発達中の不適切なp53活性化により,CHARGE症候群の特徴が誘発される
Jeanine L Van Nostrand1, Colleen A Brady2, Heiyoun Jung1
1Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature
|August 15, 2014
まとめ
発達中の腫瘍抑制剤p53の不適切な活性化により,CHARGE症候群の表型が引き起こされます. この発見は,発達障害におけるp53の重要な役割を明らかにし,CHARGE症候群のメカニズムに関する新しい洞察を提供します.
科学分野:
- 発達生物学 発達生物学とは
- 遺伝学 遺伝学とは
- 分子生物学は分子生物学である.
背景:
- CHARGE症候群は,さまざまな表型を持つ複雑な疾患であり,しばしばCHD7遺伝子における変異と関連しています.
- CHARGE症候群のフェノタイプを駆動する正確な分子経路は,ほとんど不明のままです.
- 腫瘍抑制タンパク質p53 (Trp53とも呼ばれる) は,細胞周期調節とアポトーシスにおいて重要な役割を果たします.
研究 の 目的:
- CHARGE症候群の病原性における腫瘍抑制タンパク質p53の役割を調査する.
- 発達過程におけるCHD7とp53の関係を探求する.
- CHARGE症候群の潜在的な治療標的を特定する.
主な方法:
- 野生型のp53アレルと共に安定した,転写的に死んだp53変異体 (p53(25,26,53,54) を表現するノックインマウスモデルの生成と分析.
- ミュータントマウス胚における胚死亡率とフェノタイプの特徴の評価.
- CHD7のp53プロモーターとの相互作用を調査し,マウスのニューラル・クライスト細胞と患者のサンプルでCHD7の喪失に反応するp53活性化の分析.
- Chd7-nullのマウス胚におけるCHARGE型のフェノタイプに対するp53異合性の効果の評価.
主要な成果:
- 特定のp53変異体 (p53 ((25,26,53,54)) は,CHARGE症候群のような表型を持つ妊娠期の末期の胚死亡を引き起こし,コロボーマ,耳の変形,心臓の欠陥,頭蓋の異常を含む.
- p53変異体は野生型p53を過度に活性化させ,開発中に不適切な細胞サイクル停止またはアポトーシスを引き起こした.
- CHD7は,プロモーターに結合することによってp53発現を否定的に調節する;マウスモデルとCHARGE症候群の患者におけるCHD7の喪失はp53の活性化をもたらした.
- p53ヘテロジゴシティによるChd7-nullマウス胚フェノタイプの部分的な救済は,CHARGE症候群の病原性へのp53の貢献を示唆しました.
結論:
- 胚発達中の不適切なp53活性化は,CHARGE症候群の表型に大きく寄与する要因である.
- CHD7の喪失はp53の活性化につながり,この経路がCHARGE症候群に関与している.
- p53は発達症候群において重要な役割を果たし,CHARGE症候群のメカニズムと潜在的な治療戦略に関する新しい洞察を提供します.
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