Tags

Type your tag names separated by a space and hit enter

AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells.
Cell Biochem Funct. 2004 Jul-Aug; 22(4):237-47.CB

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 kinase. Electrophoretic mobility shift assays with oligonucleotides containing AP-1 binding sites showed that Ox-LDL treatment significantly enhanced the binding activity of nuclear proteins of mesangial cells. Supershift assays demonstrated that c-Jun was present in the protein-DNA complexes under stimulation of Ox-LDL. The functional and structural results show that Ox-LDL regulates rat TGF-beta(1) gene expression through AP-1 binding sites and gives rise to the involvement of protein kinase C in Ox-LDL-induced TGF-beta(1) gene expression.

Authors+Show Affiliations

Division of Nephrology, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, P.R. China. professor-wu@yahoo.com.cnNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15248184

Citation

Wu, Zhaolong, et al. "AP-1 Complexes Mediate Oxidized LDL-induced Overproduction of TGF-beta(1) in Rat Mesangial Cells." Cell Biochemistry and Function, vol. 22, no. 4, 2004, pp. 237-47.
Wu Z, Zhou Q, Lan Y, et al. AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells. Cell Biochem Funct. 2004;22(4):237-47.
Wu, Z., Zhou, Q., Lan, Y., Wang, Y., Xu, X., & Jin, H. (2004). AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells. Cell Biochemistry and Function, 22(4), 237-47.
Wu Z, et al. AP-1 Complexes Mediate Oxidized LDL-induced Overproduction of TGF-beta(1) in Rat Mesangial Cells. Cell Biochem Funct. 2004 Jul-Aug;22(4):237-47. PubMed PMID: 15248184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells. AU - Wu,Zhaolong, AU - Zhou,Qin, AU - Lan,Yang, AU - Wang,Yuancheng, AU - Xu,Xunhui, AU - Jin,Huiming, PY - 2004/7/13/pubmed PY - 2009/6/23/medline PY - 2004/7/13/entrez SP - 237 EP - 47 JF - Cell biochemistry and function JO - Cell Biochem Funct VL - 22 IS - 4 N2 - 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 kinase. Electrophoretic mobility shift assays with oligonucleotides containing AP-1 binding sites showed that Ox-LDL treatment significantly enhanced the binding activity of nuclear proteins of mesangial cells. Supershift assays demonstrated that c-Jun was present in the protein-DNA complexes under stimulation of Ox-LDL. The functional and structural results show that Ox-LDL regulates rat TGF-beta(1) gene expression through AP-1 binding sites and gives rise to the involvement of protein kinase C in Ox-LDL-induced TGF-beta(1) gene expression. SN - 1099-0844 UR - https://www.unboundmedicine.com/medline/citation/15248184/AP_1_complexes_mediate_oxidized_LDL_induced_overproduction_of_TGF_beta_1__in_rat_mesangial_cells_ L2 - https://doi.org/10.1002/cbf.1096 DB - PRIME DP - Unbound Medicine ER -