Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 33, Issue 12, Pages 2388-2401Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00036-13
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Funding
- Ministerio de Economia y Competitividad (Plan Nacional de I + D + I) [SAF2009-09085, SAF2012-34916]
- Comunidad Autonoma de Madrid (FIBROTEAM Consortium) [2010-BMD2321]
- Fundacion Genoma Espana (MEICA project)
- Consejo Superior de Investigaciones Cientificas (Proyecto Intramural de Incorporacion) [200920I158]
- Fundacion Renal Inigo Alvarez de Toledo
- Ministerio de Economia y Competitividad (Formacion de Personal Investigador)
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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.
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