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Biological Research

Print version ISSN 0716-9760

Biol. Res. vol.35 no.2 Santiago  2002 

Biol Res 35: 295-303, 2002

Modulation of nuclear receptor dependent transcription


Department of Cancer Medicine, Faculty of Medicine, Imperial College of Science, Technology & Medicine, London, UK.


Nuclear receptors comprise a family of transcription factors that regulate gene expression in a ligand dependent manner. They can activate or repress target genes by binding directly to DNA response elements as homo- or hetero-dimers or by binding to other classes of DNA-bound transcription factors. These activities have been linked to the formation of complexes with molecules that appear to serve as coactivators or corepressors, causing local modification of chromatin structure in order to regulate expression of their target genes. Several members of nuclear receptor family are directly associated with human malignancies including breast cancer, prostate cancer and leukaemia. The pathogenesis of each of these diseases is underpinned by the activities of a member of the superfamily; estrogen receptor-a (ERa) in breast cancer, androgen receptor (AR) in prostate cancer, and retinoic acid receptor a (RARa) in acute promyelocytic leukaemia.


The nuclear receptor (NR) superfamily comprises one of the largest classes of eukaryotic transcription factors (TFs). Over 180 NR family members have been described and include TFs that are activated upon binding steroid hormones, retinoids, thyroid hormones and vitamin D3, as well as NRs that bind prostaglandins, fatty acids and bile acids. In addition, other members of the NR superfamily, whilst having similar structure, have no known ligand. These so-called orphan receptors may not require ligand binding or, may be activated by as yet unidentified ligands (Mangelsdorf et al., 1995; Olefsky, 2001).

The ligand induced NRs are activated by binding their cognate ligand, which generally enter the cell by passive diffusion due to their lipophilic nature. The subcellular localisation of unliganded NRs is variable, with some NRs, such as AR, glucocorticoid receptor (GR), and progesterone receptor (PR), residing in the cytoplasm in their unliganded state, whereas other NRs, including ERa, thyroid hormone receptor (TR), and RARa, are nuclear in their unliganded state (Mangelsdorf et al., 1995; Giguere, 1999; Olefsky, 2001).

Nuclear Receptor Structure

All members of the NR superfamily have a common modular structure, possessing four independent but interacting functional modules. These are encoded in the A/B region, the DNA-binding domain (DBD), the hinge region and the ligand-binding domain (LBD) (Parker, 1993) (Fig 1). Despite their conserved structural features, the normal physiological functions of various NRs are quite diverse, from embryonic development to metabolic homeostasis, sex determination, development of sexual characteristics and fertility. The N-terminal (A/B) region is the most variable between NRs within which is a ligand-independent activation function (AF-1) that allows constitutive activation of transcription (Jenster et al., 1995; Wilkinson and Towle, 1997). The highly conserved central DBD (region C) forms two zinc fingers and a carboxy-terminal extension (CTE) that provides interfaces for DNA response element (RE) and protein binding (Perlmann et al., 1993; Zechel et al., 1994). C-terminal of the DBD is a flexible hinge region (region D) that allows rotation of the DBD to accommodate binding to REs, and which may be involved in coregulator binding, and interaction with HSP90 (Horlein et al., 1995; Chen and Evans, 1995; Couette et al., 1996). The C-terminal LBD (E/F) is well-conserved and contains the second activation function (AF-2), which requires ligand-binding for its activity. Analysis of the crystal structures of LBDs of NRs reveals a common overall layered structure consisting of 12 a-helices (Tanenbaum et al., 1998; Moras and Gronemeyer, 1998). The striking difference between the unliganded and ligand-bound receptors is the position of the C-terminal a-helix (helix 12), which contains the core AF-2 domain. In the unliganded form of the NR, helix 12 extends away from the hydrophobic ligand-binding pocket, however on ligand binding helix 12 moves across the binding pocket like a lid (Driscoll et al., 1996; Shiau et al., 1998; Tagami and Jameson, 1998; Nichols et al., 1998).

