Inducible PDGF A-chain transcription in smooth muscle cells is mediated by Egr-1 displacement of Sp1 and Sp3.
Platelet-derived growth factor (PDGF) A-chain is expressed by vascular smooth muscle cells (SMC) in a variety of pathological settings. Phorbol 12-myristate 13-acetate (PMA) increases A-chain transcription and was used as a model agonist. Transient transfection analysis identified a region in the promoter that is required for inducibility, located between base pairs -71 and -55 from the transcription start site. This region contains overlapping recognition elements for members of the Sp and Egr families. Egr-1 transcript and protein increased after PMA treatment, whereas Sp1 and Sp3 levels remain unchanged. Egr-1 expression and PDGF A-chain promoter activity also increased in cells exposed to PDGF or mechanical injury. In vitro binding assays demonstrated that Egr-1, Sp1, and Sp3 can bind to this promoter region and that increasing Egr-1 can displace both Sp1 and Sp3. In an in vivo model of arterial injury, Egr-1 expression was induced concurrently with the expression of PDGF-A in SMC. Displacement of Sp1 and Sp3 by Egr-1 is correlated with inducible PDGF A-chain expression in the vessel wall.
Silverman
E S
ES
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Khachigian
L M
LM
Lindner
V
V
Williams
A J
AJ
Collins
T
T
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D017930:Genes, Reporter; D007700:Kinetics; D046911:Macromolecular Substances; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D051705:Sp3 Transcription Factor; D015500:Chloramphenicol O-Acetyltransferase; D013755:Tetradecanoylphorbol Acetate