Progesterone Catabolism in the Rat Ovary: A Regulatory Mechanism for Progestational Potency During Pregnancy<sup>1</sup>

Wiest, Walter G.; Kidwell, William R.; Balogh, Károly

doi:10.1210/endo-82-4-844

Cited by 223 publications

(144 citation statements)

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“…In rodents, the corpus luteum, which is the only source of progesterone throughout pregnancy (1), is also able to express the enzyme 20␣-hydroxysteroid dehydrogenase (20␣-HSD) 1 that converts progesterone into a biologically inactive steroid, thus playing a key role in the termination of pregnancy and allowing parturition to occur (2). Due to the detrimental effect of 20␣-HSD on luteal progesterone secretion, the corpus luteum of pregnancy does not express 20␣-HSD until 24 h before parturition (3). Our laboratory has previously demonstrated that the rapid appearance of luteal 20␣-HSD activity in the corpus luteum is due to the massive increase in 20␣-HSD gene expression and not to activation of an already existent enzyme (4).…”

mentioning

confidence: 99%

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

Stocco¹,

Zhong²,

Sugimoto³

et al. 2000

Journal of Biological Chemistry

120

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Prostaglandin F 2 ␣ (PGF 2 ␣) binding to its receptor on the rat corpus luteum triggers various signal transduction pathways that lead to the activation of a steroidogenic enzyme, 20␣-hydroxysteroid dehydrogenase (20␣-HSD), which in turn catabolizes progesterone. The molecular mechanism underlying PGF 2 ␣-induced 20␣-HSD enzyme activity has not yet been explored. In this report we show, using mice lacking PGF 2 ␣ receptor and pregnant rats, that PGF 2 ␣ is responsible for the rapid and massive expression of the 20␣-HSD gene at the end of pregnancy leading to a decrease in progesterone secretion. We also present evidence that PGF 2 ␣ enhances 20␣-HSD promoter activity. We have determined a region upstream of the ؊1590 position in the 20␣-HSD promoter that confers regulation by PGF 2 ␣ 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 20␣-HSD promoter activation by PGF 2 ␣. NUR77 also transactivated the 20␣-HSD promoter in transient transfection experiments in corpus luteumderived cells (GG-CL). This induction required the NUR77-transactivating domain. We also show that PGF 2 ␣ 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 20␣-HSD becomes expressed. This increase in the expression of both genes was not seen in PGF 2 ␣ receptor knockout mice. By using cyclosporin A and PGF 2 ␣ treatment, we established that inhibition of NUR77 DNA binding in vivo prevents PGF 2 ␣ induction of the 20␣-HSD gene in the corpus luteum. Taken together, our results demonstrate, for the first time, that PGF 2 ␣ 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 20␣-HSD, triggering the decrease in serum progesterone essential for parturition.In all mammalian species, progesterone plays an essential role in reproduction. The precise timing of both the synthesis and degradation of this steroid hormone is crucial for reproductive success. The expression of enzymes implicated in the synthesis and catabolism of progesterone, therefore, needs to be accurately regulated during the different reproductive states of the animal. In rodents, the corpus luteum, which is the only source of progesterone throughout pregnancy (1), is also able to express the enzyme 20␣-hydroxysteroid dehydrogenase (20␣-HSD)1 that converts progesterone into a biologically inactive steroid, thus playing a key role in the termination of pregnancy and allowing parturition to occur (2). Due to the detrimental effect of 20␣-HSD on luteal progesterone secretion, the corpus luteum of pregnancy does not express...

