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Nuclear Receptor Biomed Central Nuclear Receptor BioMed Central Research Open Access ERβ Binds N-CoR in the Presence of Estrogens via an LXXLL-like Motif in the N-CoR C-terminus Paul Webb*1, Cathleen Valentine1,2, Phuong Nguyen1, Richard H Price Jr1,2, Adhirai Marimuthu1, Brian L West1, John D Baxter1 and Peter J Kushner1,2 Address: 1Metabolic Research Unit and Diabetes Center, University of California, San Francisco, CA 94143, USA and 2Department of Medicine, University of California, San Francisco, CA 94143, USA Email: Paul Webb* - [email protected]; Cathleen Valentine - [email protected]; Phuong Nguyen - [email protected]; Richard H Price - [email protected]; Adhirai Marimuthu - [email protected]; Brian L West - [email protected]; John D Baxter - [email protected]; [email protected] * Corresponding author Published: 28 June 2003 Received: 13 May 2003 Accepted: 28 June 2003 Nuclear Receptor 2003, 1:4 This article is available from: http://www.nuclear-receptor.com/content/1/1/4 © 2003 Webb et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract Nuclear receptors (NRs) usually bind the corepressors N-CoR and SMRT in the absence of ligand or in the presence of antagonists. Agonist binding leads to corepressor release and recruitment of coactivators. Here, we report that estrogen receptor β (ERβ) binds N-CoR and SMRT in the presence of agonists, but not antagonists, in vitro and in vivo. This ligand preference differs from that of ERα interactions with corepressors, which are inhibited by estradiol, and resembles that of ERβ interactions with coactivators. ERβ /N-CoR interactions involve ERβ AF-2, which also mediates coactivator recognition. Moreover, ERβ recognizes a sequence (PLTIRML) in the N-CoR C- terminus that resembles coactivator LXXLL motifs. Inhibition of histone deacetylase activity specifically potentiates ERβ LBD activity, suggesting that corepressors restrict the activity of AF-2. We conclude that the ER isoforms show completely distinct modes of interaction with a physiologically important corepressor and discuss our results in terms of ER isoform specificity in vivo. Background vators include TRAP220[7], which is part of a larger The nuclear receptor (NR) family comprises 48 structur- complex (TRAP/DRIP/SMCC/mediator) that contacts the ally related transcription factors, many of which require basal transcription machinery and PGC-1[8], a cold their cognate ligand for activity [1–3]. The NRs regulate inducible coactivator that binds CBP and SRC-1 and pro- transcription by binding to response elements in the pro- teins involved in RNA processing [9]. NR corepressors moters of target genes and acting as scaffolds for the include NR corepressor (N-CoR) and silencing mediator assembly of large coactivator and corepressor complexes of retinoid and thyroid responsive transcription (SMRT) [4]. NR coactivators include the p160s (including GRIP1/ [4]. Both N-CoR and SMRT repress transcription, at least TIF-2, SRC-1 and AIB1/ACTR/pCIP). The p160s enhance in part, by binding to histone de-acetylases (HDACs) transcription by binding histone acetyl-transferases such either directly or indirectly through other corepressor as p300/CBP and pCAF [5]and methyl-transferases such complex components. Other known NR corepressors as CARM1 and PRMT [6] which, in turn, enhance tran- include RIP140 [10], Hairless [11], short heterodimer scription by modification of chromatin. Other NR coacti- partner (SHP) [12] and DAX [13], and receptor specific Page 1 of 15 (page number not for citation purposes) Nuclear Receptor 2003, 1 http://www.nuclear-receptor.com/content/1/1/4 corepressors such as the estrogen receptor (ER) interacting gens, but ERβ is a more potent repressor than ERα [27]. proteins REA and HET-SAFB [14,15]. However, some of the most striking isoform-specific dif- ferences in gene regulation are observed at promoters, Generally, NR transcriptional activity is dictated by the such as that of cyclin D1, which contain AP-1 sites or balance between coactivator and corepressor recruitment, related cyclic AMP response elements (CREs). ERα and one of the most important factors that influences this enhances AP-1 activity in response to estrogens, [28,29] balance is the absence or presence of agonist ligands but ERβ inhibits AP-1 activity in response to estrogens (reviewed in [4]). Unliganded NRs such as thyroid (TRs) [29–31]. ERβ also completely suppresses ERα activity at and retinoid receptors (RARs) bind corepressors, and lig- the cyclin D1 promoter and even suppresses the activity of and promotes release of corepressor and subsequent bind- an ERα mutant that is selectively superactive at AP-1 sites ing of coactivators. The mechanism of this coregulator and CREs [29]. Finally, ERβ shows a unique capacity to exchange is well understood. NRs consist of three enhance AP-1 activity in response to selective estrogen domains, the N-terminal domain (which contains a con- receptor modulators (SERMs) such as raloxifene, text-specific activation function AF-1), the central DNA tamoxifen and ICI 182,780/Faslodex (ICI) [30–32]. binding domain (DBD) and the C-terminal ligand bind- Together, these observations suggest that there are funda- ing domain (LBD), which contains a hormone-dependent mental differences in the way that the ERs bind unspeci- activation function, AF-2. The unliganded LBD recognizes fied cofactors that modulate gene expression, and that hydrophobic motifs, termed interaction domains (IDs), some of these cofactors must play a role in differential ER which are reiterated three times in N-CoR and twice in activity at AP-1 sites. SMRT and conform to the consensus L/IXXIIXXXL [4](see also[16]). By contrast, the liganded LBD binds shorter Although the poorly conserved NTD region clearly plays hydrophobic motifs termed NR boxes that are reiterated an important role in isoform-specificity [32,33], it is also several times within each coactivator and conform to the likely that there are differences in the better conserved consensus LXXLL. The LBD utilizes a large hydrophobic LBD region that contribute to differential ERα and ERβ cleft composed of residues along H3 and H5 to bind IDs activities. Phage display techniques have revealed that [17], and a smaller hydrophobic cleft that is composed of ERα and ERβ show different preferences in LXXLL binding residues in the upper part of H3 and H5 and H12 (and (reviewed in [34,35]). Moreover, some cofactors that con- corresponds to AF-2) to bind NR boxes [18]. Thus, ago- tain LXXLL motifs show differential binding to LBDs of nists promote coregulator exchange by promoting the the ER isoforms (reviewed in [36]). SHP binds ERα pref- packing of H12 over the lower part of the ID binding erentially [37], and represses ERα activity more strongly region, an event that simultaneously completes the coac- than that of ERβ. The PGC-1 related protein PERC also tivator binding surface. In other cases, however, the bal- binds ERα preferentially, and potentiates ERα activity ance of coactivator and corepressor recruitment is more strongly than that of ERβ [38]. We recently observed regulated by direct competition for the AF-2 surface, that ERα binds the C-terminal NR interacting regions of rather than ligand-dependent coregulator exchange. N-CoR and SMRT in the presence of SERMs but not estro- RIP140, Hairless and DAX possess NR boxes that interact gens [39]. In this study, we report that ERβ interactions with AF-2 [11,13,19] and these corepressors act as nega- with N-CoR and SMRT are promoted by agonists and tive regulators of the activity of the liganded NR. inhibited by SERMs. Thus, the ERs show completely opposite ligand preferences of interaction with corepres- The NR family contains two related ERs (ERα and ERβ) sors. We discuss the potential significance of these differ- that conform to the typical three domain NR structure and ent modes of ER interaction with N-CoR in terms of share extensive sequence homology in the DBD and LBD known isoform-specific behaviors. region[20,21]. Analysis of the function of the individual ERs in mouse knockout models suggests that the major Results proliferative effects of estrogen are mediated by ERα and Agonist Dependent ERβ Interactions with N-CoR and not by ERβ, which seems to play an inhibitory role in pro- SMRT liferation in some studies[22,23]. The ligand-binding To investigate ERβ interactions with corepressors, we properties of the ERs are different, with ERβ often exhibit- examined the interactions of full length ERβ (amino acids ing stronger binding to plant-derived phytoestrogens 1–530) with bacterially expressed C-terminal NR interact- [24]. More importantly, the ERs exhibit isoform-specific ing domain of N-CoR (amino acids 1944–2453) in vitro effects on gene expression. Both ERs enhance transcrip- (Fig. 1A). Fig. 1B reveals, surprisingly, that ERβ bound N- tion from genes with classical estrogen response elements CoR in the absence of hormone and in the presence of (EREs), but ERα requires less ligand to obtain maximal agonist ligands (E2, DES) and phytoestrogens (genistein, activation than ERβ [25,26]. Likewise, both ERs suppress coumestrol). Moreover, these interactions were sup- the activity of the TNFα promoter in response to estro- pressed by SERMs (ICI, raloxifene and tamoxifen). ERβ Page 2 of 15 (page number not for citation purposes) Nuclear Receptor 2003, 1 http://www.nuclear-receptor.com/content/1/1/4 ERFigureβ Binds 1 N-CoR in the Presence of Agonists ERβ Binds N-CoR in the Presence of Agonists. (A) Schematic of N-CoR primary structure. Silencing domains are indicated with hatched bars. NR binding regions (ID motifs) are illustrated with solid bars. (B) Radiolabeled ERβ retained by GST-N- CoR (amino acids 1944–2453) or GST-GRIP1 (amino acids 563–1121) after separation by SDS-PAGE.
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