AP1 Proteins Mediate the cAMP Response of the Dopamine β-Hydroxylase Gene

• Published in: The Journal of biological chemistry 1998-09, Vol.273 (37), p.24065-24074
• Main Authors: Swanson, Douglas J., Zellmer, Eustacia, Lewis, Elaine J.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding Sites; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Clone Cells; Cyclic AMP - analogs & derivatives; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Dopamine beta-Hydroxylase - biosynthesis; Dopamine beta-Hydroxylase - genetics; Enhancer Elements, Genetic; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; GTP-Binding Proteins - metabolism; Models, Genetic; Models, Molecular; Molecular Sequence Data; PC12 Cells; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; rap GTP-Binding Proteins; Rats; Recombinant Proteins - biosynthesis; TATA Box; Thionucleotides - pharmacology; Transcription Factor AP-1 - metabolism; Transcription Factors - metabolism; Transcription, Genetic; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.37.24065

Neurotransmitter biosynthesis is regulated by environmental stimuli, which transmit intracellular signals via second messengers and protein kinase pathways. For the catecholamine biosynthetic enzymes, dopamine β-hydroxylase and tyrosine hydroxylase, regulation of gene expression by cyclic AMP, diacyl glycerol, and Ca2+ leads to increased neurotransmitter biosynthesis. In this report, we demonstrate that the cAMP-mediated regulation of transcription from the dopamine β-hydroxylase promoter is mediated by the AP1 proteins c-Fos, c-Jun, and JunD. Following treatment of cultured cells with cAMP, protein complexes bound to the dopamine β-hydroxylase AP1/cAMP response element element change from consisting of c-Jun and JunD to include c-Fos, c-Jun, and JunD. The homeodomain protein Arix is also a component of this DNA-protein complex, binding to the adjacent homeodomain recognition sites. Transfection of a dominant negative JunD expression plasmid inhibits cAMP-mediated expression of the dopamine β-hydroxylase promoter construct in PC12 and CATH.a cells. In addition to the role of c-Fos in regulating dopamine β-hydroxylase gene expression in response to cAMP, a second pathway, involving Rap1/B-Raf is involved. These experiments illustrate an unusual divergence of cAMP-dependent protein kinase signaling through multiple pathways that then reconverge on a single element in the dopamine β-hydroxylase promoter to elicit activation of gene expression.