TRANSCRIPTIONAL REGULATION OF ALPHA-1 ADRENERGIC RECEPTORS

Daniel R. Scanga¹ and Debra A. Schwinn^2,3,4

School of Medicine,¹ Departments of Anesthesiology,² Surgery,³ and Pharmacology/Cancer Biology, ⁴ Duke University Medical Center, Durham, NC 27710

Received 2/25/98 Accepted 3/2/98

9. MODULATION OF GENE EXPRESSION VIA CIS-ACTING ELEMENTS

Basal promoter activity, though essential to define, does not fully define transcriptional regulation of a gene. Regions other than the promoter exist in the 5’UTR which modulate basal adrenergic receptor gene expression. In fact, binding of transcription factors distant from the transcription initiation site have been shown to induce conformational changes thought to affect RNA polymerase II stability in the promoter region. In the human alpha_1aAR gene, both enhancer and repressor sequences have been shown to reside far upstream from the transcription initiation site (enhancer 1927-2869 bp, repressor 2869-5498 bp; figure 1) (20). Several putative positive and negative response elements exist in these regions, respectively, although further investigation is required to identify specific activators and suppressors.

In addition to transcription factor-mediated enhancement and repression of basal promoter activity, gene transcription can be induced by hormones and drugs. Hormones and drugs can directly modulate gene transcription by binding to consensus sequences in the 5’UTR of a gene, or indirectly modulate expression of other transcription factors. In the adrenergic receptor family, the direct role of modulatory hormones is suggested by the presence of multiple hormone binding sites in specific genes including cAMP response elements (CRE; binding sites for the CRE binding protein CREB), glucocorticoid response elements (GRE), estrogen response elements (ERE), and insulin response elements (IRE) (table 2) (15). Supporting this contention in the human alpha_1aAR gene is evidence that beta₃AR stimulation of cAMP production in rat brown adipose tissue upregulates alpha_1aAR expression (34). Furthermore, human alpha_1aAR mRNA and protein expression levels are elevated by increasing intracellular cAMP with forskolin/IBMX treatment (20). Direct and indirect modulation of mRNA expression by hormones and drugs is an exciting area of research which may provide novel targets for therapeutic intervention in various diseases.

Table 2. Cis-Regulatory Elements in Adrenergic Receptor Genes.^a

aAdrenergic receptor genes containing ³400 bp 5’UTR were analyzed for the indicated transcription factors using consensus sequences found in MacVector 5.0 (Oxford Molecular Group PLC, Campbell, CA) as well as updated sequences from the literature [Hai, 1989 #21; Bridges, 1992 #22; O'Brien, 1995 #20; Thomas, 1992 #19; Kozak, 1984 #23; Faisst, 1992 #25; Lucas, 1992 #24]; only full consensus matches for each element were accepted; ^bAP-1[Angel, 1987 #30]; ^cAP-2 [Imagawa, 1987 #28; Mitchell, 1987 #29]; ^dcAMP response element (CRE), [Hai, 1989 #21], CRE sequences used for analysis are defined as follows: TGACGTCA (35), (TGACTCCA, CGAGGTCA, GTCGTCA) [Thomas, 1992 #19], (TACGTCA, TGACGTA, TGAGGTCT); ^eglucocorticoid response element (GRE); ^fandrogen response elements usually overlap with GRE sites, however a novel androgen binding site has recently been described [Zhou, 1997 #36]--this sequence was absent in all adrenergic receptor genes examined; ^gestrogen response element (ERE) [Lucas, 1992 #24]; and ^hinsulin response element (IRE) [O'Brien, 1995 #20; Bridges, 1992 #22]. (Modified from ref #15 with permission).