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  • br The estrogen receptors History and discovery


    The estrogen receptors: History and discovery In 1958, Elwood Jensen discovered the estrogen receptor, the first receptor ever encountered for any hormone, by showing that reproductive female tissues were able to uptake estrogen from the circulation by binding to proteins. He later demonstrated that estrogen-bound receptors were able to migrate to the nucleus, where they could stimulate gene transcription (Jensen et al., 1967; Jensen et al., 1968). More than 20years later, the first human estrogen receptor (known today as ERα) was cloned using RNA from the human breast cancer cell line MCF-7 (Green et al., 1986; Greene et al., 1986). Similarly, the second estrogen receptor (known today as ERβ) was described 10 years later by the research team lead by Dr. Jan-Ake Gustafsson (Kuiper, Enmark, Pelto-Huikko, Nilsson, & Gustafsson, 1996). Gustafsson\'s lab discovered that a newly identified protein that was mainly expressed in the secretory epithelial Heparin of the prostate and in the granulosa cells of the ovary, shared a high degree of homology with the ERα (DNA-binding domain, 95%; ligand-binding domain, 55%). As a result of these similarities, the team suggested for the protein be named ERβ. More recently, a new type of estrogen binding protein was discovered in target cells: The G Protein-Coupled Estrogen Receptor GPER1, or membrane estrogen receptor. Unlike the nuclear estrogen receptors ERα and ERβ, which were isolated by traditional biochemical approaches, GPER1 was identified by molecular cloning methods (Filardo & Thomas, 2012). Almost two decades ago, several research laboratories had reported the isolation of a G Protein-Coupled Receptor homolog, which was ascribed the orphan term GPR30 (Carmeci, Thompson, Ring, Francke, & Weigel, 1997; Feng & Gregor, 1997; Kvingedal & Smeland, 1997; O\'Dowd et al., 1998; Owman, Blay, Nilsson, & Lolait, 1996; Takada, Kato, Kondo, Korenaga, & Ando, 1997). It was assumed that the ligand for GPR30 was a hormone or chemotactic peptide due to its structural similarities to the receptors for angiotensin II and other peptides such as such as interleukin-8, monocyte chemotactic proteins, and complement factors (Filardo & Thomas, 2012). However, after screening of multiple chemotactic peptides and factors, no molecules with binding affinities to GPR30 were found, the receptor continued to be classified as orphan (Feng & Gregor, 1997). However, in the year 2000, a research team was able to show that fast estrogen-mediated activation of extracellular signal-regulated kinases (ERKs) was dependent on GPR30 (Filardo, Quinn, Bland, & Frackelton, 2000). Five years later, this and other groups were able to demonstrate direct binding of 17β-estradiol to GPR30 in GPR30-transfected cells and breast cancer cell lines (Revankar, Cimino, Sklar, Arterburn, & Prossnitz, 2005; Thomas, Pang, Filardo, & Dong, 2005). Finally, in 2007 GPR30 was officially named G protein-coupled estrogen receptor 1 (also known as GPER or GPER1), and its role in mediating fast responses to estrogens and overall physiological and pathological processes has been studied extensively in human and animal models (Boonyaratanakornkit & Edwards, 2007; Filardo et al., 2007; Molina, Figueroa, Bhoola, & Ehrenfeld, 2017; Prossnitz & Barton, 2014; Sharma & Prossnitz, 2016).
    Structural properties of estrogen receptors The full-length size of ERα is 595 amino acids and 67kDa. ERβ is 530 amino acids in length and 59kDa. The main difference between the two proteins is that ERβ has a shorter amino terminal domain than ERα (Fig. 4). As members of the nuclear hormone receptors superfamily of transcription regulators, the structures of the estrogen receptors ERα and ERβ are composed of various functional domains and have several structural regions in common (Schwabe & Teichmann, 2004). The principal functional domains are termed A/B, C, D, and E/F, and are present in both receptor full-length structures (Fig. 4). The A/B region represents the amino-terminal domain (NTD), which is involved in gene transcription transactivation, and contains a zinc-finger that mediates binding to target sequences. The C region corresponds to the DNA binding domain (DBD), which contributes to estrogen receptor dimerization and binding to specific sequences in the chromatin. These canonical sequences known collectively as estrogen response elements (ERE) (Scheidereit et al., 1986; Truss & Beato, 1993). The D domain is a hinge region that connects the C and E domains, and is able to bind to chaperone proteins. This region also contains the nuclear localization signal, that is unmasked upon estrogen binding, allowing for the receptor-ligand complexes to translocate to the nucleus. In the carboxy-terminal E/F region, also known as the ligand binding domain, contains the estrogen binding area, along with binding sites for coactivators and corepressors. Finally, two additional regulators of the estrogen receptor transcriptional activity known as activation function (AF) domains AF1 and AF2, are located within the NTD and DBD, respectively (Kumar et al., 2011). The mechanisms of transcriptional regulation mediated by these receptors appear to involve a synergistic effect of AF1 and AF2 (Tora et al., 1989). Contrarily to AF2, AF1 does not require binding to hormones or steroids to be activated (Kumar et al., 2011).