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REVIEW Estrogen Receptor-Related Receptors 349 REVIEW Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand B Horard and J-M Vanacker Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5161, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364 Lyon, France (Requests for offprints should be addressed to J-M Vanacker; Email: [email protected]) Abstract The nuclear receptor family comprises ligand-dependent and orphan receptors. To the latter group belong the estrogen receptor-related receptors (ERRs) for which conflicting results have been published concerning the nature (constitutive or liganded) of their transcriptional activities. ERRs interfere in various ways, positively and negatively, with estrogen signaling. Moreover recent data analyzing ERR expression in human breast tumors have proposed ERR and ERR as prognostic markers of these cancers. The identification of modulators (positive or negative) of ERR activities would therefore be highly useful in our understanding of estrogen-related pathologies. The purpose of this review is to summarize our knowledge of the nature of ERR activities and progresses in identifying synthetic ERR modulators. Journal of Molecular Endocrinology (2003) 31, 349–357 On nuclear receptors (NRs) in general interact with NRs, the most common being the and orphan receptors in particular three widely expressed p160 family members, SRC-1, GRIP1/TIF/SRC-2 and pCIP/AIB1/ According to a commonly used definition, NRs are SRC-3 (reviewed in McKenna et al. 1999). described as ligand-dependent transcription factors A ligand-independent transactivation domain can (Laudet & Gronemeyer 2002). With very few be found in the non-conserved N-terminal exceptions, all NR proteins share a similar part (A/B domain) of certain, but not all, NRs, organization in modular domains, two of which such as the estrogen receptor (ER) (Laudet & are remarkably conserved between members of Gronemeyer 2002). the family and across evolution. These are (i) the Receptors for classic ligands such as steroid DNA-binding domain (DBD), localized in the hormones, thyroid hormones, retinoic acids or middle of the primary structure and which vitamin D were identified on the basis of their mediates specific interaction with the target DNA capacity to transduce a previously known hormonal sequences and (ii) the ligand-binding domain signal. Besides them, the NR superfamily also (LBD), in the C-terminal part, which is responsible comprises a number of so-called orphan receptors for ligand recognition, dimerization, interaction that were isolated on the basis of their sequence with coactivators and ligand-dependent transcrip- similarity and identical domain organization to tional activation. Three-dimensional (3D) structure other NRs (Giguère 1999). Since no ligand has determination has demonstrated that ligand entry been identified that regulates them, the orphan into the binding pocket of the LBD evokes a receptors do not fulfill the above-mentioned conformational change allowing the recruitment of definition. One of the remaining questions coactivator proteins that directly or indirectly concerning orphan receptors is how their transcrip- modify chromatin and induce target gene expres- tional activities are regulated. In other words, do sion. Several coactivators have been described that they respond to a natural ligand which remains Journal of Molecular Endocrinology (2003) 31, 349–357 Online version via http://www.endocrinology.org 0952–5041/03/031–349 © 2003 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 05:24:02PM via free access 350 B HORARD AND J-M VANACKER · ERRs: orphan receptors desperately seeking ligand to be identified, or do they act in a ligand- identified (Hong et al. 1999). ERRs are present independent manner? throughout evolution, with a unique homologue This question has been at least partially answered existing in the invertebrates Drosophila, amphioxus for a number of orphan receptors. For instance, and tunicates (Dehal et al. 2002, B Horard & J-M certain oxysterols (catabolites of cholesterol) have Vanacker, unpublished observations). In terms been shown to act as ligands for LXRs, and to of sequence, ERRs are fairly similar to the ERs modulate (positively in rodent, negatively and (Fig. 1), particularly in the DBD regions (over indirectly in humans) the expression of an enzyme 60% sequence identity between human ERR and (Cyp7a) that catalyzes their degradation, thereby ER). The lower conservation level of the LBDs acting in a feed-forward mechanism (reviewed in (less than 35%) is apparently consistent with the Repa & Mangelsdorf 2000, Goodwin et al. 2003). incapacity of ERRs to bind estradiol (E2) (Giguère The LXRs can therefore be considered as et al. 1988, Yang et al. 1996). However, in silico ligand-dependent receptors. On the contrary 3D superimposition of the ligand-binding pocket of structure determination of Rev-erb has demon- ERR on that of ER has revealed a greater level strated that the putative ligand-binding pocket was of local