サイクリンE誘発の複製ストレスは,p53依存の全ゲノム複製を促進する

Jingkun Zeng¹, Stephanie A Hills¹, Eiko Ozono¹

¹Chromosome Replication Laboratory, The Francis Crick Institute, London NW1 1AT, UK.

Cell

|January 21, 2023

まとめ

逆説的にp53腫瘍抑制剤はがんにおける全ゲノム複製 (WGD) を促進する. p53によって促進されるサイクリンE1の発現は,エンドロデプリケーションと癌の進化を促します.

科学分野:

癌生物学
遺伝学
細胞生物学

背景:

全ゲノム複製 (WGD) は,がんにおける一般的な現象で,アヌプロイド症を引き起こします.
WGDにおける腫瘍抑制剤p53の役割は複雑で,バリアとファシリテーターの両方として作用します.
ワイルド型p53腫瘍におけるWGDは,しばしばE2F経路の活性化とCCNE1増幅を伴う.

研究の目的:

エンドロデュプリケーションによるWGDの促進におけるp53の役割を明らかにする.
高いサイクリンE1がWGDに寄与するメカニズムを調査する.
細胞バイパス後の細胞サイクル進行にp53がどのように影響するかを理解する.

主な方法:

シクリンE1発現率の上昇を背景に細胞サイクル調節の分析
WGDにおけるATR,Chk1,p21,Wee1,APC/Cdh1の関与を調査する.
ミトスバイパス後のp53媒介老化に対するサイクリンE1の影響を研究する.

主要な成果:

増加したサイクリンE1は,ATR/Chk1経由で複製ストレスとG2停止を誘導する.
p53,p21,およびWee1はCDKの活性を抑制し,APC/Cdh1の活性化とミトスのバイパスを促進する.
サイクリンE1はp53依存の衰老を抑制し,エンドロデプリケーションの完了を可能にします.

結論:

p53は,癌の進化に寄与し,エンドロデプリケーションを促進することによって,WGDを促進することができます.
サイクリンE1,p53と細胞サイクル調節体の相互作用は,WGDにとって極めて重要です.
この経路をターゲットにすることで WGDが誘発する癌に対する新しい治療戦略を提案できます

キーワード:

DNA複製アヌプロイドがん生物学細胞サイクルサイクリンE ミトスバイパス全ゲノム複製

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