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mentioning

confidence: 99%

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

Stocco¹,

Zhong²,

Sugimoto³

et al. 2000

Journal of Biological Chemistry

120

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“…This difference in the size of the corpus luteum supported the findings that the total progestin output from the ovary during psp. was significantly lower than that during pregnancy (Hashimoto et al, 1968 ;Zeilmaker, 1965 ;Wiest et al, 1968). Hypophysectomy before the 11th day invariably terminated pregnancy in the rat.…”

Section: Resultsmentioning

confidence: 91%

The Size of the Corpus Luteum during Pseudopregnancy and Pregnancy in the Rat

et al. 1975

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“…The addition of Zn to the (Horton & Poyser, 1976). The increase in enzyme activity is believed to require protein synthesis, since it is prevented by actinomycin D, puromycin (Strauss & Stambaugh, 1974) or cycloheximide (Wiest & Kidwell, 1969;de la Llosa-Hermier et al, 1979 produced by an excessive intake of the prostaglandin synthesis inhibitor aspirin, and Cunnane (1981) has reported that uterine strips taken from zinc-deficient hooded Lister rats 24 h pre-term exhibited a 50% decrease, compared with controls, in the rate of conversion of radiolabelled arachidonate into PGE2, PGF2 and 6-oxo-PGFIa.…”

Section: Resultsmentioning

confidence: 99%

“…Originally it was supposed that the induction of ovarian 20a-hydroxysteroid dehydrogenase initiated the decline pre partum in plasma progesterone and the rise in plasma 20a-hydroxyprogesterone AWiest et al, 1968;Wiest & Kidwell, 1969). This view has been disputed by Veomett & Daniel (1975) and Lacy et al (1976), who demonstrated that substantial changes in these plasma steroids precede, rather than follow, the detection of this enzyme in the ovaries.…”

Section: Resultsmentioning

confidence: 99%

Studies on the role of zinc in parturition in the rat

Bunce¹,

Wilson²,

Mills³

et al. 1983

Biochemical Journal

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1. Pregnant rats were fed either low (<1 p.p.m.) Zn or control (40p.p.m. Zn) diets from day 10 of gestation. They were killed at intervals during the last 96h preceding the normal time for onset of parturition, and differences in plasma progesterone, oestradiol-17, and ovarian 20a-hydroxysteroid dehydrogenase were assessed. 2. Gestation was prolonged in Zn-deficient rats. 3. Although the preparturient decline in plasma progesterone began at the same time in all groups, at term, plasma progesterone concentration in Zn-deficient rats remained significantly higher than in normal females. 4. Induction of ovarian 20a-hydroxysteroid dehydrogenase activity was delayed by about 8h by Zn deficiency. This delay was not observed if prostaglandin F2. was injected previously. 5. The results suggest a Zn-dependent step(s) in uterine synthesis and/or release of prostanoids.Zinc was first reported to be required for normal parturition in the rat by Apgar (1968a). Female rats fed a diet containing 1 p.p.m. or less of Zn beginning on the first day after mating displayed loss of appetite and lethargy. Harderian-gland pigment often accumulated on the face and paws. Delivery was difficult and prolonged and accompanied by excessive bleeding, and most of the neonates were abandoned and placentae were left unconsumed. Further studies (Apgar, 1968b(Apgar, , 1970(Apgar, , 1972(Apgar, , 1973(Apgar, , 1975(Apgar, , 1976(Apgar, , 1977aGombe et al., 1973) showed that such effects were relatively specific to Zn deficiency and were not induced by restriction either of total food intake (pair-feeding) or

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Progesterone Catabolism in the Rat Ovary: A Regulatory Mechanism for Progestational Potency During Pregnancy¹

Cited by 223 publications

References 30 publications

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

The Size of the Corpus Luteum during Pseudopregnancy and Pregnancy in the Rat

Studies on the role of zinc in parturition in the rat

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Progesterone Catabolism in the Rat Ovary: A Regulatory Mechanism for Progestational Potency During Pregnancy1

Cited by 223 publications

References 30 publications

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

Prostaglandin F2α-induced Expression of 20α-Hydroxysteroid Dehydrogenase Involves the Transcription Factor NUR77

The Size of the Corpus Luteum during Pseudopregnancy and Pregnancy in the Rat

Studies on the role of zinc in parturition in the rat

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Progesterone Catabolism in the Rat Ovary: A Regulatory Mechanism for Progestational Potency During Pregnancy¹