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  • The mechanisms by which coregulators control the actions of

    2020-10-21

    The mechanisms by which coregulators control the actions of estrogen receptors are still a topic of ongoing research. From studies in cancer cells, we have learned that a large group of coregulators have specific structural motifs that than affect their contact with ER ligand-binding domains (Heery, Kalkhoven, Hoare, & Parker, 1997). The specific motifs are called NR boxes or LXXLL motifs (X, any amino acid; L, leucine). On the other hand, we know that corepressors block ER-mediated gene transcription via (1) direct interaction with unbound estrogen receptors; (2) using their corepressor nuclear receptor box; (3) competing with coactivators (Hu & Lazar, 1999). It has also been reported that the concentration of several coregulators depends on estrogen induced-transcriptional regulation via the estrogen receptors (Mishra, Balasenthil, Nguyen, & Vadlamudi, 2004). Additionally, several post-translational modifications such as phosphorylation, methylation, ubiquitination, SUMOylation, and acetylation can impact the action of coregulators targeting gene expression (Han, Lonard, & O\'Malley, 2009; Lonard & O\'malley, 2007; O\'Malley & McKenna, 2008).
    Endogenous and exogenous estrogen receptors ligands Apart from the estrogens that are naturally produced by gonadal and other tissues in the body, there is a diverse variety of organic and inorganic molecules that are able to recognize the estrogen receptors ligand-binding domains in a precise manner (Table 1). Most of these ligands display higher selectivity toward ERα, however, several selective compounds for ERβ have recently been described (Farooq, 2015). There are five main Potassium Canrenoate of ER ligands: endoestrogens, phytoestrogens, xenoestrogens, selective estrogen receptor modulators (SERMs) and metalloestrogens. Endoestrogens are physiological estrogens that are endogenously produced by the body. Most endoestrogens (i.e., estradiol, estriol, estretrol, and estrone) were previously discussed in the chapter. Briefly, endoestrogens are steroidal compounds produced from cholesterol in the male and female gonads and other organs (Farooq, 2015). In contrast, phytoestrogens are non-steroidal compounds produced by plants. There are three known groups of phytoestrogens: isoflavones, coumestans, and lignans (Basu & Maier, 2018). Because phytoestrogens are chemically and structurally similar to estradiol, they can participate in both estrogenic and antiestrogenic effects through activation or blocking of the estrogen receptor ligand-binding domains (Turner, Agatonovic-Kustrin, & Glass, 2007). Interestingly, the phytoestrogens genistein, coumestrol, and liquiritigenin have been reported to display more affinity toward ERβ than to ERα, but the implications of these differences remain unknown (Kuiper et al., 1998; Manas, Xu, Unwalla, & Somers, 2004; Mersereau et al., 2008; Nilsson, Kuiper, & Gustafsson, 1998). Xenoestrogens are another group of ligands that comprise an extensive variety of non-natural synthetic chemical compounds with estrogenic effects. The family of xenoestrogens can be divided into five major types: medicinal drugs, food additives, body cosmetics, environmental pesticides, and industrial chemicals (Farooq, 2015). Drugs such as diethylstilbestrol (DES) and ethinyl estradiol were specifically synthesized to mimic the action of endoestrogens, and have been extensively to treat many conditions in women (Gennari, Merlotti, Valleggi, Martini, & Nuti, 2007; Maximov, Lee, & Jordan, 2013). However, it has been found that these compounds can affect cellular and molecular processes leading to severe effects on health, and their use in medical therapeutics remains controversial (Aravindakshan, Gregory, Marcogliese, Fournier, & Cyr, 2004; Aravindakshan et al., 2004; Arukwe, Celius, Walther, & Goksøyr, 2000; Christin et al., 2004; Golden et al., 1998; Iorga et al., 2017; Vajda et al., 2008; Williams, Lech, & Buhler, 1998). In the past few years, a wealth of evidence has been accumulated demonstrating that estrogens regulate many facets of the inflammatory response and the immune system via complex molecular mechanisms that are also sex dependent (Khan & Ansar Ahmed, 2015). It is now plausible that any immune cell that expresses estrogen receptors can potentially respond to ligand binding in a context-dependent manner, which will affect the outcome of the overall immune response. Thus, given the known spatial and temporal expression of the estrogen receptors, it is important to consider this aspect when designing potential therapeutic therapies targeting the estrogen receptor signaling pathways (Arnal et al., 2017). Additionally, precise timing of treatment initiation and duration may be required to determine the true efficacy of estrogen treatment (Burns & Korach, 2012; Hamilton, Hewitt, Arao, & Korach, 2017).