LOXL4 Is Induced by Transforming Growth Factor β1 through Smad and JunB/Fra2 and Contributes to Vascular Matrix Remodeling
LOXL4 Is Induced by Transforming Growth Factor β1 through Smad and JunB/Fra2 and Contributes to Vascular Matrix Remodeling
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DOI：
10.1128/mcb.00036-13
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发表时间：
2013-06-01
影响因子：
5.3
通讯作者：
Rodriguez-Pascual, Fernando
中科院分区：
文献类型：
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作者：
Busnadiego, Oscar;Gonzalez-Santamara, Jose;Rodriguez-Pascual, Fernando
转化生长因子β 1（TGF-β 1）是一种参与细胞外基质（ECM）合成和重塑调节的多效性因子。为了寻找介导TGF-β 1对血管ECM作用的新基因，我们鉴定了基质重塑酶赖氨酰氧化酶家族成员赖氨酰氧化酶样4（LOXL 4），作为主动脉内皮细胞中TGF-β 1的直接靶点，并剖析了其诱导的分子机制。LOXL 4启动子的缺失作图和诱变分析证明了绝对需要含有激活蛋白1（AP-1）位点和TGF-β 1的Smad结合元件的远端增强子来诱导LOXL 4表达。Smad蛋白与AP-1复合物（由JunB/Fra 2组成）之间的功能合作解释了TGF-β 1的作用，其涉及Fra 2的细胞外信号调节激酶（ERK）依赖性磷酸化。我们还提供了LOXL 4细胞外分泌并显著促进ECM沉积和组装的证据。这些结果表明，L0 XL 4的TGF-β 1依赖性表达在血管ECM稳态中起作用，有助于与ECM重塑和纤维化相关的血管过程。
Transforming growth factor beta 1 (TGF-beta 1) is a pleiotropic factor involved in the regulation of extracellular matrix (ECM) synthesis and remodeling. In search for novel genes mediating the action of TGF-beta 1 on vascular ECM, we identified the member of the lysyl oxidase family of matrix-remodeling enzymes, lysyl oxidase-like 4 (LOXL4), as a direct target of TGF-beta 1 in aortic endothelial cells, and we dissected the molecular mechanism of its induction. Deletion mapping and mutagenesis analysis of the LOXL4 promoter demonstrated the absolute requirement of a distal enhancer containing an activator protein 1 (AP-1) site and a Smad binding element for TGF-beta 1 to induce LOXL4 expression. Functional cooperation between Smad proteins and the AP-1 complex composed of JunB/Fra2 accounted for the action of TGF-beta 1, which involved the extracellular signal-regulated kinase (ERK)-dependent phosphorylation of Fra2. We furthermore provide evidence that LOXL4 was extracellularly secreted and significantly contributed to ECM deposition and assembly. These results suggest that TGF-beta 1-dependent expression of LOXL4 plays a role in vascular ECM homeostasis, contributing to vascular processes associated with ECM remodeling and fibrosis.