title: Estrogen receptor (ER)beta isoforms rather than ERalpha regulate corticotropin-releasing hormone promoter activity through an alternate pathway.
abstract: The hypothalamic-pituitary-adrenal axis regulates mammalian stress responses by secreting glucocorticoids. The magnitude of the response is in part determined by gender, for in response to a given stressor, circulating glucocorticoids reach higher levels in female rats than in males. This gender difference could result from estrogen regulation of the corticotropin-releasing hormone (CRH) promoter via either of its receptors: estrogen receptor (ER)alpha or ERbeta. Immunocytochemistry revealed that a subset (12%) of medial parvocellular CRH neurons in the rat hypothalamus contain ERbeta but not ERalpha. To determine whether ERs could regulate CRH promoter activity, we cotransfected cells with a CRH promoter construct and either ERalpha or individual ERbeta isoforms. ERalpha weakly stimulated CRH promoter transcriptional activity in a ligand-independent manner. Conversely, all ERbeta isoforms tested stimulated CRH promoter activity with different ligand profiles. ERbeta1 and ERbeta2delta3 displayed constitutive activity (ERbeta1 more than ERbeta2delta3). Ligand-dependent activity of beta isoforms 1 and 2 was altered by an Exon3 splice variant (delta3) or by the additional 18 amino acids in the ligand-binding domain of ERbeta2 isoforms. Lastly, we suggest that ER regulation of CRH takes place through an alternate pathway, one that requires protein-protein interactions with other transcription factors or their associated complexes. However, a pure ER-activator protein-1 alternate pathway does not appear to be involved.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, Virginia 22908-0904, USA.
authors.forename: William J Schouler
authors.initials: WJ
authors.lastname: Miller
authors.forename: Shotaro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Lydia K
authors.initials: LK
authors.lastname: Miller
authors.forename: Robert
authors.initials: R
authors.lastname: Handa
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Uht
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000502:physiology; D047629:Estrogen Receptor beta / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D020033:Protein Isoforms; D018808:Transcription Factor AP-1; D003346:Corticotropin-Releasing Hormone