Regulation of the tyrosine hydroxylase and dopamine beta-hydroxylase genes by the transcription factor AP-2

J Neurochem. 2001 Jan;76(1):280-94. doi: 10.1046/j.1471-4159.2001.00044.x.


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 beta-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Catecholamines / metabolism
  • Cell Line
  • Central Nervous System / cytology
  • Central Nervous System / enzymology
  • DNA Footprinting
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dopamine beta-Hydroxylase / genetics
  • Dopamine beta-Hydroxylase / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mutagenesis, Site-Directed
  • Neurons / cytology
  • Neurons / enzymology*
  • Organ Specificity
  • Peripheral Nervous System / cytology
  • Peripheral Nervous System / enzymology
  • Promoter Regions, Genetic / genetics
  • Rats
  • Regulatory Sequences, Nucleic Acid / genetics
  • Transcription Factor AP-2
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation / genetics
  • Transfection
  • Tyrosine 3-Monooxygenase / genetics
  • Tyrosine 3-Monooxygenase / metabolism*


  • Catecholamines
  • DNA-Binding Proteins
  • Transcription Factor AP-2
  • Transcription Factors
  • Tyrosine 3-Monooxygenase
  • Dopamine beta-Hydroxylase