AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells

Cell Biochemistry and Function
Zhaolong WuHuiming Jin

Abstract

Oxidized Low Density Lipoprotein (Ox-LDL)-induced overproduction of the prosclerotic cytokine transforming growth factor-beta1 (TGF-beta(1)) has been implicated in the pathogenesis of renal fibrosis and sclerosis. Because Ox-LDL increases TGF-beta(1) mRNA levels in rat mesangial cells, our investigation was designed to characterize these effects on the rat TGF-beta(1) promoter activity. We transfected luciferase reporter gene constructs containing TGF-beta(1) 5'-flanking sequence (from -1550 to +57 bp) into mesangial cells. By assaying progressively deleted mutations in the promoter, we found two regions that were responsible for the induction. One is a negative regulatory region (-422 to -629) which represses the transcription of the TGF-beta(1) gene, the other is a positive regulatory region (-845 to -1550) which enhances the transcription unit efficiently. There is an activating protein-1(AP-1) binding site in the latter region. Mutagenesis in the AP-1 binding sites abolished the Ox-LDL effect. Furthermore, addition of the AP-1 inhibitor curcumin obliterated the Ox-LDL response. The Ox-LDL-induced TGF-beta(1) promoter activation was also prevented by inhibitors of protein kinase C, but not by p38 mitogen-activated protein ki...Continue Reading

Citations

Apr 29, 2009·Expert Reviews in Molecular Medicine·Amber Paratore Sanchez, Kumar Sharma
Jan 5, 2007·Journal of the American Society of Nephrology : JASN·Frank Y MaDavid J Nikolic-Paterson
Nov 11, 2008·Free Radical Biology & Medicine·Cécile Mazière, Jean-Claude Mazière

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