Induction of certain genes by estrogens involves the interaction of the hormone with a receptor protein. The specificity and responsiveness of tissues to hormonal stimulation are governed in most part by the presence and biochemical action of this receptor protein. We have purified and characterized the receptor protein and its intracellular site(s) of action. Earlier observations had indicated during uterine estrogen stimulation a bimodal nuclear receptor occupancy. New findings have shown a change in chromatin receptor acceptor sites and nuclear matrix binding coordinately with the receptor pattern indicating a possible alteration in the pattern of gene expression at the different times. The estrogen receptor protein has been purified from mouse uterus by steroid affinity and oligonucleotide chromatography. Molecular properties of the protein have been analyzed by epitope specific antibodies to understand the mechanism of receptor activation and conformation. Characterization of the receptor has indicated multiple forms which are proteolytic fragments and not separate gene products. The protease action results in a receptor form which has lost its ability to interact with other transcription factors and DNA responsive sequences and, consequently, its biological activity. We have shown that the nuclear estrogen receptor specifically exhibits a doublet form when bound by biologically active estrogens. Studies of receptor DNA interactions have indicated multiple complexes by band shift assays. The specificity and stability of these complexes vary depending on the biological potency of the ligands. The higher molecular weight component of the doublet is phosphorylated and associated with tightly bound chromatin sites. Weak estrogens or antiestrogens transiently produce the doublet form. These findings suggest that this form of the estrogen receptor may be involved in gene activation and hormone responsiveness. Cell culture studies have indicated the production of stable transfectant clones of the estrogen receptor and reporter gene constructs. These systems are being used as in vitro test systems for studies of estrogen receptor protein structure and gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES070065-15
Application #
3855967
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1991
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Li, Yin; Perera, Lalith; Coons, Laurel A et al. (2018) Differential in Vitro Biological Action, Coregulator Interactions, and Molecular Dynamic Analysis of Bisphenol A (BPA), BPAF, and BPS Ligand-ER? Complexes. Environ Health Perspect 126:017012
Burns, Katherine A; Thomas, Seddon Y; Hamilton, Katherine J et al. (2018) Early Endometriosis in Females Is Directed by Immune-Mediated Estrogen Receptor ? and IL-6 Cross-Talk. Endocrinology 159:103-118
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Li, Yin; Arao, Yukitomo; Hall, Julie M et al. (2014) Research Resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol 28:2072-81
Wall, Emma H; Case, Laure K; Hewitt, Sylvia C et al. (2014) Genetic control of ductal morphology, estrogen-induced ductal growth, and gene expression in female mouse mammary gland. Endocrinology 155:3025-35
Devanathan, Sriram; Whitehead, Timothy; Schweitzer, George G et al. (2014) An animal model with a cardiomyocyte-specific deletion of estrogen receptor alpha: functional, metabolic, and differential network analysis. PLoS One 9:e101900

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