Fig. 1. Schematic representation of a nuclear receptor.
A typical nuclear receptor is composed of several functional domains. The variable NH2-terminal region (A/B) contains the ligand-independent AF-1 transactivation domain. The conserved DNA-binding domain (C). A variable linker region (D) connected to the conserved E/F region that contains the ligand-binding domain, the dimerisation surface and the ligand-dependent AF-2 transactivation domain.

Nuclear receptors can activate target genes by binding directly to REs as homo- or- hetero-dimers or, by binding to other classes of DNA-bound TFs. Furthermore, a subset of NRs, including TR and RAR, can actively repress target genes in the presence or absence of ligand binding, and many NRs have been demonstrated to inhibit transcription in a ligand-dependent manner by antagonising the transcriptional activities of other classes of TFs. These transcriptional control activities have been linked to interactions with general classes of molecules that serve coactivator or corepressor function.

Coactivators in transcriptional regulation by NRs

Biochemical and expression cloning approaches have been used to identify a large number of factors that interact with NRs in either a ligand-dependent or ligand-independent manner. Many of these factors have been demonstrated to be capable of potentiating NR activity in transient cotransfection assays, suggesting their ability to serve as NR coregulators. Although the abundance of coactivators is partly a reflection of tissue specific expression of different coactivators, co-expression of multiple coactivators in a single tissue is also prevalent (McKenna and O'Malley, 2000). As is the case in the assembly of the transcription preinitiation complex, it can be presumed that NR interaction with and/or recruitment of different coactivators and coactivator complexes occurs in a defined order, culminating in transcription (Klinge, 2000).

The so-called p160 or SRC family of NR-interacting proteins interact with the AF-2 of the NR LBD in a ligand-dependent manner, through a conserved leucine-rich LXXLL motif. Hydrophobic residues within helix 12 of NRs have been demonstrated to be of reciprocal importance for this interaction (Heery et al., 1997; Webb et al., 1998). Each p160 coactivator protein possesses transactivation functions, has intrinsic histone acetyltransferase (HAT) activity and/or can interact with other HAT proteins such as CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF) (Blanco et al., 1998; Alen et al., 1999; Klinge, 2000; Glass and Rosenfeld, 2000).

In yeast, SWI/SNF complexes facilitate binding of sequence specific TFs to nucleosomal DNA and can cause local changes in chromatin structure in an ATP-dependent manner. BRG1 (Brahma-related gene-1) and hBrm (human brahma), the mammalian homologues of drosophila SWI2/SNF2, function as components of large multiprotein complexes that alter nucleosome structure, an essential regulatory step in the NR-mediated transactivation of many genes (Jenster et al., 1997). BRG1 and hBrm have been found to interact with and enhance the ligand-dependent activation of GR, ERa and RAR (Fryer and Archer, 1998; DiRenzo et al., 2000), indicating an important role in NR action.

In addition to coactivators that possess ATP-dependent HAT or nucleosome remodelling activities, other NR-interacting coactivator proteins have been identified. The best characterised of these is the TR-associated proteins/VDR interacting proteins/activator-recruited cofactor (TRAP/DRIP/ARC) complex, which enhances the transcriptional activities of NRs and other signal-dependent TFs (Naar et al., 1999). The TRAP/DRIP/ARC complex consists of over 12 polypeptides and is recruited to NRs in a ligand-dependent manner via a 220kDa component, referred to as PBP (PPARg-interacting protein)/TRAP220/DRIP205, which contains two alternatively utilised LXXLL NR interaction motifs (Zhu et al., 1997; Yuan et al., 1998; Treuter et al., 1999; Burakov et al., 2000). Constituents of the TRAP/DRIP/ARC complex were initially identified using epitope-tagged TR or VDR to affinity purify TR-associated proteins (TRAPs) or VDR-associated proteins (DRIPs). TRAPs were found to enhance transcriptional activation of TR in a chromatin-free system and DRIPs potentiated ligand-dependent VDR transactivation of a chromatinized template in vitro (Fondell et al., 1996; Rachez et al., 1998). At least nine proteins of between 70 - 230 kDa were found within each complex and several have been shown to bear significant homology to protein constituents of the CRSP, NAT and SMCC complexes. The latter have been shown to be required for transactivation from chromatin templates by a number of other TFs including SREBP, NFkB and VP16 (reviewed in Glass and Rosenfeld, 2000).

