ReviewEstrogen dependent signaling in reproductive tissues – A role for estrogen receptors and estrogen related receptors
Highlights
► Estrogens regulate the reproductive and cardiovascular systems, the skeleton and the brain. ► Estrogen receptor (ERα, β) genes are subject to alternative splicing. ► Ratios of ER subtypes/variants in cells determines the impact of estrogens on tissue function. ► ERα, β, and ERβ variants, have unique patterns of expression in reproductive tissues. ► Estrogen related receptors (α, β, γ) may play a role in regulation of cell metabolism.
Section snippets
Background
Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. Estrogens are key regulators of fertility in both males and females. The biological effects of estrogens are classically mediated via their interaction with nuclear receptors that are members of a superfamily of ligand-activated transcription factors (http://www.nursa.org/). A recent review (Levin, 2010) has provided a
Structure of estrogen and estrogen-related receptors
ERs and ERRs, like other members of the NR3A family, contain a conserved arrangement of structural and functional domains (A–F) including a conserved DNA-binding domain (DBD, domain C) consisting of two zinc fingers and a C-terminal domain (domain E/F) that contains amino acids involved in ligand binding, receptor dimerisation and nuclear localization (reviewed in Tremblay and Giguere, 2007, Nilsson et al., 2001) (Fig. 1).
The ligand binding domains of ERα and ERβ have both been crystallized and
Estrogen receptor isoforms
Ponglikitmongkol et al. (1988) reported that the human ERα gene is more than 140 kb in length and is split into eight exons. The human ERβ gene also contains 8 exons and there is considerable conservation between the arrangement of the coding exon/intron boundaries between human and mouse (Enmark et al., 1997).
Human ESR1 and ESR2 are both subject to alternative splicing and although they have similar exon and functional domain organization the splice variant isoforms identified appear to be
Molecular signaling pathways/functional interactions
The effects of estrogens can be mediated through several different pathways (reviewed in Nilsson et al., 2001, Hall et al., 2001, Matthews and Gustafsson, 2003). Classically, ligand-activated ERs form homo- or hetero-dimers that interact with response elements (called EREs, estrogen response elements) within the promoter regions of genes (reviewed in Nilsson et al., 2001). Gene transfer and band shift assays were originally used to identify an ERE consensus binding site within the promoter
Estrogen receptor related proteins – functional activation and potential cross-talk with estrogen receptors
Binding site selection experiments have demonstrated that ERR α binds to a response element (ERRE) containing a single consensus half-site, TNAAGGTCA, as either a monomer or a dimer (Sladek et al., 1997). It has been reported that ERs and ERRs have the capacity for transcriptional cross-talk with E-dependent genes such as osteopontin (reviewed in Vanacker et al., 1999). More recently studies using genomic analyses of binding sites have reported that ERRα and ERα display strict binding site
Expression in the normal reproductive tissues and in reproductive cancers
Estrogen receptors are widely expressed in reproductive tissues details are given in the following sections and summarised in Table 2.
Female reproductive system
The estrogen receptor α knockout (ERαKO) mouse has an ovarian phenotype that is characterized by cystic and hemorrhagic follicles as well as anovulation. Couse et al. (1999) showed this phenotype could be reversed by addition of exogenous gonadotropin concluding the ovarian phenotype was due to disruption of the HPA axis. It was noted that ERαKO mice had an inefficient ovulatory capacity that may suggest an intra-ovarian role for ERα (Couse et al., 1999). The ovaries of theca-specific estrogen
Future perspectives
Estrogen receptors play an essential role in the development and normal physiological function of reproductive and other tissues. The relative expression of both full length and variant isoforms of ERs varies between cells within different tissues and this, together with variations in ligand availability adds to the complexity of responses to natural and synthetic ligands. Cancers of reproductive tissues are often hormone responsive and this has prompted the development of therapies based on
References (144)
- et al.
ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart
Cell Metab.
(2007) - et al.
Structure-function relationship of estrogen receptor alpha and beta: impact on human health
Mol. Aspects Med.
(2006) - et al.
