p53はリシン脱甲基酵素LSD1によって調節される
Jing Huang1, Roopsha Sengupta, Alexsandra B Espejo
1The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature
|September 7, 2007
まとめ
腫瘍抑制剤p53は,ライシンメチル化と脱メチル化によって調節される. デメチラーゼLSD1は,特定のメチレーションマークを逆転させ,遺伝子の活性化とアポトーシスに影響を与え,p53の活動を制御する.
科学分野:
- 分子生物学は分子生物学である.
- エピジェネティクス エピジェネティクス
- がん研究 がん研究
背景:
- 重要な腫瘍抑制剤であるp53は,ライシンメチル化のような翻訳後の改変によって調節されます.
- ヒストンライシンメチル化が可逆性があることは知られていますが,ヒストン以外のタンパク質の可逆性は確立されていません.
- 特定のメチル化マークがp53の機能とコアクティベーターとの相互作用に与える役割は不明でした.
研究 の 目的:
- ヒストンライシン特異性デメチラーゼLSD1が腫瘍抑制剤p53.3をデメチル化するかどうかを調査する.
- LSD1とp53の相互作用がp53媒介の転写活性化とアポトーシスに及ぼす影響を決定する.
- p53.5のK370における異なるメチル化状態の異なる役割を解明する.
主な方法:
- LSD1とp53.5の相互作用を研究するためのインビトロおよびインビボアッセイ.
- K370.0でp53のメチル化と脱メチル化の分析
- LSDの存在下でのp53の転写活動とアポトーシス促進の評価1.1.
- コアクティベーター53BP1とp53の関連性を調べた.
主要な成果:
- LSD1はp53と相互作用し,その転写活性化とアポトーシスを促進する機能を抑制する.
- LSD1は,p53のモノメチル化 (K370me1) と二メチル化 (K370me2) を,p53のK370でin vitro除去し,K370me2を vivoで優先する.
- K370me1はp53の機能を抑制し,K370me2はp53と53BP1.1の結合を促進する.
- LSD1は53BP1との相互作用を防ぐことでp53の機能を阻害する.
結論:
- p53はヒストンと似て,ライシンメチル化と脱メチル化によって動的に調節されます.
- p53のK370でのメチル化状態は,異なる規制結果を決定する.
- LSD1は,脱メチル化によってp53の活性を調節する上で重要な役割を果たし,がんにおける潜在的な治療標的を提供している.
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