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Characterization of the Human Corticotropin-Releasing Factor_2(a) Receptor Promoter: Regulation by Glucocorticoids and the Cyclic Adenosine 5'-Monophosphate Pathway

Departments of Psychiatry (S.A.N., P.H.R., G.A.N., J.M.S., N.H.K.), Pharmacology (P.H.R.), and Psychology (N.H.K.), University of Wisconsin-Madison, Madison, Wisconsin 53719

Address all correspondence and requests for reprints to: Dr. Patrick H. Roseboom, 6001 Research Park Boulevard, Madison, Wisconsin 53719-1176. E-mail: roseboom{at}wisc.edu.

Corticotropin-releasing factor (CRF) is a neurotransmitter and hormone believed to integrate responses to stress. Evidence suggests central CRF systems are overactive in some individuals suffering from depression and anxiety disorders. CRF receptor antagonism blocks stress-induced endocrine, autonomic, and behavioral effects in animal models, and studies have implicated the CRF₂ receptor in anxiety-related behaviors. Greater understanding of the regulation of CRF₂ expression may facilitate understanding mechanisms underlying anxiety. The present studies are the first to characterize the transcriptional regulation of the human CRF_2(a), the predominant CRF₂ isoform in brain. Four kilobase pairs of sequence immediately upstream of the first exon of CRF_2(a) represented our full-length promoter region. Sequentially smaller fragments of the CRF_2(a) promoter region were generated by PCR and cloned upstream of a luciferase reporter gene. Expression was monitored from these constructs within Chinese hamster ovary-K1 cells and within rat aortic A7R5 cells that express CRF₂. Glucocorticoid treatment decreased expression and elevating intracellular cAMP increased expression from the human CRF_2(a) promoter. The regions of the CRF_2(a) promoter that regulate the inducible expression were determined, and the functional cAMP response element and glucocorticoid response element cis-regulatory elements within these regions were identified using a combination of site-directed mutagenesis and EMSAs. Given the possibility of species-specific differences in gene expression, interpretation of gene expression studies from rat and mouse model systems is difficult. Examination of expression from the human CRF_2(a) promoter will provide insight into these model systems and may translate more readily to the development of therapeutics to treat human psychiatric illness.

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