A fourth class of coactivators involved in NR activation is the E3 ubiquitin-protein ligases, RPF-1 and E6-AP. Rather than HAT or ATPase activity, this class of coactivators possess ubiquitin-protein ligase activity. These factors are thought to play a role in defining the substrate specificity of the ubiquitin-proteosome degradation system, however the domain regulating this activity was not found to be required for enhancement of transcription by these proteins (reviewed in Klinge, 2000).

A novel coactivator, SRA (steroid receptor RNA activator) was identified by a yeast-two hybrid screen using the AF-1 of PR. SRA is unique among coactivators in that it does not appear to be a protein but rather seems to function as an RNA molecule in vivo. SRA has been shown to enhance CAT activity from reporters for PR, GR, AR and ERa, but not TR, RAR, RXR and PPAR. SRA coimmunoprecipitated with SRC-1 in transfected HeLa cells and is thought to exist with SRC-1 in a distinct NR coactivator complex (Lanz et al., 1999).

It is difficult to understand how the extraordinary number of factors that appear to be involved in transcriptional activation by NRs cooperate in gene activation. It is conceivable that the SWI/SNF chromatin remodelling complexes and the CBP/p160/P/CAF complexes containing HAT activity are initially recruited to the promoter. These factors may relieve the repressive actions of high-order chromatin structure and allow a second acetylation-dependent step of gene activation. Activation would require the combinatorial of subsequent action of additional complexes that include TRAP/DRIP/ARC complex (Fig 2).

Fig. 2. Ligand-dependent recruitment of multiple coactivator complexes.
Upon ligand binding to the ligand binding domain (E), the nuclear receptor recruits different coactivator complexes. The SWI/SNF complex possesses ATP-dependent chromatin remodelling activities. The CBP and P/CAF complexes possess histone acetyltransferase activities. These complexes may act in concert to relieve chromatin-mediated repression, with the TRAP/DRIP/ARC complex functioning to recruit core transcription factors.

Corepressors in transcriptional regulation by NRs

In addition to ligand-dependent gene activation, selected receptors including TR and RAR repress basal transcription in the absence of ligand. Binding of hormonal ligand to the receptor releases the transcriptional silencing and leads to gene activation. Baniahmad et al. (1992) first demonstrated the existence of active silencing domains in TR and showed that these domains functioned as repressors when fused to a heterologous DBD. Squelching experiments also suggested the existence of inhibitory cellular factors necessary for transcriptional silencing that dissociated from TR and RAR in a ligand-dependent manner (Casanova et al., 1994; Baniahmad et al., 1995). A search for proteins that mediated these effects led to the identification of a ~270kDa protein that associated with DNA-bound unliganded RAR or TR. This resulted in the cloning of NCoR (nuclear receptor corepressor) (Horlein et al., 1995). A second closely related corepressor, SMRT (silencing mediator for retinoid and thyroid hormone receptor), was reported as a protein that formed a ternary complex with unliganded RAR or with TR (Chen and Evans, 1995). Ligand binding caused decreased interaction of NCoR and SMRT to TR and RAR on most DNA sites (Horlein et al., 1995; Chen and Evans, 1995). The two closely related corepressors are now known additionally to interact with antagonist-bound NRs, such as ERa and PR (Heinzel et al., 1997; Jackson et al., 1997; Smith et al., 1997).

Both NCoR and SMRT contain two independent receptor-interacting domains in their C-terminal regions, ID1 and ID2, which may form amphipathic a-helices (reviewed in Love et al., 2000. Each minimal interacting domain is independently sufficient to mediate interaction with unliganded NRs and to mediate release on ligand binding. Further studies have demonstrated that motifs within ID1 and ID2 called CoRNR (corepressor-nuclear receptor) boxes (1 and 2) are responsible for NR interactions. Each CoRNR box contains a 1/L XX 1/V I motif (Hu and Lazar, 1999; Nagy et al., 1999). This motif is predicted to form an extended a-helix, one helical turn longer than the LXXLL motif found in coactivators and has led to the suggestion that corepressor-NR interactions might be analogous to coactivator-NR interactions and perhaps the two types of molecule compete for the overlapping interaction domains on the surface of the receptor (Hu et al., 2001).

