LOXL4 Is Induced by Transforming Growth Factor β1 through Smad and JunB/Fra2 and Contributes to Vascular Matrix Remodeling
- Oscar Busnadiegoa,
- José González-Santamaríaa,
- David Lagaresb,
- Juan Guinea-Viniegrac,
- Cathy Pichol-Thievendc,
- Laurent Mullera and
- Fernando Rodríguez-Pascuala
+ Author Affiliations
- Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas/Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spaina
- Fundación Banco Bilbao Vizcaya-CNIO Cancer Cell Biology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spainb
- College de France, Center for Interdisciplinary Research in Biology, Paris, Francec
Transforming growth factor β1 (TGF-β1) 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-β1 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-β1 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-β1 to induce LOXL4 expression. Functional cooperation between Smad proteins and the AP-1 complex composed of JunB/Fra2 accounted for the action of TGF-β1, 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-β1-dependent expression of LOXL4 plays a role in vascular ECM homeostasis, contributing to vascular processes associated with ECM remodeling and fibrosis.
- Received 9 January 2013.
- Returned for modification 22 January 2013.
- Accepted 1 April 2013.
- Address correspondence to Fernando Rodríguez-Pascual, firstname.lastname@example.org.
- Published ahead of print 9 April 2013
- Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00036-13.
- Copyright © 2013, American Society for Microbiology. All Rights Reserved.