Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components

Geier, Avraham; Bella, R.; Beery, Rachel; Haimsohn, Michal; Lunenfeld, Bruno

doi:10.1016/0167-4889(87)90052-8

Cited by 11 publications

(1 citation statement)

References 12 publications

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“…We have shown that the C-terminal epitope recognized by this MAb is accessible when PR are bound with RU486 yet is completely occluded when receptors are bound to progesterone or R5020 (Weigel etal., 1992). Others have similarly reported structural differences when PR are bound to RU486 or progestin agonists, indicating that RU486 binds to PR differently and/or induces a distinct conformation (Geier et al, 1987;Skafar, 1991b). Several estrogen antagonists, that do not interfere with binding of estrogen receptors to specific DNA sites, have also been shown to induce alterations in the mobility of receptors bound to specific DNA (Fawell et al, 1990;Green, 1990; Kumar & Chambon, 1988;Pham et al, 1991), suggesting that antiestrogens induce a distinct conformation in ER.…”

Section: Discussionmentioning

confidence: 98%

Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor

DeMarzo

Oñate²,

Nordeen³

et al. 1992

Biochemistry

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We previously reported, using a coimmunoprecipitation assay, that the B form (PR-B) of the human progesterone receptor from T47D human breast cancer cells dimerizes in solution with the A receptor (PR-A) and that the extent of dimerization correlates with receptor binding activity for specific DNA sequences [DeMarzo, A.M., Beck, C.A., Oñate, S.A., & Edwards, D.P. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 72-76]. This suggested that solution dimerization is an intermediate step in the receptor activation process. The present study has tested the effects of the progesterone antagonist RU486 on solution dimerization of progesterone receptors (PR). As determined by the coimmunoprecipitation assay, RU486 binding did not impair dimerization of receptors; rather, the antagonist promoted more efficient solution dimerization than the progestin agonist R5020. This enhanced receptor dimerization correlated with a higher DNA binding activity for transformed receptors bound with RU486. RU486 has been shown previously to produce two other alterations in the human PR when compared with R5020. PR-RU486 complexes in solution exhibit a faster sedimentation rate (6 S) on salt-containing sucrose density gradients than PR-R5020 complexes (4 S), and PR-DNA complexes have a faster electrophoretic mobility on gel-shift assays in the presence of RU486. We presently show that the 6 S PR-RU486 complex is a receptor monomer, not a dimer. The increased sedimentation rate and increased mobility on gel-shift assays promoted by RU486 were also observed with recombinant PR-A and PR-B separately expressed in insect cells from baculovirus vectors. These results suggest that RU486 induces a distinct conformational change both in PR monomers in solution and in dimers bound to DNA. We also examined whether conformational changes in PR induced by RU486 would prevent a PR polypeptide bound to RU486 from heterodimerization with another PR polypeptide bound to R5020. To evaluate this, PR-A and PR-B that were separately bound to R5020 or RU486 in whole cells were mixed in vitro. PR-A-RU486 was capable of dimerization with PR-B-R5020, and this was demonstrated for heterodimers both formed in solution and bound to specific DNA. The capability to form heterodimers in vitro raises the possibility that the antagonist action of RU486 in vivo could in part be imposed in a dominant negative fashion through heterodimerization between one receptor subunit bound to an agonist and another bound to RU486.

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Section: Discussionmentioning

confidence: 98%

Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor

DeMarzo

Oñate²,

Nordeen³

et al. 1992

Biochemistry

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Steroid Hormone Receptor Families

Hurd

Moudgil

1998

Comprehensive Physiology

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The sections in this article are: Molecular Composition of Receptor Proteins: Primary Structural Homologies and Functional Domains The A/B Region of Steroid Receptors Contains a Hormone‐Independent Activation Function The C Region Encodes a Specific DNA‐Binding Function The D Region (the Hinge Domain) Contains a Nuclear Localization Signal The E/F Region Contains the Hormone‐Binding Domain, a Dimerization Motif, Steroid Receptor Repressor Activity, and a Receptor Agonist‐Dependent Transcriptional Activation Function Receptor‐Associated Proteins and the Oligomeric Structure of Steroid Receptors Major Heat Shock Proteins Cross‐Talk with Other Signal‐Transduction Pathways Cyclic Adenosine Monophosphate and Activation of Steroid Receptors Transcriptional Interference Pathways That Converge on the Estrogen Receptor Role of Phosphorylation in Steroid Receptor Structure and Function Sites of Phosphorylation, Functional Significance, and Regulatory Kinases Estrogen Receptor Phosphorylation Progesterone Receptor Phosphorylation Glucocorticoid Receptor Phosphorylation Vitamin D Receptor Phosphorylation Transactivation by Steroid Receptors Antihormones and Their Modes of Action RU486, an Agonist/Antagonist of Progesterone Receptor ZK98299, a Full Antagonist of Progesterone Receptor Antiestrogens and Estrogen Receptor Function Steroid Receptors and Clinical Management of Cancer Cancer: Molecular Aspects Breast Cancer, Tumor Suppressors, and Estrogen Paradoxical Effects of Estrogen: Molecular Aspects Future Directions

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Progesterone receptors in breast cancer

Beck¹,

Edwards²

1991

Cancer Treatment and Research

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Differences in the association of the progesterone receptor ligated by antiprogestin RU38486 or progestin ORG 2058 to chromatin components

Cited by 11 publications

References 12 publications

Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor

Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor

Steroid Hormone Receptor Families

Progesterone receptors in breast cancer

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