるTip60の役割を調査する.
- Tip60の腫瘍抑制活性が,DDRおよびARF-p53経路におけるその機能と関連しているかどうかを判断する.
主な方法:
- Tip60ノックアウトアレル (Tip60+/-) に対してヘテロジゴットであるE(mu) -mycトランスジェニックマウスを利用した.
- Myc誘発リンパマゲネシス,DDR,転写,増殖,ARF-p53経路を評価した.
- TIP60遺伝子変異とタンパク質発現のためにヒトリンパ腫と癌を分析した.
主要な成果:
- Tip60ヘテロジゴシティ (Tip60+/-) は,腫瘍前または早期の段階で,Myc誘発リンパマゲネシスをハプロ不十分な方法で抵消した.
- Tip60のヘテロジゴシティは,Myc誘発のDDRを低下させましたが,B細胞の一般的なDDR欠陥を引き起こしませんでした.
- 人間のTIP60 (HTATIP) は,リンパ腫と癌において,疾患のグレードとp53変異と相関する,頻繁なモノアレル損失を示した.
結論:
- Tip60は,ARF-p53経路におけるその役割とは独立して,マウスとヒトの両方で,ハプロ不十分な腫瘍抑制活性を示す.
- 十分なTip60レベルは,発症中の腫瘍細胞に腫瘍遺伝子誘発のDDRをマウントするために不可欠です.
- Tip60不全によるDDRの失敗は,p53変異と連携して腫瘍の進行を促進する可能性があります.
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