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In Vivo and in Vitro Inhibition of cyp19 Gene Expression by Prostaglandin F₂ in Murine Luteal Cells: Implication of GATA-4

Department of Obstetrics, Gynecology & Reproductive Science, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Carlos Stocco, Department of Obstetrics, Gynecology & Reproductive Science, Yale University School of Medicine, 333 Cedar Street, P.O. 208063, New Haven, Connecticut 06520. E-mail: carlos.stocco{at}yale.edu.

A major function of the corpus luteum (CL) is to secrete progesterone. In rats, this gland also produces significant amounts of 17ß-estradiol. Progesterone and 17ß-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) F₂ plays a key role in the regulation of luteal function at the end of pregnancy, the purpose of this investigation was to determine whether PGF₂ affect the expression of P450arom in the CL before parturition. PGF₂ 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 PGF₂ receptor knockout mice. The time course of the decrease in P450arom mRNA by PGF₂ reflected the P450arom mRNA half-life determined by actinomycin D. Moreover, nuclear run-on assay showed that PGF₂ attenuates P450arom gene transcription. Gel shift assays revealed that GATA-4 binds to the P450aromatase promoter, and that such binding is increased by PGF₂. It is concluded that PGF₂ decreases luteal P450arom mRNA levels at the end of pregnancy in rodents by inhibiting cyp19 expression.

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