Document Detail


Peroxide-inducible Ets-1 mediates platelet-derived growth factor receptor-alpha gene transcription in vascular smooth muscle cells.
MedLine Citation:
PMID:  16192649     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of vascular occlusive disorders such as atherosclerosis and restenosis in part due to its regulation of smooth muscle cell phenotype. The molecular mechanisms regulating the expression of PDGF-Ralpha, which binds all known dimeric forms of PDGF except PDGF-DD, are poorly understood. Here we demonstrate that the winged helix-turn-helix proto-oncogene Ets-1 controls PDGF-Ralpha transcription and mRNA expression in smooth muscle cells. Mutational analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation revealed the existence of a reverse Ets binding motif (-45TTCC-42) in the proximal region of the PDGF-Ralpha promoter, which bound both recombinant and endogenous Ets-1. Ets-1-inducible PDGF-Ralpha expression depended on the integrity of both the -45TTCC-42 motif and the -61G10(-52) element, which resides upstream of -45TTCC-42 and mediates Sp1 induction. Hydrogen peroxide (H2O2) at nanomolar concentrations stimulated levels of Ets-1 and increased PDGF-Ralpha transcription and mRNA expression without affecting Sp1 expression. H2O2 activation of the PDGF-Ralpha promoter was abolished by disrupting -45TTCC-42 or -61G10(-52). These studies identify a functional Ets motif in the PDGF-Ralpha promoter that plays a pivotal role in agonist-inducible PDGF-Ralpha transcription.
Authors:
Michelle R Bonello; Yuri V Bobryshev; Levon M Khachigian
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The American journal of pathology     Volume:  167     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-29     Completed Date:  2005-11-21     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1149-59     Citation Subset:  AIM; IM    
Affiliation:
Centre for Vascular Research, Department of Pathology, The University of New South Wales, Sydney, NSW 2052, Australia.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta / cytology
Arteriosclerosis / metabolism,  pathology
Blotting, Western
Carotid Arteries / pathology
Cell Proliferation
Cells, Cultured
Chromatin Immunoprecipitation
Dose-Response Relationship, Drug
Electrophoretic Mobility Shift Assay
Genes, Reporter
Humans
Hydrogen Peroxide / pharmacology*
Luciferases / metabolism
Muscle, Smooth, Vascular / metabolism*
Mutation
Oligonucleotides, Antisense / pharmacology
Oxidants / pharmacology*
Promoter Regions, Genetic
Proto-Oncogene Protein c-ets-1 / genetics,  metabolism*
RNA, Messenger / metabolism
Rats
Rats, Inbred WKY
Receptors, Platelet-Derived Growth Factor / genetics*
Sp1 Transcription Factor / metabolism
Transcription, Genetic*
Chemical
Reg. No./Substance:
0/ETS1 protein, human; 0/Oligonucleotides, Antisense; 0/Oxidants; 0/Proto-Oncogene Protein c-ets-1; 0/RNA, Messenger; 0/Sp1 Transcription Factor; 7722-84-1/Hydrogen Peroxide; EC 1.13.12.-/Luciferases; EC 2.7.10.1/Receptors, Platelet-Derived Growth Factor
Comments/Corrections

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