BAP1は,細胞変容を抑制するミトコンドリアへのIP3R3媒介のCa2+流を調節する

Angela Bononi¹, Carlotta Giorgi², Simone Patergnani²

¹University of Hawaii Cancer Center, University of Hawaii, Honolulu, Hawaii 96813 USA.

Nature

|June 15, 2017

まとめ

BRCA1関連タンパク質1 (BAP1) 変異は,その核および細胞質の機能を損ない,癌を引き起こす. 減少したBAP1レベルは,DNA損傷後のアポトーシスを防止し,キャリアの腫瘍発症を促進します.

科学分野:

腫瘍学
分子生物学
遺伝学

背景:

BRCA1関連タンパク質1 (BAP1) は,ゲノムの完全性にとって重要な腫瘍抑制剤です.
遺伝的なBAP1変異 (BAP1+/-) は,メソテリオマとウエアルメラノマを含む様々な癌を引き起こす.
DNA修復におけるBAP1の核の役割は確立されているが,細胞質の機能は不明である.

研究の目的:

BAP1の未知の細胞質の機能を調査する.
BAP1がDNA損傷と環境発がん物質に対する細胞反応における役割を明らかにする.
BAP1+/- キャリアにおける癌の発症のメカニズムを理解する.

主な方法:

BAP1のサブセルラー部位を特定するための局所化研究
BAP1の相互作用相手と基質を特定するための生化学的測定.
BAP1レベルが異なる細胞におけるカルシウム流量測定とアポトーシス測定
遺伝子毒性ストレスにさらされた後の細胞変容の評価

主要な成果:

BAP1はエンドプラズマの網膜に局所することが判明した.
BAP1はイノシトール三酸塩受容体3型 (IP3R3) に結合し,デウビキチラ化し,安定させます.
BAP1のレベルが低下すると,DNA損傷後のカルシウム放出とアポトーシスの誘発が妨げられ,細胞の変容率が増加します.

結論:

エンドプラズマ網膜におけるBAP1の細胞質活動が,アポトーシスの誘導と腫瘍抑制に不可欠である.
BAP1+/- キャリアにおける核および細胞質BAP1機能の欠乏は,がんの発症に寄与する.
BAP1は,がん発生過程で遺伝子と環境の相互作用を調節する上で重要な役割を果たします.

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