|Peroxide-inducible Ets-1 mediates platelet-derived growth factor receptor-alpha gene transcription in vascular smooth muscle cells.|
|PMID: 16192649 Owner: NLM Status: MEDLINE|
|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.|
|Michelle R Bonello; Yuri V Bobryshev; Levon M Khachigian|
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|Type: Journal Article; Research Support, Non-U.S. Gov't|
|Title: The American journal of pathology Volume: 167 ISSN: 0002-9440 ISO Abbreviation: Am. J. Pathol. Publication Date: 2005 Oct|
|Created Date: 2005-09-29 Completed Date: 2005-11-21 Revised Date: 2009-11-19|
Medline Journal Info:
|Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States|
|Languages: eng Pagination: 1149-59 Citation Subset: AIM; IM|
|Centre for Vascular Research, Department of Pathology, The University of New South Wales, Sydney, NSW 2052, Australia.|
|APA/MLA Format Download EndNote Download BibTex|
Aorta / cytology
Arteriosclerosis / metabolism, pathology
Carotid Arteries / pathology
Dose-Response Relationship, Drug
Electrophoretic Mobility Shift Assay
Hydrogen Peroxide / pharmacology*
Luciferases / metabolism
Muscle, Smooth, Vascular / metabolism*
Oligonucleotides, Antisense / pharmacology
Oxidants / pharmacology*
Promoter Regions, Genetic
Proto-Oncogene Protein c-ets-1 / genetics, metabolism*
RNA, Messenger / metabolism
Rats, Inbred WKY
Receptors, Platelet-Derived Growth Factor / genetics*
Sp1 Transcription Factor / metabolism
|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 188.8.131.52/Receptors, Platelet-Derived Growth Factor|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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