Transcriptional regulation of tyrosine hydroxylase by estrogen:: opposite effects with estrogen receptors α and β and interactions with cyclic AMP

Reported effects of estrogen administration on tyrosine hydroxylase (TH) gene expression are confusing. Therefore, we studied the mechanism of regulation of TH transcription by estrogen with different estradiol receptor (ER) subtypes. PC12 cells, transiently co-transfected with expression vector for ER alpha or ER beta, and luciferase gene under control of the TH promoter, were treated with 17 beta-estradiol (E-2). E-2 doubled luciferase activity with ER alpha; however, it was decreased with ER beta. Mapping the TH promoter showed that the putative half estrogen response element (ERE) motif at - 675, as well as the activation protein 1 motif at - 205, were not required for response to E-2 with either ER. The specificity protein 1/early growth response gene 1 (Egr 1) motif was required for the E-2-elicited response with ER beta, but not with ER alpha. Deletion of the cyclic AMP/Ca2+ response element (CRE/CaRE) nearly abolished E-2-triggered responses with either ER. Further analysis revealed an imperfect canonical putative ERE overlapping with CRE/CaRE and Nurr1 response element. Oligonucleotides spanning this ERE displayed binding to ER, Cyclic AMP Response Element Binding Protein (CREB) and other proteins. Moreover, E-2 attenuated the increase in TH transcription seen with cyclic AMP analogs. Thus, TH is transcriptionally regulated by estradiol in opposite directions depending on ER subtype. The overlapping ERE and CRE/CaRE may integrate interactions elicited by various regulators of TH transcription including cAMP and estrogens.