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Sp1 Dependence of Natriuretic Peptide Receptor A Gene Transcription in Rat Aortic Smooth Muscle Cells¹

Metabolic Research Unit and Department of Medicine, University of California, San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. David G. Gardner, Box 0540, Metabolic Research Unit, University of California, San Francisco, California 94143. E-mail: gardner{at}itsa.ucsf.edu

The atrial natriuretic peptide receptor (NPR-A) Is expressed in smooth muscle cells of the vasculature, where it is thought to signal the vasodilatory properties of the peptide. Despite its important role as a regulator of cardiovascular homeostasis, relatively little is known of the genomic factors governing expression of this gene. We show here that NPR-A promoter activity is reduced by 50–75% when any of three GC-rich sites are mutated. Simultaneous mutation of all three leads to a >90% reduction in NPR-A promoter activity. Transfection of wild-type, but not mutant, decoy oliogonucleotides encoding any one of the sites reduces NPR-A activity, presumably reflecting competition for a common transcription factor. Gel shift analyses show that each of the wild-type, but not the mutant, sites interferes with the formation of selected DNA-protein complexes on the other sites. These complexes share similar electrophoretic mobility. Immunoperturbation studies show that one of these shared complexes contains Sp1, whereas two others contain Sp3. Overexpression of either Sp1 or Sp3 in a cell type containing very low levels of these transcription factors (i.e. Drosophila Schneider cells) leads to induction of the wild-type, but not the mutant, NPR-A promoter. The data suggest that the Sp1 family of transcription factors plays a central role in NPR-A gene transcription. The association of Sp1 family members with transcriptional regulation of a number of genes involved in hemodynamic control will be discussed.

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