br Acknowledgments This work was supported by
Acknowledgments This work was supported by grants from the “Agence Nationale de la Recherche” ANR-09-CESA-006 program, the Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail (Anses, Project n° 2012-2-077) and the Interdisciplinary Program “Longévité et Vieillissement” of the CNRS.
Introduction The androgen receptor (AR) is one of the 49 members of the steroid receptor family of ligand-activated transcription factors (Tsai and O'Malley, 1994). The steroid or nuclear hormone receptors play pivotal roles in the organogenesis, physiology, and pathology of a variety of tissues (Tsai and O'Malley, 1994, Evans, 1988). These receptors are promiscuously activated by wide-ranging ligands, including natural hormones, growth factors, peptides, or synthetic molecules (Power et al., 1992, Mani et al., 1996, Nazareth and Weigel, 1996). The steroid receptor family is organized into three histone deacetylase inhibitors (Tsai and O'Malley, 1994). Class I is comprised of receptors for hormones such as androgens, progestins, estrogens, and corticosteroids. Receptors for vitamins and thyroid hormones belong to class II, while receptors for bile acids and for which natural ligands have not yet been identified are relegated to class III. Hormone signaling is under tight control with several context specific means of regulating both the potency of a hormone response and the cellular outcome of hormone-receptor interactions. Hormone signaling is modulated by the expression of various metabolic enzymes (Penning et al., 2000, Imperato-McGinley et al., 1975, Schindler, 1975), expression of coactivators and corepressors (Liao et al., 2003, Shang et al., 2002), and the activity of various kinases and growth factors. For example, the estrogens have beneficial effects in bone and brain, while having growth-promoting effects in uterus and breast (Hall et al., 2001, Rodan and Martin, 2000, Dhandapani and Brann, 2002, Burns and Korach, 2012). Activation of the estrogen receptor (ER) by the principal circulating estrogen, estradiol, may not only result in the prevention or treatment of osteoporosis, but may concurrently cause mammary and uterine hyperplasia. Although both the beneficial and the growth-promoting effects arise from agonistic activities of estrogens, the tissue of action determines whether the effect is beneficial or detrimental. As it is ideal to have targeted therapeutic effects, the ubiquitous expression of receptors presents a therapeutic challenge and precludes wider use of exogenous hormone administration. To circumvent the limitations resulting from global receptor activation, researchers sought ligands, referred to as Selective Receptor Modulators (SRMs) that activate receptors in a tissue-specific manner. Selective Estrogen Receptor Modulators (SERMs) were the first SRMs to be characterized and developed (Charles et al., 1963). Tamoxifen and raloxifene are classical examples of SERMs that function as antagonists in the breast, but as agonists in the uterus or bone, respectively, either directly or through metabolic conversion (Kedar et al., 1994, Lahti et al., 1993, Deligdisch et al., 2000, Mincey et al., 2000). Decades after the discovery of SERMs, Selective Androgen Receptor Modulators (SARMs) (Dalton et al., 1998) were first described and subsequently developed to facilitate tissue-selective activation of the AR. This was followed by the discovery of Selective Glucocorticoid Receptor Modulators (SGRMs) (Link et al., 2005), Selective Progesterone Receptor Modulators (SPRMs) (Tabata et al., 2003) and others. Recently, a tissue-selective Farnesoid X receptor modulator was discovered with potential as a treatment for metabolic diseases (Fang et al., 2015), further increasing the number of tissue-selective nuclear receptor modulators available for therapeutic purposes.
Structure of the AR Eight exons code for a 90 KB AR gene located in the X chromosome (Lubahn et al., 1988, Chang et al., 1988). The AR is expressed in diverse mammalian tissues such as skeletal muscle, testes, prostate, breast, and uterus (Fujimoto et al., 1994, Ruizeveld de Winter et al., 1991, Sinha-Hikim et al., 2004). The AR is comprised of four distinct domains. The N-terminal domain (NTD) of the AR (spanning from amino acids 1–559) is the least homologous domain among the class I members, with a homology of less than 15–20% (Simental et al., 1991, Jenster et al., 1995). The activation function-1 (AF-1) domain located in the NTD plays a pivotal role in AR's function (Jenster et al., 1995). Deletion of the AR-AF-1 leads to a significant loss in AR's transcriptional capacity (Simental et al., 1991, Jenster et al., 1991, Bevan et al., 1999, Alen et al., 1999). The AF-1 of AR contains all, save three, of AR's phosphorylation sites, and hence is the target of various growth factors (Ward and Weigel, 2009) that phosphorylate the sites and activate the AR ligand independently (Kato et al., 1995). The AF-1 domain is an intrinsically disordered domain and plays a role in the stabilization of the AR, resulting from the interaction between its N-terminus and the C-terminus domains. Dr. McEwan and colleagues have used biophysical methods such as fluorescence polarization to elegantly demonstrate the folding and stabilization of this domain and its interaction with coactivators (Lavery and McEwan, 2008, Watt and McEwan, 2009). The DNA Binding Domain (DBD) is highly conserved between receptors, has two zinc finger motifs that are responsible for DNA recognition and dimerization, and plays a role in AR binding to Androgen Responsive Elements (ARE) within the regulatory regions of androgen responsive genes (Clinckemalie et al., 2013, Moehren et al., 2008, Verrijdt et al., 2006). The hinge region that lies between the DBD and the Ligand Binding Domain (LBD) is a lysine rich region and is important for the nuclear localization of the receptor (Ylikomi et al., 1992). Deletion of this domain eliminates nuclear localization and transcriptional activity of the AR in the presence of ligand (Zhou et al., 1994). The LBD of the AR is responsible for ligand binding, is only moderately conserved among the receptors, and contains AF-2 which is important for the ligand-dependent full activation of the receptor.