Nuclear Hormone Receptor Coregulators In Action: Diversity For Shared Tasks

Daniel Robyr1, Alan P. Wolffe and Walter Wahli

Institut de Biologie animale (D.R., W.W.) Université de Lausanne Bâtiment de Biologie CH-1015 Lausanne, Switzerland
Laboratory of Molecular Embryology (A.P.W.) National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland 20892-5431


    INTRODUCTION
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
The nuclear hormone receptors are transcriptional regulators that activate gene expression upon binding of their respective ligands. A new class of protein, termed coregulators, has emerged during the last few years. These proteins have the faculty to repress (corepressors) or to enhance (coactivators) the activity of genes regulated by nuclear hormone receptors in a ligand-dependent fashion. In this review we describe most of these coregulators and discuss their mode of action. In particular, we comment on the link between coregulators and histone acetylation, which is a crucial event in the transcriptional response within chromatin. We describe novel alternative pathways, which elicit the recruitment of coregulators independently of the presence of any ligand and speculate on how the convergence of ligand-dependent and -independent mechanisms might enhance the transcriptional response of target genes.


    DESCRIPTION OF THE NUCLEAR HORMONE RECEPTORS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
Nuclear hormone receptors are ligand-inducible transcription factors that are involved in a number of physiological and cellular events (see Table 1Go for nuclear receptor nomenclature). Together, they form a superfamily, which includes the classic steroid receptors (androgen, estrogen, glucocorticoid, mineralocorticoid, and progesterone receptors), the thyroid, vitamin D, and retinoid receptors, as well as many others that have been characterized more recently. All of them share common functional domains named A to F. The N-terminal A/B region is weakly conserved among the members of the superfamily, has a variable length, and contains an autonomous activation function (AF-1). The conserved C domain is the DNA-binding domain, which consists of two zinc-finger-like motifs. The D domain is a variable hinge. The multifunctional C-terminal half of the protein (domain E) encompasses the ligand-binding domain (LBD), a second activation function (AF-2), a dimerization domain, and a region involved in nuclear localization. The AF-2 autonomous activation domain (AF-2 AD) is composed of an amphipathic {alpha}-helix that is highly conserved among nuclear receptors and is critical for transcriptional activation (1, 2, 3, 4). The most C-terminal region (domain F) is variable and has no known function. This domain is absent in some receptors such as the progesterone receptor (PR), peroxisome proliferator-activated receptors (PPAR), and retinoid receptors [retinoic acid receptor (RAR), retinoid X receptor (RXR)].


View this table:
[in this window]
[in a new window]
 
Table 1. Nomenclature According to the Nuclear Receptors Nomenclature Committee, 1999

 
Transcriptional activation by both AF-1 and AF-2 of the estrogen receptor (ER) is cell type specific and relies on the promoter context of the hormone-response element (HRE) (5). This suggests the existence of different mediating or coactivating proteins, several of which have been identified to date (see below). These mediators interact with the LBD and some are capable of increasing the AF-2 response in a ligand-dependent fashion. On certain promoters, AF-1 and AF-2 must synergize to reach efficient transactivation.


    NUCLEAR RECEPTOR COACTIVATORS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
The observation of transcriptional interference or squelching between steroid hormone receptors provided evidence for the existence of limiting common transcriptional cofactors that mediate AF-2 function (6, 7). The subsequent biochemical identification of several nuclear receptor-interacting proteins in a ligand-dependent manner supported this hypothesis (8) (Table 2GoGoGoGoGo). These mediators or coactivators are required to achieve efficient transcription (reviewed in Refs. 9, 10, 11).


View this table:
[in this window]
[in a new window]
 
Table 2. Nuclear Receptor Cofactors—Part I

 

View this table:
[in this window]
[in a new window]
 
Table 2A. Continued

 

View this table:
[in this window]
[in a new window]
 
Table 2B. Continued

 

View this table:
[in this window]
[in a new window]
 
Table 2C. Continued

 

View this table:
[in this window]
[in a new window]
 
Table 2D. Continued

 

    COACTIVATORS, A GROWING FAMILY
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
Numerous potential receptor-interacting proteins were identified and described in the past few years (Table 2GoGoGoGoGo), and many others will certainly be discovered in the near future. This rapid increase has led to some confusion in the nomenclature and raised questions about the definition of a coactivator. A real coactivator must fulfill certain requirements. First it must interact directly with the activation domain of a nuclear receptor in an agonist-dependent manner (but not in the presence of an antagonist), leading to enhancement of the receptor activation function. Most of the potential cofactors meet this definition. A coactivator should also interact with components of the basal transcription machinery. Finally, coactivators should not enhance the basal transcriptional activity by their own, although they contain an autonomous activation function (12, 13). Indeed, in the absence of a nuclear hormone receptor, coactivators cannot be recruited to promoters and therefore cannot coactivate transcription. Here, we will first discuss some well characterized coactivators and then we will comment on proteins whose coactivator status is not clearly established.


    SRC-1/CBP/p300/pCAF: A COACTIVATION COMPLEX?
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
Among all the described coactivators to date, SRC-1 (steroid receptor coactivator 1) has attracted much attention. The human SRC-1 was first discovered as a ligand-dependent interacting protein for the progesterone receptor (14). It appeared, however, that the original cDNA clone was truncated at the N terminus (15, 16). In addition to the full-length SRC-1 (mSRC-1a, NCoA-1), several splice variants have been described, e.g. SRC-1b, -c, -d, and -e (15, 17).

The isoform SRC-1e is a more potent coactivator for ER than SRC-1a (13). For instance, the estrogen-regulated rat oxytocin promoter (-363/+16) is coactivated by SRC-1e but not by SRC-1a, as analyzed by transient transfection assay in Cos-1 cells. On the other hand, both SRC-1 isoforms stimulate ER-mediated transcription from an artificial ERE-containing promoter. Thus, coactivation by SRC-1a appears to rely on the promoter context of the receptor target gene. Both isoforms contain three nuclear receptor-interacting motifs (LXXLL) found in many co-factors (18). SRC-1a however possesses a fourth LXXLL motif at its C terminus (13). The function of this additional motif is unclear since its mutation does not affect transcription. The difference in activity results most likely from the presence of two distinct activation domains in SRC-1. The first domain interacts with the mediator CREB-binding protein (CBP)/p300, whereas the second domain activates transcription independently of CBP/p300. It seems that the extra C-terminal portion of SRC-1a, which is not present in SRC-1e, represses this CBP/p300-independent activation domain. The fact that the promoter context influences the ability of SRC-1a to coactivate ER suggests strongly that the recruitment of p300/CBP by SRC-1 is not always sufficient on some promoters. The target factor of the second activation domain is not known to date.

The interaction of SRC-1 with the estrogen receptors depends on ligand and the integrity of helix 12 within the LBD and requires the presence of two functional AF-2 domains in a receptor dimer (13). The ligand-dependent interaction between SRC-1 and TR was analyzed in detail (19). Five independent mutations within the LBD of TR abolished SRC-1a binding. These mutations include residues from helix 3, 5, and 12, which form a small interaction surface encircling a hydrophobic cleft. A similar mutation (K366 in helix 3) in the mouse ER was shown to interfere with SRC-1 recruitment (20). More recently, a complex containing the liganded PPAR-{gamma} LBD (homodimer) and a portion of human SRC-1(623–710) was resolved at 2.3 Å (21). The crystal structure showed that each member of the receptor dimer interacts with a single and different LXXLL motif of the same SRC-1 molecule. The hydrophobic face of the LXXLL helix packs into a hydrophobic pocket formed by helices 3, 4, 5, and 13 (H12 in other receptors) of PPAR-{gamma}. The nuclear hormone receptors contain similar LXXLL motifs within their own AF-2. Surprisingly, the crystal structure of the unliganded PPAR-{gamma} homodimer indicates that the AF-2 helix of one receptor can interact with the LBD of a second receptor (21). This suggests that the ligand-dependent activation leads to the displacement of the AF-2 helix from the LBD of the other receptor in favor of the recruitment of an LXXLL motif of SRC-1. This model was also proposed for the RXR/RAR heterodimer (22).

SRC-1 is also capable of interacting with both the A/B and D/E regions of PR and ER through multiple receptor-interaction sites (23, 24). Furthermore, the binding of SRC-1 to steroid receptors is more efficient when both AF-1 and AF-2 are present. This could potentially explain the transcriptional synergy observed between AF-1 and AF-2 (5).

The ligand-dependent interaction between SRC-1 and nuclear receptors is established, but the way the transcriptional activation signal is transmitted to the transcriptional machinery remains obscure. One possibility is the direct binding of SRC-1 to the basal transcription machinery through TFIIB or TATA-binding protein (TBP) (17). Alternatively, SRC-1 may be part of a larger coactivator complex. Hence, upon estrogen binding, ER becomes associated with numerous proteins, including SRC-1 and p300 together with proteins of 140 (ERAP140), 100, 90, and 30 kDa (25). However, there is no clear evidence that these proteins are part of the same complex. Nevertheless, it was not surprising when SRC-1 was shown to interact directly with a conserved region in the C terminus of p300 and its homolog CBP (15, 16). Moreover, CBP/p300 is a coactivator that binds to nuclear hormone receptor in a ligand-dependent manner (26) and enhances steroid-dependent transcription in synergy with SRC-1 (27). However, there is increasing evidence indicating that the limiting CBP/p300 factor serves a broader function, i.e. as an integrator of many different activation pathways (28, 29, 30). Indeed, CBP/p300 has been shown to interact with an increasing number of other DNA-binding factors and with components of the basal transcription machinery. p300/CBP-associated factor (P/CAF) and p300/CBP cointegrator-associated protein (p/CIP) are two other nuclear hormone receptor coactivators that can associate with CBP/p300 (31, 32, 33). Both CBP/p300 and p/CIP, together with SRC-1 (NCoA-1), are required to allow full ligand-activated gene transcription in several cell lines (32). Finally, p/CIP and SRC-1 can bind P/CAF (34). Despite all the described potential interactions between all these cofactors, there is little biochemical evidence of the existence of such a complex in vivo. Some interactions may be mutually exclusive. Alternatively, various combinations of subsets of these coactivators may coexist in the cell, giving rise to a number of possibilities in term of specificity of regulation. In an attempt to isolate such complexes, cells were recently subjected to biochemical fractionation (35). This study indicates that the different cofactors cofractionate in various stable subcomplexes. These data also suggest that the liganded progesterone receptor recruits a preformed complex that contains SRC-1 and TIF2. Although many receptors can bind to a given coactivator, it is possible that they compete with each other and that each has a different cofactor affinity (36).

Interestingly, P/CAF, CBP/p300, and SRC-1 present histone acetyltransferase activity (HAT) (33, 37, 38). Since histone acetylation correlates with promoter activation (reviewed in Ref. 58), it may explain how these cofactors increase the transcriptional activation by nuclear receptors. But are all the different HATs required for the coactivation or do they have some specificity? It appears that inactivation of the HAT domains of CBP or SRC-1 has no influence on the coactivation of RAR (34). However, the HAT domain of P/CAF is indispensable for nuclear receptor activation. On the other hand, CREB (CRE-binding protein) function needs CBP-HAT activity and not P/CAF-HAT. This suggests that there is a selectivity in the specific HAT activity required for the action of different classes of transcription factors. In addition, P/CAF acetylates preferentially nucleosomal histone H3, whereas p300/CBP acetylates all nucleosomal core histones (SRC-1 and ACTR have a specificity for histones H3 and H4) (33, 37, 38, 40, 41). The presence of multi-HAT activities within a given complex may lead to various patterns of histone acetylation that are specific for a particular transactivator or for a promoter context. Interestingly, P/CAF and p300/CBP have the property to acetylate nonhistone proteins such as TFIIEß, TFIIF (RAP74 and RAP30), EKLF, GATA-1, and p53 (42, 43, 44, 45).

Recently, VDR-interacting protein (DRIP) was isolated and purified as a new coactivator complex (46, 47). Despite the lack of HAT activities, DRIP is a potent coactivator of the vitamin D receptor in a chromatin context. Any chromatin remodeling activity related to DRIP (directly or not) has not been identified to date. Interestingly, some DRIP subunits are homologous to components of mediator complex that are found associated with the RNA polymerase II complex as well. This finding gives us a clue as to how DRIP may target the RNA polymerase II to the promoter. Surprisingly, DRIP, and most probably its related TRAP (48) complex, shares most of the subunits with yet another complex, ARC (activator-recruited cofactor) (49). The latter, however, is a coactivator for transcription factors such as SREBP-1a, VP16, and NF-{kappa}B (p65 subunit) within chromatin. It appears likely that there is a convergence in the coactivation pathways of many transcriptional activators, the differences residing in the fine composition of coactivator complexes or subcomplexes.


    OTHER POTENTIAL COACTIVATORS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
According to the definition stated earlier in this review, a coactivator must interact directly with the activation domain of a nuclear receptor in an agonist-dependent manner but not in the presence of an antagonist. Rap46 was shown to interact in vitro with numerous receptors (ER, AR, GR, PR, TR) independently of the presence of any ligands, agonist or antagonist (50), but so far, no functional experiments have been performed. Another protein, RSP5/RPF1, potentiates hormone-dependent activation of transcription by GR and PR (51), although no direct interaction with either receptors was ever documented (M.O. Imhof, personal communication). Interestingly, in one case, there is ligand-dependent release of a coactivator. The constitutive androstane receptor ß (CAR-ß) is active in absence of its ligand. Surprisingly, the addition of androstenol or of androstanol promotes the dissociation of the steroid receptor coactivor 1 (SRC-1) and leads to transcriptional repression (52).

Another criterion for belonging to the coactivator family is the ability to enhance receptor function. This basic requirement is not observed with TIF1{alpha}, which down-regulates transactivation by ER, RAR, and RXR in Cos-1 cells (53). It is possible, however, that overexpression of TIF1 titrates out an essential limiting nuclear protein required for AF-2 activity. Proteins such as SUG1 (suppressor of a mutation in the transcriptional activation domain of the yeast activator Gal4) and Trip1 (TR-interacting protein 1) interact with several nuclear hormone receptors in a ligand-dependent fashion as well as with TBP (54, 55). The fact that SUG1 was proposed to be a component of the RNA polymerase II holoenzyme reinforced its classification as a coactivator (56). However, SUG1 is a subunit of the 26S proteasome (57, 58) and Trip1 inhibits transactivation (54). Therefore, it is likely that these proteins are not coactivators but rather are involved in receptor degradation.

A third criterion is the requirement for a direct contact between the cofactor itself and the basal transcription machinery in light of the bridging model. This aspect is difficult to assess and was not determined for all potential coactivators. One can also envision that individual cofactors are part of a larger complex, limiting the need for a direct interaction with basal transcription factors. Although RIP140 interacts with several nuclear receptors in vitro and enhances weakly ER function in vivo, it is not able to associate with either TFIIB or TBP (59, 60, 61). Does this disqualify it as a nuclear hormone receptor coactivator ? It is still possible that it interacts with other basal transcription factors. Moreover, the fact that RIP140 inhibits transcription upon overexpression argues in favor of the need for another intermediary factor (60).

Finally, coactivators should not enhance the basal transcriptional activity on their own, although they contain an autonomous activation function (12, 13). Indeed, in the absence of a nuclear hormone receptor, coactivators cannot be recruited to promoters and therefore cannot coactivate transcription.

The first described nuclear hormone-positive regulators are members of the SWI/SNF family of proteins. Ligand-dependent transcriptional enhancement of GR or ER in yeast requires several SWI gene products, such as SWI1, SWI2, and SWI3 (62), which are part of a large SWI/SNF chromatin remodeling complex (63, 64). The human homologs of SWI2, termed SNF2{alpha}, SNF2ß, or brahma, were also shown to coactivate ER, GR, and RAR in mammalian cells (65, 66). It has not been established, however, whether or not the described interaction between SW3 and GR (which requires SWI1 and SW2) is direct (62). The finding that SWI1 contains nuclear hormone receptor-binding motifs (LXXLL), present in many cofactors (18), is puzzling and might suggest that it is potentially a coactivator (67). However, the importance of these LXXLL motifs was not tested for SW1.

COACTIVATOR AND LIGAND-INDEPENDENT TRANSACTIVATION
A list of nonsteroid compounds or extracellular signals can efficiently activate the ER including dopamine (68), EGF (epidermal growth factor) (69, 70), TGF{alpha} (tumor growth factor {alpha}) (70), cAMP (69, 71), insulin-like growth factor I (71), phorbol ester (tetradecanoylphorbol acetate) (69), and many others. Since all these molecules induce protein phosphorylation, it is likely that altered phosphorylation of the receptors (and/or associated proteins) is a key event in the ligand-independent activation. Moreover, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, is also able to activate ER-dependent transcription (69).

Ligand-independent phosphorylation of the steroid hormone receptors has been known for a long time (reviewed in Refs. 63, 64). The ER is mainly phosphorylated on serines residues in the A/B domain (74) although phosphorylation of a tyrosine residue in the E/F domain was also reported (75, 76). The chain of events linking EGF to ER phosphorylation has been analyzed more extensively. EGF activates the Ras-Raf-MAPK cascade through its membrane receptor and leads to phosphorylation of hER on serine 118 and to enhancement of transcription (69, 77). However, the functional relationship between a particular phosphorylation site and transcriptional activation remained elusive until recently. Effectively, phosphorylation of two ERß serines residues (Ser 102 and Ser 124 within the AF-1 domain), via the MAPK cascade, promotes the recruitment of SRC-1 in the absence of estrogen (Fig. 1Go) (78). Similar findings were made with the orphan nuclear receptor SF-1 (steroidogenic factor 1). Intriguingly, phosphorylation enhances the recruitment of both a coactivator [GR-interacting protein 1 (GRIP1)] and a corepressor [silencing mediator for retinoid and thyroid hormone receptor (SMRT)] to SF-1 (79). In this particular situation, the functional importance of phosphorylation in transcriptional activation appears unclear.



View larger version (44K):
[in this window]
[in a new window]
 
Figure 1. The ER Can Activate Transcription Through Different Mechanisms.

A, Ligand-independent recruitment of coactivators by the ER. The MAPK-dependent phosphorylation of serine residues within the AF-1 domain allows the functional interaction with SRC-1 (left panel). Alternatively, the need for a ligand is abolished by the presence of cyclin D1, which acts as a bridging protein between the ER AF2 domain and SRC-1 and or P/CAF (right panel). In the latter situation, the described synergism between estradiol and cyclin D1 might result from their cooperation in the recruitment of SRC1. The presence of SRC-1 and/or P/CAF suggests that other components of a coactivation complex might be present as well (dashed oval). B, Ligand-dependent recruitment of coactivators by the ER. The presence of the ligand induces a conformational switch in the ER ligand binding domain that leads to the recruitment of a coactivation complex (left panel, see also Fig. 2Go) containing protein such as SRC-1, P/CAF, p300/CBP, p/CIP, and possibly many others (dashed oval). It is possible that ligand-dependent and -independent mechanisms cooperate to provide maximal transcriptional competency to the receptor (right panel).

 
Phosphorylation is not the only event that directs ligand-independent transactivation. Cyclin D1 has the property to potentiate the activity of the ER in a cyclin-dependent kinase-independent mechanism (80, 81). Interestingly, cyclin D1 is able to interact with SRC-1 through a region that resembles the receptor leucine-rich coactivator binding motif (LLxxxL) in AF-2 (Fig. 1Go) (82). Cyclin D1 is essential for proper recruitment of coactivators to unliganded ER and functions as a bridging factor between the receptor and SRC-1. Similarly, recent experiments have shown that P/CAF associates functionally with cyclin D1 (83). Thus, cyclin D1 plays a crucial role in ER activation by recruiting HAT activities in the absence of any ligand. Altogether, these results indicate that the activity of a receptor can be modulated in multiple ways. The combination of various mechanisms could elicit widespread responses to different cellular stimuli (Fig. 1Go).


    NUCLEAR RECEPTOR COREPRESSORS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
Transcriptional activation is mediated by the recruitment of coactivators by the activated receptor. However, nuclear hormone receptors can repress transcription under various circumstances (reviewed in Refs. 9, 74). Repression occurs mostly in the absence of a ligand or when an antagonist is bound to the receptor. In the latter situation, the antagonist competes away the natural ligand, preventing proper activation. Transcriptional repression involves several mechanisms (85). It may result from the binding of a repressor directly to DNA, leading either to a competition for the same DNA element (thus preventing the binding of the activator), to an interference with the activator function after binding to a nonoverlapping site (quenching), or to the direct silencing of the basal transcription machinery irrespective of the presence or absence of the activator. Alternatively, repression may be achieved after the recruitment of a limiting corepressor to the promoter by protein-protein interaction with the activator (Fig. 2Go). In this situation, the corepressor is not able to bind to DNA on its own. We will focus here on the repression mediated by the recruitment of a corepressor (Table 3GoGo).