sequence identity, suggesting that structur- actually packed with amino acid side-chains ally close ligands could be bound by both receptors rendering the entry of a ligand very unlikely (Chen et al. 2001). (Renaud et al. 2000). Rev-erb, which is in fact a In the past years, numerous interconnections transcriptional repressor, is therefore considered between the ERRs and estrogen signaling have as a non-liganded, constitutively acting receptor. been documented, and these are thoroughly However, it should be remembered that a discussed in a recently published review (Giguère constitutive activity does not exclude the existence 2002) (see Fig. 2 for summary). For instance, ERRs of a ligand, as exemplified by CAR. Indeed, the and ERs share common transcriptional target activity of this receptor, originally described as genes, such as lactoferrin, osteopontin and pS2, on constitutive, can be down-regulated by androstane which they can either synergize or compete with metabolites (Forman et al. 1998), but also further one another (Yang et al. 1996, Vanacker et al. activated by phenobarbital (Tzameli et al. 2000). 1999a,Luet al. 2001, Kraus et al. 2002). In spite of the examples quoted above, there are Furthermore, Yang et al. (1996) found that human some orphan receptors for which the existence of a ERR interacts with human ER at least in vitro ligand is still an open question. Although they were through protein–protein contacts. Moreover, the the first orphan receptors to be identified, this is aromatase gene, encoding the enzyme catalyzing the case for the estrogen-receptor related receptors the conversion of androgens to estrogens, is a (ERRs), to which this review is dedicated. transcriptional target of ERR (Yang et al. 1998). Furthermore, even if a receptor is recognized as Altogether, these finding have raised the possibility constitutively active, it could still be (at least that the ERRs (at least ERR) might directly and theoretically) possible to modulate its activity using indirectly modulate the estrogenic response. a synthetic agonist or antagonist. In this respect, Little is known about the in vivo functions of the recent data have identified synthetic antagonists of ERRs. It has been proposed that ERR plays a the ERRs. Given the wide variety of develop- role in bone formation. Indeed this receptor is mental, physiological and metabolic processes expressed in ossification zones of the mouse embryo controlled by NRs, finding a way to modulate the (Bonnelye et al. 1997a) and up-regulates the activity of these transcription factors is an issue of expression of the osteopontin gene (Vanacker et al. considerable importance. 1998) coding for an extracellular matrix protein involved in bone remodeling. More recently, Bonnelye et al. (2001) have found that ERR plays On ERRs a role in in vitro osteoprogenitor cell proliferation and differentiation. Both ERR and ERR are also ERR and were isolated in 1988 by mean of highly expressed in muscle, heart and adipose a low-stringency screen with the DBD of ER tissues (Bonnelye et al. 1997b, Hong et al. 1999, (Giguère et al. 1988). More recently, a third Heard et al. 2000). In adipose tissues, ERR has member of the subfamily (ERR) has been been suggested to participate in the control of Journal of Molecular Endocrinology (2003) 31, 349–357 www.endocrinology.org Downloaded from Bioscientifica.com at 09/30/2021 05:24:02PM via free access ERRs: orphan receptors desperately seeking ligand · B HORARD AND J-M VANACKER 351 Figure 1 The ER/ERR subfamily A schematic representation of the two mouse ERs and the three mouse ERRs is displayed. Percentage of sequence identity within the DBD and the LBD is indicated. energy expenditure through the regulation of the NR) response element (SFRE: TCAAGGTCA) expression of the MCAD (medium-chain acyl (Pettersson et al. 1996, Bonnelye et al. 1997a, dehydrogenase) gene (Sladek et al. 1997, Vega & Johnston et al. 1997, Hong et al. 1999, Vanacker Kelly 1997). In the central nervous system, both et al. 1999b, Hentschke et al. 2002a). Transcriptional ERR and ERR possess a complex pattern of activation through each of these sites occurs in an expression (Bonnelye et al. 1997b, Hermans- apparent ligand-independent manner as no ex- Borgmeyer et al. 2000, Lorke et al. 2000) but no ternal compound needs to be added to the culture function has yet been attributed to the receptors. medium. However, at least in the case of ERR, ERR is mainly expressed during early mouse these transcriptional activities are exerted in a development (Pettersson et al. 1996) where it is cell-specific manner (Bonnelye et al. 1997b). This necessary for proper trophoblastic cell proliferation could indicate the requirement for a ligand present and differentiation as demonstrated by the placen- in the permissive cells and not in the restrictive tation defects observed in mice lacking ERR (Luo ones. In support of this hypothesis, rat osteosar- et al. 1997). coma ROS 17·2/8 cells cultured for 2 weeks with charcoal-treated serum (i.e.
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