The corepressors NCoR and SMRT possess regions that are able to repress the transactivation ability of the proteins with which they associate, e.g., NRs. These independent transferable repressor domains have been shown to be capable of transferring active repression to a heterologous DNA binding domain (Horlein, et al., 1995; Chen and Evans, 1995).

NCoR and SMRT were found to associate with a multiprotein complex, the mSin3 complex (Alland et al., 1997; Heinzel et al., 1997; Nagy et al., 1997). The complex consists of the mammalian homologues of yeast Sin3, mSin3A and mSin3B, histone deacetylases, HDAC1 or HDAC2 (homologues of yeast Rpd3p), along with the histone binding proteins RbAp46, RbAp48 (Rb-associated proteins), and two small proteins SAP18 (mSin3-associated polypeptide-18) and SAP30. This suggests that SMRT and NCoR repress transcription at least in part, by targeting histone deacetylation to unliganded or antagonist-bound receptors.

The mammalian Sin3 proteins possess four conserved paired amphipathic helical (PAH-1 to PAH-4) domains postulated to mediate protein-protein interactions. NCoR interacts with both PAH1 and a second region centred around PAH3 of mSin3 by means of a COOH-terminal region and an NH2-terminal repression domain (Heinzel et al.,1997; Nagy et al., 1997).

SAP30 associates with HDAC, Sin3 and additionally with one of the repression domains of NCoR (Laherty et al., 1998). Evidence suggests SAP30 acts as a specificity factor to direct or stabilise the formation of a repressive complex between NCoR and mSin3, enhancing mSin3-HDAC1-mediated repression by NCoR/SMRT (Zhang et al., 1997; Knoepfler and Eisenman, 1999). SAP30 has been shown to be required for repression by ERa, but not by TR or RAR/RXR, suggesting that it may have a gene specific role in corepressor function (Laherty et al., 1998).

RbAp46 and RbAp48 share 90% identity and belong to the WD-repeat family of proteins involved in highly diverse cellular processes. RbAp48 was found to be a subunit of human HDAC1 and although not required for histone deacetylase activity, interacts with histone H4. It has been suggested that RbAp48 targets HDAC1 to core histone proteins, by acting as a "metabolic bridge" between histone metabolic enzymes and core histones (Taunton et al., 1996; Parthun et al., 1996). The degree of homology between RbAp46 and RbAp48 suggests that the former may also have a role in targeting of HDAC1.

SAP18 has been shown to weakly interact with HDAC1 as well as with mSin3 (Zhang et al., 1997).

Different transcription factors may associate with mSin3 complex simultaneously. For instance, the repressor Mad appears to be present not only in complexes involved in repression at Mad-1 binding sites but also in complexes mediating repression by NRs (Nomura et al., 1999).

Thus NCoR/SMRT mediated recruitment of the HDAC complex on chromatin instigates deacetylation of histones with consequent gene repression. Deletion of the HDAC binding site of mSin3, mutation of HDAC1, or addition of HDAC inhibitors significantly inhibits mSin3 repression indicating a critical role for HDAC interaction in mSin3 mediated repression. However that the repression is not totally abrogated suggests the existence of other modes of mSin3-mediated repression (Hassig et al., 1997; Knoepfler and Eisenman, 1999).

The corepressors were thought to act exclusively through the above-described indirect recruitment of HDAC1or-2 (class I deacetylases), via the adaptor mSin3 protein. Recently a new family of histone deactylases (class II deactylases) including HDAC 4 and HDAC 5 has been identified (Grozinger et al., 1999), and a two-hybrid screen on SMRT-interacting proteins has led to the isolation of a further family member, HDAC7 (Kao et al., 2000). One of the multiple non-redundant repression domains, conserved in NCoR and SMRT, has been demonstrated to repress transcription by directly interacting with class II HDACs. Endogenous NCoR and SMRT each associated with class II HDACs in a complex that did not contain mSin3 or HDACI (Huang et al., 2000; Kao et al., 2000). Therefore, a single corepressor can use distinct domains to engage class I HDAC complexes in a Sin3A-dependent manner and class II HDAC complexes in a Sin3A-independent manner. Furthermore, a novel SMRT-containing complex has been isolated containing HDAC3 and transducin beta-like protein 1 (TBL1), a protein that interacts with histone H3. In vivo, TBL1 is bridged to HDAC3 through SMRT and can potentiate repression by TR (Guenther et al., 2000).

