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Review
.2019:116:135-170.
doi: 10.1016/bs.apcsb.2019.01.001. Epub 2019 Feb 4.

Estrogen receptor signaling mechanisms

Affiliations
Review

Estrogen receptor signaling mechanisms

Nathalie Fuentes et al. Adv Protein Chem Struct Biol.2019.

Abstract

The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.

Keywords: G-protein coupled estrogen receptor; Gene expression; Nuclear estrogen receptor; Steroidogenesis; Transcriptional control.

© 2019 Elsevier Inc. All rights reserved.

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Figures

Figure 1
Figure 1. Chemical structures of endogenous estrogens.
Estrone (E1; orange), estradiol (E2; blue), estriol (E3; green) and estretrol (E4; yellow).
Figure 2
Figure 2. Association of theca and granulosa cell in estrogen synthesis.
The luteinizing hormone (LH) induces the production of androgens in theca cells. The follicle-stimulating hormone (FSH) stimulates granulosa cells via aromatization of androgens to estrogens and by using cholesterol to produce pregnenolone. The process occurs in the ovarian follicle, which is composed of granulosa cells, oocyte, basal lamina and theca cells. CREB, cyclic AMP response element binding protein; PKA, protein kinase A; LDL, low density lipoproteins; cAMP, cyclic adenosine monophosphate; StAR, steroid acute regulatory protein; P450c17, 17α-hydroxylase/lyase; 17βHSD, 17β-hydroxysteroid dehydrogenase.
Figure 3
Figure 3. Estrogen biosynthesis pathway.
The estrogen biosynthetic pathway involves the conversion of cholesterol to progestogens, androgens and finally estrogens. The conversion of androgen to estrone (E1) and estradiol (E2) catalyzed by aromatase is the final step for synthesis of estrogen.
Figure 4
Figure 4. Structural organization of estrogen receptors.
Structural domains of estrogen receptor α (ERα) (595aa) and ERβ (530aa) are labeled A-F. Both receptors have 6 different structural and functional domains: N- terminal (NTD, A/B domains, AF-1), DNA binding domain (DBD, C domain), the hinge (D domain), the C-terminal region containing the ligand binding domain (LBD, E/F domain, AF-2).
Figure 5
Figure 5. Estrogen receptor alpha (ERα) isoforms.
The domain organization of the full-length 595 amino acid ERα (67kDa), and truncated shorter isoforms (62kDa, 53kDa, 46kDa, 45kDa, and 36kDa) resulting from alternative splicing and/or alternate translation start sites are illustrated. Protein domains are labeled as A to F with numbering denoting amino acid sequence number based on the full-length protein (595 aa). ERα domains: N-terminal (NTD, A/B domains, AF-1), DNA binding domain (DBD, C domain), hinge (D) domain, and C-terminal region containing the ligand binding domain (LBD, E/F domain, AF-2).
Figure 6
Figure 6. Estrogen receptor beta (ERβ) isoforms.
The domain organization of the full-length 530 amino acid ERβ (59kDa), truncated shorter isoforms (54 kDa, 49 kDa, and 44 kDa), and elongated isoform (61kDa), resulting from alternative splicing and/or alternate translation start sites are illustrated. Protein domains are labeled as A to F with numbering denoting amino acid sequence number based on the full-length protein (595 aa). ERβ domains: N-terminal (NTD, A/B domains, AF-1), DNA binding domain (DBD, C domain), hinge (D) domain, and C-terminal region containing the ligand binding domain (LBD, E/F domain, AF-2).
Figure 7
Figure 7. Genomic and non-genomic estrogen signaling pathways.
There are different estrogen-mediated signaling mechanisms. 1) Direct genomic signaling: estrogen binds to ERs. The complex dimerizes and translocate to the nucleus inducing transcriptional changes in estrogen-responsive genes with or without EREs. 2) Indirect genomic signaling: the membrane bound receptor induces cytoplasmic events such as modulation of membrane-based ion channels, second-messenger cascades and transcription factors. 3) ER-independent: estrogen exerts antioxidant effects in an ER-independent manner. 4) Estrogen independent: ligand-independent genomic events.
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