The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT
- PMID: 9171233
- DOI: 10.1210/mend.11.6.0004
The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT
Abstract
Steroid receptor antagonists, such as the antiestrogen tamoxifen or the antiprogestin RU486, can have inappropriate agonist-like effects in tissues and tumors. To explain this paradox we postulated that coactivators are inadvertently brought to the promoters of DNA-bound, antagonist-occupied receptors. The human (h) progesterone receptor (PR) hinge-hormone binding domain (H-HBD) was used as bait in a two-hybrid screen of a HeLa cDNA library, in which the yeast cells were treated with RU486. We have isolated and characterized two interesting steroid receptor-interacting proteins that regulate transcription in opposite directions. The first is L7/SPA, a previously described 27-kDa protein containing a basic region leucine zipper domain, having no known nuclear function. When coexpressed with tamoxifen-occupied estrogen receptors (hER) or RU486-occupied hPR or glucocorticoid receptors (hGR), L7/SPA increases the partial agonist activity of the antagonists by 3- to 10-fold, but it has no effect on agonist-mediated transcription. The interaction of L7/SPA with hPR maps to the hinge region, and indeed, the hPR hinge region squelches L7/SPA-dependent induction of antagonist-mediated transcription. Interestingly, pure antagonists that lack partial agonist effects, such as the antiestrogen ICI164,384 or the antiprogestin ZK98299, cannot be up-regulated by L7/SPA. We also isolated, cloned, and sequenced the human homolog (hN-CoR) of the 270-kDa mouse (m) thyroid/retinoic acid receptor corepressor. Binding of hN-CoR maps to the hPR-HBD. mN-CoR, and a related human corepressor, SMRT, suppress RU486 or tamoxifen-mediated partial agonist activity by more than 90%. This suppression is completely squelched by overexpression of the hPR H-HBD. Additionally, both corepressors reverse the antagonist-dependent transcriptional up-regulation produced by L7/SPA. Our data suggest that the direction of transcription by antagonist-occupied steroid receptors can be controlled by the ratio of coactivators to corepressors recruited to the transcription complex by promoter-bound receptors. In normal tissues and in hormone-resistant breast cancers in which the agonist activity of mixed antagonists predominates, steroid receptors may be preferentially bound by coactivators. This suggests a strategy by which such partial agonist activity can be eliminated and by which candidate receptor ligands can be screened for this activity.
Similar articles
-
Thoughts on tamoxifen resistant breast cancer. Are coregulators the answer or just a red herring?J Steroid Biochem Mol Biol. 2000 Nov 30;74(5):255-9. doi: 10.1016/s0960-0760(00)00101-1. J Steroid Biochem Mol Biol. 2000. PMID: 11162933 Review.
-
Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied steroid receptors.J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):45-50. doi: 10.1016/s0960-0760(98)00148-4. J Steroid Biochem Mol Biol. 1999. PMID: 10418980 Review.
-
A nuclear receptor corepressor modulates transcriptional activity of antagonist-occupied steroid hormone receptor.Mol Endocrinol. 1998 Apr;12(4):513-24. doi: 10.1210/mend.12.4.0089. Mol Endocrinol. 1998. PMID: 9544987
-
The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor.Mol Cell Biol. 1998 Mar;18(3):1369-78. doi: 10.1128/MCB.18.3.1369. Mol Cell Biol. 1998. PMID: 9488452 Free PMC article.
-
Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors.Mol Endocrinol. 1993 Oct;7(10):1256-65. doi: 10.1210/mend.7.10.8123133. Mol Endocrinol. 1993. PMID: 8123133
Cited by
-
Selected Fungicides as Potential EDC Estrogenic Micropollutants in the Environment.Molecules. 2023 Nov 5;28(21):7437. doi: 10.3390/molecules28217437. Molecules. 2023. PMID: 37959855 Free PMC article.
-
Progesterone Receptor Gene Polymorphisms and Breast Cancer Risk.Endocrinology. 2023 Feb 11;164(4):bqad020. doi: 10.1210/endocr/bqad020. Endocrinology. 2023. PMID: 36702635 Free PMC article.
-
Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.J Med Chem. 2022 May 12;65(9):6888-6902. doi: 10.1021/acs.jmedchem.2c00235. Epub 2022 May 3. J Med Chem. 2022. PMID: 35503419 Free PMC article.
-
Computer-Aided Ligand Discovery for Estrogen Receptor Alpha.Int J Mol Sci. 2020 Jun 12;21(12):4193. doi: 10.3390/ijms21124193. Int J Mol Sci. 2020. PMID: 32545494 Free PMC article. Review.
-
Progesterone-Related Immune Modulation of Pregnancy and Labor.Front Endocrinol (Lausanne). 2019 Mar 29;10:198. doi: 10.3389/fendo.2019.00198. eCollection 2019. Front Endocrinol (Lausanne). 2019. PMID: 30984115 Free PMC article. Review.
Publication types
MeSH terms
Substances
Associated data
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials