Document Detail


AP-1 complexes mediate oxidized LDL-induced overproduction of TGF-beta(1) in rat mesangial cells.
MedLine Citation:
PMID:  15248184     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Zhaolong Wu; Qin Zhou; Yang Lan; Yuancheng Wang; Xunhui Xu; Huiming Jin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell biochemistry and function     Volume:  22     ISSN:  1099-0844     ISO Abbreviation:  Cell Biochem. Funct.     Publication Date:    2004 Jul-Aug
Date Detail:
Created Date:  2004-07-12     Completed Date:  2009-06-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8305874     Medline TA:  Cell Biochem Funct     Country:  England    
Other Details:
Languages:  eng     Pagination:  237-47     Citation Subset:  IM    
Copyright Information:
Copyright 2004 John Wiley & Sons, Ltd.
Affiliation:
Division of Nephrology, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, P.R. China. professor-wu@yahoo.com.cn
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Curcumin / pharmacology
Gene Expression Regulation / drug effects
Glomerular Mesangium / cytology,  metabolism*
Humans
Lipoproteins, LDL / pharmacology*
Male
Mutagenesis, Site-Directed
Nuclear Proteins / metabolism
Promoter Regions, Genetic / drug effects
Protein Kinase C / metabolism
Proto-Oncogene Proteins c-jun / metabolism
RNA, Messenger / biosynthesis,  genetics
Rats
Rats, Sprague-Dawley
Recombinant Fusion Proteins / biosynthesis,  genetics
Regulatory Sequences, Nucleic Acid / drug effects
Sequence Deletion
Signal Transduction / drug effects
Transcription Factor AP-1 / antagonists & inhibitors,  physiology*
Transforming Growth Factor beta1 / biosynthesis*,  genetics
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/Lipoproteins, LDL; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Recombinant Fusion Proteins; 0/Transcription Factor AP-1; 0/Transforming Growth Factor beta1; 0/oxidized low density lipoprotein; 458-37-7/Curcumin; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

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