In vivo and in vitro inhibition of cyp19 gene expression by prostaglandin F2alpha in murine luteal cells: implication of GATA-4.
A major function of the corpus luteum (CL) is to secrete progesterone. In rats, this gland also produces significant amounts of 17beta-estradiol. Progesterone and 17beta-estradiol are important regulators of rat luteal cell function. Estrogen biosynthesis is catalyzed by P450aromatase (P450arom), which is encoded by the cyp19 gene. In the rat CL, P450arom is expressed throughout pregnancy until the day before parturition, when it rapidly decreases. The mechanisms that control P450arom expression in luteal cells, particularly, the one or more factors that cause its rapid fall before parturition, are not known. Inasmuch as prostaglandin (PG) F(2alpha) plays a key role in the regulation of luteal function at the end of pregnancy, the purpose of this investigation was to determine whether PGF(2alpha) affect the expression of P450arom in the CL before parturition. PGF(2alpha) decreased luteal P450arom mRNA and protein levels in vivo and in vitro. A decrease in P450arom mRNA was also observed in mice CL just before parturition, but this change did not take place in PGF(2alpha) receptor knockout mice. The time course of the decrease in P450arom mRNA by PGF(2alpha) reflected the P450arom mRNA half-life determined by actinomycin D. Moreover, nuclear run-on assay showed that PGF(2alpha) attenuates P450arom gene transcription. Gel shift assays revealed that GATA-4 binds to the P450aromatase promoter, and that such binding is increased by PGF(2alpha). It is concluded that PGF(2alpha) decreases luteal P450arom mRNA levels at the end of pregnancy in rodents by inhibiting cyp19 expression.
Department of Obstetrics, Gynecology & Reproductive Science, Yale University School of Medicine, 333 Cedar Street, P.O. 208063, New Haven, Connecticut 06520, USA. carlos.stocco@yale.edu
Carlos
C
Stocco
D000818:Animals; D001141:Aromatase / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015237:Dinoprost / Q000494:pharmacology*; D005260:Female; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008184:Luteal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010120:Oxytocics / Q000494:pharmacology*; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D010120:Oxytocics; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D014157:Transcription Factors; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D001141:Aromatase