Prostaglandin F2alpha-induced expression of 20alpha-hydroxysteroid dehydrogenase involves the transcription factor NUR77.
Prostaglandin F(2)alpha (PGF(2)alpha) binding to its receptor on the rat corpus luteum triggers various signal transduction pathways that lead to the activation of a steroidogenic enzyme, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), which in turn catabolizes progesterone. The molecular mechanism underlying PGF(2)alpha-induced 20alpha-HSD enzyme activity has not yet been explored. In this report we show, using mice lacking PGF(2)alpha receptor and pregnant rats, that PGF(2)alpha is responsible for the rapid and massive expression of the 20alpha-HSD gene at the end of pregnancy leading to a decrease in progesterone secretion. We also present evidence that PGF(2)alpha enhances 20alpha-HSD promoter activity. We have determined a region upstream of the -1590 position in the 20alpha-HSD promoter that confers regulation by PGF(2)alpha in ovarian primary cells. This region encompasses a unique transcription factor-binding site with a sequence of a NUR77 response element. Deletion of this motif or overexpression of a NUR77 dominant negative protein caused a complete loss of 20alpha-HSD promoter activation by PGF(2)alpha. NUR77 also transactivated the 20alpha-HSD promoter in transient transfection experiments in corpus luteum-derived cells (GG-CL). This induction required the NUR77-transactivating domain. We also show that PGF(2)alpha induces a very rapid expression of NUR77 that binds to a distal response element located at -1599/-1606 but does not interact with another proximal putative NUR77 response element located downstream in the promoter. A rapid increase in NUR77 mRNA was observed in mice corpora lutea just before parturition at a time when 20alpha-HSD becomes expressed. This increase in the expression of both genes was not seen in PGF(2)alpha receptor knockout mice. By using cyclosporin A and PGF(2)alpha treatment, we established that inhibition of NUR77 DNA binding in vivo prevents PGF(2)alpha induction of the 20alpha-HSD gene in the corpus luteum. Taken together, our results demonstrate, for the first time, that PGF(2)alpha induces in the corpus luteum the expression of the nuclear orphan receptor and transcription factor, NUR77, which in turn leads to the transcriptional stimulation of 20alpha-HSD, triggering the decrease in serum progesterone essential for parturition.
Stocco
C O
CO
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Zhong
L
L
Sugimoto
Y
Y
Ichikawa
A
A
Lau
L F
LF
Gibori
G
G
D015089:20-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D043607:20-alpha-Hydroxysteroid Dehydrogenase; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015237:Dinoprost / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C539818:Nr4a1 protein, mouse; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015237:Dinoprost; D015089:20-Hydroxysteroid Dehydrogenases; D043607:20-alpha-Hydroxysteroid Dehydrogenase