Regulation of the tyrosine hydroxylase and dopamine β-hydroxylase genes by the transcription factor AP-2
Article first published online: 22 APR 2009
Journal of Neurochemistry
Volume 76, Issue 1, pages 280–294, January 2001
How to Cite
Kim, H.-S., Hong, S. J., LeDoux, M. S. and Kim, K.-S. (2001), Regulation of the tyrosine hydroxylase and dopamine β-hydroxylase genes by the transcription factor AP-2. Journal of Neurochemistry, 76: 280–294. doi: 10.1046/j.1471-4159.2001.00044.x
- Issue published online: 22 APR 2009
- Article first published online: 22 APR 2009
- Received June 15, 2000; revised August 22, 2000; accepted August 29, 2000.
- cell-type specific transcription;
- cis-acting element;
- dopamine β-hydroxylase;
- neurotransmitter phenotype;
- transcription factor AP2;
- tyrosine hydroxylase
The retinoic acid-inducible and developmentally regulated transcription factor AP-2 plays an important role during development. In adult mammals, AP-2 is expressed in both neural and non-neural tissues. However, the function of AP-2 in different neuronal phenotypes is poorly understood. In this study, transcriptional regulation of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) genes by AP-2 was investigated. AP-2 binding sites were identified in the upstream regions of both genes. Electrophoretic mobility shift assays (EMSA) and DNase I footprinting analyses indicate that the AP−2 interaction with these motifs is more prominent in catecholaminergic SK-N-BE(2)C and CATH.a than in non-catecholaminergic HeLa and HepG2 cell lines. Exogenous expression of AP-2 robustly transactivated TH and DBH promoter activities in non-catecholaminergic cell lines. While AP-2 regulates the DBH promoter activity via a single site, transactivation of the TH promoter by AP-2 appears to require multiple sites. In support of this, mutation of multiple AP-2 binding sites but not that of single site diminished the basal promoter activity of the TH gene in cell lines that express TH and abolished transactivation by exogenous AP-2 expression in cell lines that do not express TH. In contrast, mutation of a single AP-2 binding site of the DBH gene completely abolished transactivation by AP-2. Double-label immunohistochemistry showed that AP-2 is coexpressed with TH in noradrenergic and adrenergic neurons in both the central and peripheral nervous systems of adult rodents. Numerous non-catecholaminergic cell groups within the spinal cord, medulla, cerebellum, and pons also express AP-2. The concentration of AP-2 in dorsomedial locations along the neuraxis suggests a regionally specific role for this transcription factor in the regulation of neuronal function. Based on these findings we propose that AP-2 may coregulate TH and DBH gene expression and thus participate in expression/maintenance of neurotransmitter phenotypes in (nor)adrenergic neurons and neuroendocrine cells.