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Vol. 61, Issue 2, 379-390, February 2002
1-Adrenergic Receptor
Gene Transcription by Sp1 and Early Growth Response Gene 1: Induction
of EGR-1 Inhibits the Expression of the
1-Adrenergic Receptor Gene
Department of Pharmacology, College of Medicine, the University of
Tennessee Health Sciences Center, Memphis, Tennessee
The 
1-adrenergic receptor (1-AR) plays a
key role in regulating heart rate and contractility in response to
catecholamines. Our studies have focused on defining the factors that
regulate the expression of the 1-AR gene. We determined
that a 65-base-pair (bp) region in the 1-AR promoter
between bp 
394 and bp 330 directs basal transcription. An element
located between 377 and 365 can bind Sp1 and Sp3. In
Drosophila melanogaster SL2 cells, Sp1 stimulated the
expression of the 1-AR promoter, whereas Sp3 was unable
to activate transcription. Site-directed mutagenesis indicated that an
intact Sp1-binding site is essential for maintaining the activity of
the basal promoter. In addition to binding Sp family members, the
nucleotides between 381 and 367 can bind the zinc-finger
transcription factor Egr-1. The Egr-1 and Sp1 binding sites are
partially overlapping and their binding sequence is conserved among
mammalian 1-AR genes. The induction of Egr-1 in rat
neonatal ventricular myocytes with phorbol-12-myristate-13-acetate or
in HeLa S3 cells by regulated expression of Egr-1 in a
tetracycline-responsive promoter, suppressed expression from the
1-AR promoter. Overexpression of Sp1 in SK-N-MC cells
increased 1-AR mRNA by 2.4-fold, whereas overexpression
of Egr-1 reduced 1-AR mRNA by 40%. Coexpression of
Egr-1 with Sp1 reduced Sp1-mediated up-regulation of
1-AR mRNA by 60%. Mutagenesis revealed that an intact
Sp1-binding site is essential for observing transcriptional repression
by Egr-1 and that Egr-1 suppressed the transcription of the
1-AR gene by competing with Sp1 for binding to their
overlapping sites. These results reveal a novel physiologically
relevant transcriptional mechanism for reciprocal regulation of
1-AR gene expression.
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