title: LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling.
abstract: 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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa and Laboratorio Mixto Consejo Superior de Investigaciones Científicas/Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Busnadiego
authors.forename: José
authors.initials: J
authors.lastname: González-Santamaría
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.forename: Juan
authors.initials: J
authors.lastname: Guinea-Viniegra
authors.forename: Cathy
authors.initials: C
authors.lastname: Pichol-Thievend
authors.forename: Laurent
authors.initials: L
authors.lastname: Muller
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Pascual
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D051785:Smad Proteins / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C497872:FOSL2 protein, human; D051921:Fos-Related Antigen-2; C581727:JunB protein, human; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051785:Smad Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D008249:Protein-Lysine 6-Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases