Progesterone receptor and the mechanism of action of progesterone antagonists

Edwards, Dean P.; Altmann, Magda; DeMarzo, Angelo M.; Zhang, Yixian; Weigel, Nancy L.; Beck, Candace A.

doi:10.1016/0960-0760(95)00091-d

Cited by 78 publications

(32 citation statements)

References 48 publications

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“…Agonist R5020 and antagonist RU486 can promote the binding of PRB to HREs in DNA, with RU486 being reported to have a higher-affinity interaction than R5020 in vitro (9,11). Evidence for PR binding in the presence of R5020 and RU486 has been obtained mainly from gel shift experiments with naked DNA (9).…”

Section: Discussionmentioning

confidence: 99%

Ligand-Specific Dynamics of the Progesterone Receptor in Living Cells and during Chromatin Remodeling In Vitro

Rayasam

Elbi

Walker

et al. 2005

Molecular and Cellular Biology

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100

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Progesterone receptor (PR), a member of the nuclear receptor superfamily, is a key regulator of several processes in reproductive function. We have studied the dynamics of the interaction of PR with a natural target promoter in living cells through the use of fluorescence recovery after photobleaching (FRAP) analysis and also have characterized the dynamics of the interaction of PR with the mouse mammary tumor virus (MMTV) promoter reconstituted into chromatin in vitro. In photobleaching experiments, PR in the presence of the agonist R5020 exhibits rapid exchange with the MMTV promoter in living cells. Two PR antagonists, RU486 and ZK98299, have opposite effects on receptor dynamics in vivo. In the presence of RU486, PR binds to the promoter and is exchanged more slowly than the agonist-activated receptor. In contrast, PR bound to ZK98299 is not localized to the promoter and exhibits higher mobility in the nucleoplasm than the agonist-bound receptor. Significantly, PR bound to R5020 or RU486 can recruit the SWI/SNF chromatin remodeling complex to the promoter, but PR activated with ZK98299 cannot. Furthermore, we found ligand-specific active displacement of PR from the MMTV promoter during chromatin remodeling in vitro and conclude that the interaction of PR with chromatin is highly dynamic both in vivo and in vitro. We propose that factor displacement during chromatin remodeling is an important component of receptor mobility and that ligandspecific interactions with remodeling complexes can strongly influence receptor nuclear dynamics and rates of exchange with chromatin in living cells.

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Section: Discussionmentioning

confidence: 99%

Ligand-Specific Dynamics of the Progesterone Receptor in Living Cells and during Chromatin Remodeling In Vitro

Rayasam

Elbi

Walker

et al. 2005

Molecular and Cellular Biology

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100

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“…Smaller amount of progestagenic compounds are generated in the 3β-OH-tibolone-treated cultures, and therefore lower concentrations of mifepristone are needed to counteract the effect of 3β-OH-tibolone. Higher concentrations of mifepristone are not efficacious perhaps because mifepristone has some intrinsic progestagenic agonist activity that may override its antiprogestagenic effects, as has been shown in other systems 23 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Barbier

Kloosterboer²,

Kaufman

2008

Reprod. Sci.

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In human endometrium, cell proliferation is regulated by ovarian steroids through heterotypic interactions between stromal and epithelial cells populating this tissue. We tested the proliferative effects of tibolone and its metabolites using endometrial co-cultures that mimic the normal proliferative response to hormones. We found that both the Δ 4 -tibolone metabolite and the pure progestin ORG2058 counteract estradiol-driven epithelial cell proliferation. Surprisingly, the estrogen receptor binding 3-hydroxyl-metabolites of tibolone also counteracted estradiol-driven proliferation. Inhibition of proliferation by 3β-OH-tibolone was abrogated by low doses of the progesterone receptor antagonist mifepristone, This suggests that 3β-OH-tibolone is converted to a progestagenic metabolite. We found that the stromal cells used in the co-cultures express high levels of the ketosteroid dehydrogenase, AKR1C2, which is able to oxidize 3β-OH-tibolone back to tibolone. Thus the unexpected progestagenic effect of 3β-OH-tibolone in these co-cultures may be due to metabolic activity present in the stromal cells of the co-cultures.

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“…The dose dependence of these agonists was similar to that of P4. RU486 10 and ZK98299, 11 which usually act as progesterone receptor antagonists, also inhibited thymidine incorporation in ML5 cells and thus acted like agonists with regard to their effects on DNA synthesis (Fig. 3A).…”

Section: Effects Of Reproductive Hormones On Dna Synthesis In Culturedmentioning

confidence: 99%

Effect of Reproductive Hormones on Ovarian Epithelial Tumors: I. Effect

Zhou

Luo

Schönthal

et al. 2002

Cancer Biology & Therapy

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We examined the effects of the 4 major female reproductive hormones, estradiol (E2), progesterone (P4), follicle stimulating hormone (FSH), and luteinizing hormone (LH) on thymidine incorporation in benign and malignant ovarian epithelial tumors cultured in vitro. Treatment of these tumors with E2, FSH and LH resulted in increased thymidine incorporation while treatment with P4 inhibited growth as well as thymidine incorporation. The inhibitory effect of progesterone could not be reproduced by treating the cells with ligands for other steroid hormone receptors known to interact with P4 such as the mineralocorticoid and glucocorticoid receptors. All cells lines expressed at least the PR-A isoform of the progesterone receptor. ORG2058, R5020, RU486, and ZK98299 acted as progesterone receptor agonists with regard to their effect on thymidine incorporation. P4 down-regulated cyclin B1 expression and cdk1 activity and up-regulated the p21 and p27 proteins. Expression of a reporter gene downstream to an AP-1 responsive element in a plasmid construct transfected into ovarian epithelial tumor cells was induced by P4 and inhibited by RU486. We conclude that P4 inhibits cell cycle activity in ovarian epithelial tumors, in part via down-regulation of the cdk1/cyclin B complex. This inhibitory effect may have therapeutic utility against ovarian epithelial tumors.

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Progesterone receptor and the mechanism of action of progesterone antagonists

Cited by 78 publications

References 48 publications

Ligand-Specific Dynamics of the Progesterone Receptor in Living Cells and during Chromatin Remodeling In Vitro

Ligand-Specific Dynamics of the Progesterone Receptor in Living Cells and during Chromatin Remodeling In Vitro

Effects of Tibolone Metabolites on Human Endometrial Cell Lines in Co-culture

Effect of Reproductive Hormones on Ovarian Epithelial Tumors: I. Effect

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