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大学・研究所にある論文を検索できる 「IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

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IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells

安藤, 美波 大阪大学 DOI:10.18910/87838

2022.03.24

概要

Nuclear Factor-κB (NFκB) シグナル経路は幅広い種類の細胞外と細胞内シグナルを伝達して、多様な細胞応答を制御する。この過程で、NFκBの核内動態は3つのIB蛋白質(IκBα、IκBβとIκBε)による制御の絶妙なバランスによって制御されている。腫瘍壊死因子(TNF)刺激後、IκBα、IκBβとIκBεはリン酸化された後に分解され、これによってNFκBは核内に移行して転写制御を行うが、IκBαはNFκB活性の持続時間を制限し、応答する遺伝子の発現を抑制する負のフィードバック因子としてよく知られる。しかし、IκBαを介したNFκBの急速な活性化が標的遺伝子発現においてどのような生物学的な意義があるかは解明されていない。そこで、本研究では、ヒト乳癌細胞(MCF-7)におけるTNFに誘導されるNFκBの標的遺伝子発現誘導におけるIκBαの生物学的な役割について調べた。

そこで、IκBα存在下とNFκBをノックダウンした場合の二つの条件でNFκBの標的遺伝子の発現誘導の変化量を比較すると、一部の遺伝子ではIκBαをノックダウンした場合の方が、IκBα存在下よりも最大値が減少していた。そこで、数理モデルを用いてこれらの遺伝子を制御する転写制御メカニズムを調べた。その結果、IκBαをノックダウンした細胞において見られた、一部のNFκBの標的遺伝子の発現誘導の変化量の減少はインコヒーレントフィードフォワードループ(IFFL) モデルによって説明できることがわかった。さらに、IκBαのノックダウンによって負のフィードバック制御が無くなり、NFκBは持続的な活性を示したにも関わらず、一部のNFκB標的遺伝子の発現誘導のパターンは一過性であった。このことは、クロマチンの開閉の転写制御を表した循環型のクロマチンの状態遷移モデルによって遺伝子発現誘導が制御されていることを示唆した。JUNBやKLF10のような炎症に関連する重要な転写因子をコードする遺伝子の発現誘導のパターンは、このIFFLモデルと循環型のクロマチンの状態遷移モデルの両方を組み合わせたモデルによって最も正確に再現された。これらの結果から、炎症性の遺伝子が過剰に発現誘導されないようにブレーキを掛ける転写制御様式があることが明らかになった。そして、IκBαにはNFκBに対する負の制御因子としての役割だけでなく、刺激応答後にNFκBに制御される炎症性の標的遺伝子の発現誘導の変化量を高くする役割があることが明らかになった。これらの知見は、乳がん細胞におけるTNFに対する炎症性反応において、IκBαが複雑な役割を担っていることを示した。最後に、新型コロナウィルス感染症の後遺症に繋がる可能性があるNFκBの標的遺伝子の過剰な発現とNFκBの結合部位のアクセシビリティの増加が回復期にある重症の患者で見られた。

本研究の生物学的な意義は、IκBαにはNFκBに対する負の制御因子としての役割だけでなく、刺激応答後にNFκBに制御される炎症性の標的遺伝子の発現誘導を可能にする役割があることが明らかになったことである。また、NFκBシグナル経路における炎症性の遺伝子の過剰発現を抑制するための遺伝子発現制御メカニズムがあることも明らかになった。

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