title: Estradiol regulation of lipocalin-type prostaglandin D synthase promoter activity: evidence for direct and indirect mechanisms.
abstract: In the CNS, lipocalin-type prostaglandin D synthase (L-PGDS) is predominantly a non-neuronal enzyme responsible for the production of PGD(2), an endogenous sleep promoting substance. We have previously demonstrated that estradiol differentially regulates L-PGDS transcript levels in the rodent brain. In hypothalamic nuclei, estradiol increases L-PGDS transcript expression, whereas in the ventrolateral preoptic area L-PGDS gene expression is reduced after estradiol treatment. In the present study, we have used an immortalized glioma cell line transfected with a L-PGDS reporter construct and estrogen receptor (ER) alpha and ERbeta expression plasmids to further elucidate the mechanisms underlying estradiol regulation of L-PGDS gene expression. We found that physiologically relevant concentrations of estradiol evoked an inverted U response in cells expressing ERalpha. The most effective concentration of estradiol (10(-11)M) increased the promoter activity 3-fold over baseline. Expression of ERbeta did not increase activity over control and when ERbeta was co-expressed with ERalpha there was a significant attenuation of the promoter activity. While ERalpha significantly increased L-PGDS promoter activity, our previous in vivo studies demonstrate a greater magnitude of change in L-PGDS gene expression in the presences of estradiol. This led us to ask whether estradiol is signaling via a paracrine factor released by the neighboring neurons. Conditioned media from estradiol treated neurons applied to the glioma cell line resulted in a significant 7-fold increase in L-PGDS promoter activity supporting the possibility that neuronal-glial interactions are involved in estradiol regulation of L-PGDS.
authors.affiliation: Laboratory of Neurobiology and Behavior, Rockefeller University, 1230 York Ave, New York, NY 10021, United States.
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Ko
authors.initials: K
authors.lastname: Fujimori
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Donald W
authors.initials: DW
authors.lastname: Pfaff
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Mong
mesh_terms: D001685:Biological Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D019899:Paracrine Communication; D014158:Transcription, Genetic
chemical_list: D001685:Biological Factors; D017077:Culture Media, Conditioned; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D054834:Lipocalins; D004958:Estradiol; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase