title: Transcriptional regulation of tyrosine hydroxylase by estrogen: opposite effects with estrogen receptors alpha and beta and interactions with cyclic AMP.
abstract: 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 ERalpha or ERbeta, and luciferase gene under control of the TH promoter, were treated with 17 beta-estradiol (E2). E2 doubled luciferase activity with ERalpha; however, it was decreased with ERbeta. 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 E2 with either ER. The specificity protein 1/early growth response gene 1 (Egr 1) motif was required for the E2-elicited response with ERbeta, but not with ERalpha. Deletion of the cyclic AMP/Ca2+ response element (CRE/CaRE) nearly abolished E2-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, E2 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Shreekrishna
authors.initials: S
authors.lastname: Maharjan
authors.forename: Lidia
authors.initials: L
authors.lastname: Serova
authors.forename: Esther L
authors.initials: EL
authors.lastname: Sabban
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000235:genetics; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000235:genetics; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D005809:Genes, Regulator / Q000187:drug effects / Q000235:genetics; D017930:Genes, Reporter; D005822:Genetic Vectors; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000235:genetics; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D002395:Catecholamines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011960:Receptors, Estrogen; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase