NF-kappaBの標的遺伝子を介してJNK活性化の抑制
G Tang1, Y Minemoto, B Dibling
1Ben May Institute for Cancer Research, Committee on Cancer Biology, University of Chicago, 5841 S. Maryland Avenue, MC 6027, Chicago, Illinois 60637, USA.
Nature
|November 20, 2001
まとめ
腫瘍死滅因子アルファ (TNF-alpha) 信号には複雑な相互作用が伴う. IKK/NF-kappaB経路は,部分的にXIAP経由でJNK活性化を抑制することによって,TNF-α誘発のアポトーシスを抑制する.
科学分野:
- 細胞および分子生物学
- 免疫学 免疫学とは
- シグナルトランスデュークション
背景:
- 腫瘍死滅因子アルファ (TNF-alpha) は,免疫反応,炎症,アポトーシスの重要な調節因子である.
- TNF-α被曝による細胞運命を決定することは,IkappaBキナーゼ (IKK),c-Jun N-末端タンパク質キナーゼ (JNK),およびカスペーゼなどの効果因子からの信号を統合することに依存しています.
- TNF-α誘発のアポトーシスにおけるIKK/NF-kappaBとJNK経路の相互作用は,まだ完全に理解されていません.
研究 の 目的:
- TNF-alpha.への反応としてIKKとJNKの信号伝達経路の交信を調査する.
- TNF-α誘発アポトーシスの調節におけるこのクロスストックの役割を明らかにする.
主な方法:
- IKKbetaまたはRelA/p65 (NF-kappaBサブユニット) のいずれかに欠陥のあるマウインの胚性線維芽細胞を使用した.
- IKK/NF-kappaB経路調節がTNF-α媒介のJNK活性化に与える影響を分析した.
- このクロストークにおけるX染色体関連アポトーシス阻害剤 (XIAP) の貢献を評価した.
主要な成果:
- IKK/NF-kappaB経路は,TNF-α媒介のJNK活性化を否定的に調節する.
- この負のクロスストックは,NF-kappaB誘発のXIAPによって部分的に媒介されます.
- 観察されたJNK活性化の負の調節は,TNF-αシグナル伝達に特異的であり,IL-1によるJNK活性化に影響を与えない.
結論:
- IKK/NF-kappaB経路は,TNF-alpha.の下流にあるJNKの活性化を積極的に抑制する.
- XIAPを含むこの阻害的なクロスストックは,TNF-α誘発のアポトーシスの全体的な抑制に貢献します.
- 発見は,主要な炎症シグナル伝達経路間のクロスレギュレーションの新しいメカニズムを明らかにしています.
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