Arthritis Center, Boston University School of Medicine, Boston, Massachusetts, USA.
J Invest Dermatol. 2011 Jul;131(7):1469-76. doi: 10.1038/jid.2011.63. Epub 2011 Mar 31.
Estrogen is an important regulator of dermal fibroblast functions, including extracellular matrix (ECM) synthesis. Estrogen mediates its effects through estrogen receptors (ERs), ERα and ERβ; however, regulation of ERs in dermal fibroblasts remains poorly understood. Friend leukemia integration factor 1 (Fli1), a member of the Ets transcription factor family, has been shown to play a pivotal role in regulation of the ECM genes in dermal fibroblasts. The aim of this study was to examine a possible interaction between Fli1 and estrogen pathways, focusing on ERα. We show that treatment of human dermal fibroblasts with transforming growth factor-β (TGF-β) increases ERα protein and mRNA levels. Similarly, ERα expression was increased in response to small interfering RNA (siRNA)-mediated depletion of Fli1, suggesting that Fli1 is a mediator of the TGF-β effects on ERα expression. Accordingly, we showed that Fli1 binds to the most proximal region of the ERα promoter, and dissociates from the promoter upon TGF-β treatment. An inverse correlation between Fli1 and ERα expression levels was confirmed in cultured skin fibroblasts obtained from Fli1(+/-) mice and in the skin of Fli1(+/-) mice in vivo. This study supports a role of Fli1 as a negative regulator of the ERα gene in dermal fibroblasts.
雌激素是真皮成纤维细胞功能的重要调节剂，包括细胞外基质（ECM）的合成。雌激素通过雌激素受体（ERs），即 ERα 和 ERβ 来发挥其作用；然而，真皮成纤维细胞中 ERs 的调节仍知之甚少。Friend 白血病整合因子 1（Fli1）是 Ets 转录因子家族的一员，已被证明在真皮成纤维细胞 ECM 基因的调节中发挥关键作用。本研究旨在探讨 Fli1 与雌激素途径之间的可能相互作用，重点关注 ERα。我们发现转化生长因子-β（TGF-β）处理人真皮成纤维细胞会增加 ERα 蛋白和 mRNA 水平。同样，siRNA 介导的 Fli1 耗竭也会增加 ERα 的表达，表明 Fli1 是 TGF-β 对 ERα 表达影响的介导物。因此，我们表明 Fli1 结合到 ERα 启动子的最近端区域，并且在 TGF-β 处理时从启动子解离。在从 Fli1(+/-) 小鼠获得的培养皮肤成纤维细胞中和在体内 Fli1(+/-) 小鼠的皮肤中，证实了 Fli1 和 ERα 表达水平之间存在负相关。这项研究支持了 Fli1 作为真皮成纤维细胞中 ERα 基因的负调节剂的作用。
