From an enhanceosome to a repressosome: Molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing
From an enhanceosome to a repressosome: Molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing
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DOI：
10.1016/j.jmb.2004.11.027
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发表时间：
2005-02-04
影响因子：
5.6
通讯作者：
Tomic-Canic, M
中科院分区：
文献类型：
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作者：
Lee, B;Vouthounis, C;Tomic-Canic, M
伤口愈合的复杂性取决于许多信号通路的协同活动。在这里，我们分析了糖皮质激素（GC）、视黄酸（RA）和表皮生长因子（EGF）同时存在如何在分子、细胞和组织水平上影响伤口愈合。我们发现GC通过抑制角质细胞迁移来抑制伤口愈合，而RA则没有。此外，GC会阻断egf介导的迁移，而RA则不会。在分子水平上，这些化合物靶向最早的伤口愈合标志物之一、细胞骨架成分、角蛋白K6和K16的表达。GC和RA均抑制其转录，而EGF则诱导其转录。有趣的是，GC抑制是由GC受体、β -连环蛋白和辅激活物相关精氨酸-甲基转铁酶-1的四个单体组成的抑制体复合物介导的。GC是显性的，EGF不能挽救GC介导的抑制。用GC预处理角质形成细胞使平衡向抑制体转移，即使在EGF或c-fos/c-jun存在的情况下，也允许K6的显性抑制。虽然RA受体γ和糖皮质激素受体结合到抑制角蛋白K6/K16转录的相同反应元件，但RA受体与egf增强体(共激活因子：糖皮质激素受体相互作用蛋白-1（GRIP-1)/类固醇受体共激活因子-1(SRC-1)）的组分相互作用而不破坏它。因此，RA与EGF具有共显性作用：当同时存在时，它们的作用相互平衡。当用丝裂原活化蛋白激酶（MAPK）抑制剂预处理角质形成细胞，从而阻断EGF时，平衡转向RA抑制。与临床发现相似，用RA预处理角质形成细胞可阻断gc介导的抑制。总之，我们的研究结果确定了RA减轻gc介导的伤口愈合抑制的复杂分子机制。(C) 2004, Elsevier Ltd.；版权所有。
Wound healing in its complexity depends on the concerted activity of many signaling pathways. Here, we analyzed how the simultaneous presence of glucocorticoids (GC), retinoic acid (RA) and epidermal growth factor (EGF) affect wound healing at the molecular, cellular and tissue levels. We found that GC inhibit wound healing by inhibiting keratinocyte migration, whereas RA does not. Furthermore, GC block EGF-mediated migration, whereas RA does not. On the molecular level, these compounds target expression of one of the earliest markers of wound healing, cytoskeletal components, keratins K6 and K16. Both GC and RA repress their transcription, whereas EGF induces it. Interestingly, the GC inhibition is mediated by a repressosome complex consisting of four monomers of the GC receptor, beta-catenin and coactivator-associated-arginine-methyltrans-ferase-1. GC are dominant, EGF can-not rescue GC-mediated inhibition. Pre-treatment of keratinocytes with GC shifts the balance towards the repressosome, allowing for dominant inhibition of K6 even in the presence of EGF or c-fos/c-jun. Although RA receptor gamma and glucocorticoid receptor bind to the same response element repressing transcription of keratins K6/K16, RA receptor interacts with the components of the EGF-enhanceosome (co-activators: glucocorticoid-receptor-interacfive protein-1(GRIP-1)/steroid-receptors coactivator-1 (SRC-1)) without breaking it. Consequently, RA has a co-dominant effect with EGF: when present simultaneously, their effects balance each other. When keratinocytes are pre-treated with mitogen-activated protein kinase (MAPK) inhibitor, thus blocking EGF, the balance is shifted towards the RA repression. Similar to clinical findings, pre-treatment of keratinocytes with RA blocks GC-mediated inhibition. In summary, our results identify complex molecular mechanisms through which RA alleviates GC-mediated inhibition of wound healing. (C) 2004, Elsevier Ltd. All rights reserved.