Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-κB inhibition
Altered subcellular distribution of MSK1 induced by glucocorticoids contributes to NF-κB inhibition
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DOI：
10.1038/emboj.2008.95
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发表时间：
2008-06-18
期刊：
影响因子：
11.4
通讯作者：
De Bosscher, Karolien
中科院分区：
文献类型：
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作者：
Beck, Ilse Me;Vanden Berghe, Wim;De Bosscher, Karolien
糖皮质激素是广泛使用的抗炎和免疫调节剂，其作用机制主要是通过激素激活的糖皮质激素受体(GR)干扰核因子-kappaB等转录因子的活性。除了GR和NF-kappa B之间基于相互作用的相互抑制机制外，还有其他机制在起作用，这有助于解释糖皮质激素介导的基因抑制的有效性。在这方面，我们发现糖皮质激素抵消了炎症基因启动子上激活的丝裂原和应激激活蛋白激酶-1(MSK1)的招募，从而抑制了NF-kappa B p65的反式激活和组蛋白H3的同时磷酸化。此外，我们观察到激活的GR可以通过依赖CRM1的输出机制触发核MSK1的重新分布到细胞质，这是连接的GR和激活的MSK1相互作用的结果。这些发现揭示了GR介导的NF-kappa B靶向抗炎机制中的一个新方面。
Glucocorticoids are widely used anti-inflammatory and immunomodulatory agents, of which the action mechanism is mainly based on interference of hormone-activated glucocorticoid receptor (GR) with the activity of transcription factors, such as nuclear factor-kappa B (NF-kappa B). In addition to the well described interaction-based mutual repression mechanism between the GR and NF-kappa B, additional mechanisms are at play, which help to explain the efficacy of glucocorticoid-mediated gene repression. In this respect, we found that glucocorticoids counteract the recruitment of activated Mitogen-and Stress-activated protein Kinase-1 (MSK1) at inflammatory gene promoters resulting in the inhibition of NF-kappa B p65 transactivation and of concurrent histone H3 phosphorylation. Additionally, we observed that activated GR can trigger redistribution of nuclear MSK1 to the cytoplasm through a CRM1-dependent export mechanism, as a result of an interaction between liganded GR and activated MSK1. These findings unveil a novel aspect within the GR-mediated NF-kappa B-targeting anti-inflammatory mechanism.