Home
/
Data resources
/
Literature
/
23572561
LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling.

Mol Cell Biol, 2013/6;33(12):2388-401.

Busnadiego O[1], González-Santamaría J, Lagares D, Guinea-Viniegra J, Pichol-Thievend C, Muller L, Rodríguez-Pascual F

Affiliations

PMID: 23572561DOI: 10.1128/MCB.00036-13

Impact factor: 5.069

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.
MeSH terms
Animals; Aorta; Base Sequence; Binding Sites; Cattle; Cells, Cultured; Endothelial Cells; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fos-Related Antigen-2; HEK293 Cells; Humans; Mice; Phosphorylation; Promoter Regions, Genetic; Protein-Lysine 6-Oxidase; RNA Interference; RNA, Small Interfering; Recombinant Proteins; Sequence Alignment; Smad Proteins; Transcription Factor AP-1; Transcription Factors; Transforming Growth Factor beta1
More resources
EndNote: Download