Thus NCoR and SMRT not only provide a platform for recruitment of HDACs but also form an integral component of functional HDAC complexes (Guenther et al., 2001).


The current understanding of the role of coactivators and corepressors in NR mediated regulation of eukaryotic gene transcription indicates that transcriptional activation or repression is determined by the balance between histone acetylation and deacetylation activities. NR agonists serve as a switch to recruit multiple protein complexes with nucleosome remodelling and/or HAT activity that facilitate access of TFs to the basal transcriptional machinery for transcriptional activation. This is accompanied by the dismissal of HDAC-associated complexes. Some unliganded NRs (TR and RAR) and antagonist-bound NRs, e.g., tamoxifen- bound ERa, can bind to their cognate DNA response elements. However, in this situation they interact with corepressors such as NCoR/SMRT to recruit HDAC complexes and repress transcription of their target genes.

The above observations suggest that compactation of chromatin structure due to recruitment of HDAC complexes by corepressors is involved in transcriptional silencing by unliganded receptors. Ligand binding allows release of corepressors and enables the receptor to recruit coactivators and stimulate transcription (Fig 3).

Fig. 3.Coactivator and complexes and histone acetylation.
In the absence of ligand, the nuclear receptor homo- or hetero-dimer is associated with corepressor complexes. The corepressors (SMRT/NCoR) recruit histone deactylases either directly or through their interaction with Sin 3 complex. Deacetylation of histone tails leads to chromatin compaction and transcriptional repression. Ligand binding causes release of the corepressor complex and the AF-2- dependent recruitment of a coactivator complex that contains at least the p160 coactivators (P/CIP or SRC-1), CBP/p300, and P/CAF. All of these proteins possess histone acetyltransferase activity that allows chromatin decompactation and gene activation.

The molecular strategies that underlie regulated gene transcription by NRs appear to involve the combinatorial actions of a large number of coregulators. Together they act to provide a range of effects on transcription from total silencing to strong activation. Because each component of these large regulatory complexes is under transcriptional and post-transcriptional control, the complexity of the coregulatory network itself may be sufficient to underlie the gene-specificity required to meet the demands of developmental and homeostatic gene regulation. The next few years should see many new insights into the detailed molecular mechanisms underlying these events.

Based on our current understanding of these mechanisms, the possibility exists to utilise the factors that govern the regulation of gene transcription by NRs in vivo, to specifically target genes for transcriptional activation, or for transcriptional silencing.

A novel approach to gene silencing is to use the cellular mechanisms of eukaryotic transcriptional regulation in a gene-targeted manner. This is the central tenet of the technique developed in this laboratory called Gene Inactivation by Chromatin Engineering, or "Gene ICE".

The rationale was that in order to specifically target genes and bring about essentially irreversible inactivation, a protein with a sequence-specific DNA-binding capacity, in this case an NR, could be coupled to a second protein capable of recruiting a histone deacetylase activity. The NR would target histone deacetylase activity, recruited by its fusion partner, to the histones associated with the specific REs, leading to local chromatin modification and preventing access of TFs to the target DNA. The result would be transcriptional repression of NR regulated target genes. Thus we perceive that Gene ICE repressors would behave in a dominant negative manner and would potentially bring about long-term gene silencing through chromatin remodelling. Gene ICE technology may be a powerful research tool, as it would potentially facilitate the identification of genes regulated by the TF of interest using techniques such as microarray analysis. And ultimately, in the event of efficient delivery systems, Gene ICE repressors might offer a useful gene therapy approach for the treatment of cancer.


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Corresponding author: Stephen M Hart. Dept. of Cancer Medicine, Division of Medicine, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Du Cane Road, London W12 0NN. UK. Tel +44 (0)20 8383 5836. Fax +44 (0)20 8383 5830. e-mail

Received: May 23, 2002. In revised form: July 11, 2002. Accepted: July 15, 2002

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