| Project/Area Number |
20591089
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KITAGAWA Hirochika The University of Tokyo, 生体調節研究所, 教授 (20345234)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEYAMA Kenーichi 東京大学, 分子細胞生物学研究所, 講師 (30323570)
TAKADA Ichiro 東京大学, 分子細胞生物学研究所, 助教 (50361655)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | グルココルチコイド / 炎症 / Sumo化 / 炎症制御 / 分解制御 / 炎症反応 / 核内受容体 / クロマチン / マクロファージ / 炎症制御転写因子 / 炎症シグナル / タンパク分解機能制御 |
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| Research Abstract |
Glucocorticoid is clinically successful in attenuating inflammation caused by diverse diseases, and its anti-inflammatory actions via nuclear glucocorticoid receptor (GR) are known to be mediated by transcriptional repression of inflammatory transcription factors like AP-1 and NF-kB. However, the molecular mechanism underlying hormonal transrepression largely remains to be uncovered at the level of chromatin. Here, we report that glucocorticoid-induced sumoylation of c-Jun via GR triggers transcriptional repression of AP-1 through a histone inactivating methylation (H3K27me3) by recruitment of a polycomb (PRC2) complex. Liganded GR serves as an adaptor for Sumo E3 ligase (PIAS1) to sumoylate c-Jun in the AP-1 unit, but not NF-kB. Sumoylated c-Jun induces association with a PRC2 complex, leading to H3K27 methylation by EZH2 and silencing of AP-1 binding sites on pro-inflammatory cytokine gene promoters. Ablation of EZH2 in mice abrogates glucocorticoid-induced transrepression of the cytokine genes that are induced by activated AP-1. Thus, these findings uncover a molecular mechanism of anti-inflammatory glucocorticoid actions for transrepression of AP-1 through repressive chromatin reorganization, and provide a clue for development of desirable GR synthetic ligands.
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