Castañares Cristina, Redondo-Horcajo Mariano, Magan-Marchal Noemi, Lamas Santiago, Rodriguez-Pascual Fernando
Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Instituto Reina Sofía de Investigaciones Nefrológicas, Ramiro de Maeztu 9, E-28040, Madrid, Spain.
Exp Biol Med (Maywood). 2006 Jun;231(6):700-3.
Expression of the endothelin (ET)-1 gene is subject to complex regulation by numerous factors, among which the cytokine transforming growth factor-beta (TGF-beta) is one of the most important. TGF-beta action is based on the activation of the Smad signaling pathway. Smad proteins activate transcription of the gene by cooperation with activator protein-1 (AP-1) at specific sites on the ET-1 promoter. Smad signaling pathway is initiated by binding of the cytokine to a heteromeric complex of type I and type II receptors. Signal is then propagated to the nucleus by specific members of the Smad family. Most cell types contain a type I receptor known as ALK5. However, endothelial cells are unique because they coexpress an additional type I receptor named ALK1. These forms do not constitute redundant receptors with the same function, but they actually activate different Smad-mediated expression programs that lead to specific endothelial phenotypes. TGF-beta/ALK5/Smad3 pathway is associated to a mature endothelium because it leads to inhibition of cell migration/proliferation. Conversely, TGF-beta/ALK1/Smad5 activates both processes and is more related to the angiogenic state. We have analyzed the TGF-beta receptor subtype requirements for the activation of the ET-1 gene. For that purpose, we have overexpressed type I receptor and Smad isoforms in endothelial cells and analyzed the effect on ET-1 expression. Our experiments indicate that TGF-beta induces ET-1 expression preferentially through the activation of the ALK5/Smad3 pathway and, therefore, the expression of the vaso-constrictor may be associated to a quiescent and mature endothelial phenotype.
内皮素（ET）-1基因的表达受到多种因素的复杂调控，其中细胞因子转化生长因子-β（TGF-β）是最重要的因素之一。TGF-β的作用基于Smad信号通路的激活。Smad蛋白通过与ET-1启动子上的特定位点的激活蛋白-1（AP-1）协同作用来激活该基因的转录。Smad信号通路由细胞因子与I型和II型受体的异源复合物结合而启动。然后信号通过Smad家族的特定成员传递到细胞核。大多数细胞类型都含有一种称为ALK5的I型受体。然而，内皮细胞是独特的，因为它们共表达另一种名为ALK1的I型受体。这些形式并不构成具有相同功能的冗余受体，实际上它们激活不同的Smad介导的表达程序，导致特定的内皮细胞表型。TGF-β/ALK5/Smad3通路与成熟内皮细胞相关，因为它导致细胞迁移/增殖的抑制。相反，TGF-β/ALK1/Smad5激活这两个过程，并且与血管生成状态更相关。我们分析了激活ET-1基因所需的TGF-β受体亚型。为此，我们在内皮细胞中过表达I型受体和Smad亚型，并分析了对ET-1表达的影响。我们的实验表明，TGF-β优先通过激活ALK5/Smad3通路诱导ET-1表达，因此，血管收缩剂的表达可能与静止和成熟的内皮细胞表型相关。