Differential distribution of splice variants of estrogen receptor beta in human testicular cells suggests specific functions in spermatogenesis
J. Steroid Biochem. Mol. Biol.
(2004) - et al.
Modulation of ER alpha transcriptional activity by the orphan nuclear receptor ERR beta and evidence for differential effects of long- and short-form splice variants
Mol. Cell Endocrinol.
(2010) - et al.
Aromatase and estrogen receptors in male reproduction
Mol. Cell Endocrinol.
(2006) - et al.
Estrogen receptor in carcinoma in situ of the cervix
J. Surg. Oncol.
(1992) - et al.
Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR
Gene
(1999) - et al.
Estrogen and ERalpha: culprits in cervical cancer?
Trends Endocrinol. Metab.
(2010) - et al.
Estrogen receptors alpha and beta form heterodimers on DNA
J. Biol. Chem.
(1997) - et al.
Estrogen receptor activation and cardioprotection in ischemia reperfusion injury
Trends Cardiovasc. Med.
(2010)
Ovarian steroid receptors and their role in ovarian function
Mol. Cell Endocrinol.
Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks
Mitochondrion.
Aromatase and regulating the estrogen:androgen ratio in the prostate gland
J. Steroid Biochem. Mol. Biol.
Clinical implication of estrogen-related receptor (ERR) expression in uterine endometrial cancers
J. Steroid Biochem. Mol. Biol.
Estrogen-related receptor expression in placenta throughout gestation
J. Steroid Biochem. Mol. Biol.
Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers
J. Steroid Biochem. Mol. Biol.
Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer
Biochem. Biophys. Res. Commun.
To ERR in the estrogen pathway
Trends Endocrinol. Metab.
The multifaceted mechanisms of estradiol and estrogen receptor signaling
J. Biol. Chem.
The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload
Cell. Metab.
Estrogen receptor alpha and beta expression in uterine leiomyomas from premenopausal women
Fertil. Steril.
Prostate phenotypes in estrogen-modulated transgenic mice
Trends Endocrinol. Metab.
A novel estrogen receptor-related protein gamma splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors
J. Steroid Biochem. Mol. Biol.
Upstream open reading frames regulate the translation of the multiple mRNA variants of the estrogen receptor alpha
J. Biol. Chem.
Potentiation of ICI182, 780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790
J. Biol. Chem.
Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression
J. Biol. Chem.
Cloning and characterization of human estrogen receptor beta isoforms
Biochem. Biophys. Res. Commun.
Estrogen and SERM neuroprotection in animal models of Parkinson’s disease
Mol. Cell Endocrinol.
The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro
Biochem. Biophys. Res. Commun.
Age-, cell- and region-specific immunoexpression of estrogen receptor alpha (but not estrogen receptor beta) during postnatal development of the epididymis and vas deferens of the rat and disruption of this pattern by neonatal treatment with diethylstilbestrol
Endocrinology
Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists
Mol. Pharmacol.
Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes
Mol. Endocrinol.
Estrogen receptor related beta is expressed in human endometrium throughout the normal menstrual cycle
Hum. Reprod.
A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism
J. Clin. Endocrinol. Metab.
Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation
Rev. Endocr. Metab. Disord.
Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha
J. Med. Chem.
Genome-wide analysis of estrogen receptor binding sites
Nat. Genet.
Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding
Mol. Endocrinol.
Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
Cancer Epidemiol. Biomarkers Prev.
Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues
J. Clin. Endocrinol. Metab.
Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors
J. Clin. Endocrinol. Metab.
Transrepression of estrogen receptor beta signaling by nuclear factor-kappab in ovarian granulosa cells
Mol. Endocrinol.
Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer
Cancer Res.
Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha
BMC Cancer
Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-alpha knockout mouse
Endocrinology
Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta
Science
Hormone receptor dynamics in a receptive human endometrium
Reprod. Sci.
Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium
J. Clin. Endocrinol. Metab.
Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle
J. Clin. Endocrinol. Metab.
Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent
Biol. Reprod.
Cited by (83)
Bisphenol A and genistein have opposite effects on adult chicken ovary by acting on ERα/Nrf2-Keap1-signaling pathway
2021, Chemico-Biological Interactions