View larger version (34K):
[in this window]
[in a new window]
 
Figure 2. Ligand-Dependent Switch between A Nuclear Hormone Receptor Associated Either with a Corepression or a Coactivation Complex

The nuclear hormone receptor (NR) is associated with a corepressor (N-CoR, SMRT), which in turn recruits a histone deacetylase (HDAC) through its interaction with Sin3. Deacetylation of histone tails leads to transcriptional repression. Addition of the ligand disrupts this repression complex in favor of the association of a coactivation complex (SRC-1, P/CAF, p300/CBP, pCIP, and others). These proteins possess a histone acetyltransferase activity that allows chromatin decompaction through histone modifications. The interaction between the nuclear hormone receptor AF-2 domain and the coactivation complex occurs through the LXXLL motif found in many coactivators. The coactivator and corepressor complexes are represented with dashed lines since their exact composition in vivo is not determined.

 

View this table:
[in this window]
[in a new window]
 
Table 3. Nuclear Receptor Corepressors

 

View this table:
[in this window]
[in a new window]
 
Table 3A. Continued

 
A true corepressor must fulfill several criteria. First it has to interact directly with the unliganded receptor, leading to enhancement of basal transcription repression. A corepressor should also interact with components of the basal transcription machinery and possess an autonomous repression domain.


    DISCOVERY OF COREPRESSORS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
The active repression mediated by some members of the nuclear receptor superfamily in the absence of ligand has attracted a lot of interest. The unliganded TR, which is able to bind DNA, is not only transcriptionally incompetent but acts as a repressor (86, 87, 88, 89, 90). The finding that TR-mediated repression is reversed by cotransfection of either the unliganded RAR or the C terminus of the oncogene v-ErbA (viral TR homologue) revealed that TR corepressors might exist within the cell (86). Three such corepressors were then identified (Table 3Go): SMRT (91), N-CoR (nuclear receptor copressor) (92, 93), and SUN-CoR (small ubiquitous nuclear corepressor) (94). These proteins have the characteristic to interact with the unliganded TR or RAR associated with their RXR heterodimeric partner on DNA. The C terminus of N-CoR interacts with TR and RAR in a region encompassing the hinge domain (region D) and a portion of the ligand-binding domain (92). Interestingly, this interaction region (CoR box) is significantly conserved only between TR, v-ErbA, and RAR but not among the receptors that do not associate naturally with N-CoR such as ER (see below). Silencing is abolished upon ligand-dependent release of the repressor from the receptor. Protease resistance assays have suggested that the release of SMRT from TR is imposed by the conformational switch of the LBD (helix 12) upon hormone binding (95). Importantly, the constitutively inactive viral oncogene v-ErbA is associated with SMRT regardless of the presence or absence of a ligand. The behavior of v-ErbA argues that the release of SMRT is a prerequisite for proper transcriptional activation. Interestingly, the point mutant TR160 (Pro160->Arg), which is incapable of silencing but retains its ligand-dependent transactivation, cannot efficiently recruit SMRT, indicating that silencing is linked to the recruitment of SMRT (91). The necessity for a receptor to release a corepressor to activate transcription is well illustrated with the RAR/RXR heterodimer. It is well documented that RXR and RAR activate transcription from direct repeats when spaced by five nucleotides (DR5), but not when spaced by only one nucleotide (DR1) (96, 97). This differential regulation stems from the incapacity of all-trans-retinoic acid to dissociate N-CoR from the RAR/RXR heterodimer on a DR1 DNA element and therefore to relieve repression (93). It appeared that RXR and RAR occupy the 5'- and 3'-half-sites of a DR5 element, respectively, whereas the polarity is inverted on a DR1 element (98). The latter polarity is likely to impose allosteric constraints on RAR, preventing the release of N-CoR. However, the occupancy of either a DR1 or DR5 response element by RAR/RXR has no impact on the ligand-dependent recruitment of coactivators (93).

It was first reported that ER and PR are unable to interact with either N-CoR or SMRT, in the absence of any ligand (92). It appeared, however, that their respective antagonists (tamoxifen and RU486) induce such an interaction. Interestingly, these antagonists switch into perfect agonists when the receptor ligand-independent activation function (AF-1) is activated by the MAPK pathway. This activation is concomitant to the release of the corepressors and to the recruitment of components of the coactivator complex (99). This phenomenon may explain why patients, treated for breast cancer, eventually acquire resistance to tamoxifen. Intriguingly, a small coactivator (L7 or SPA for switch protein for antagonist) has been recently identified and whose coexpression enhances transcription of antagonist- occupied ER and GR (100). Surprisingly, L7/SPA has no effect on agonist-dependent transcription by these receptors. In light of these data, it is possible that the cellular ratio between corepressors and coactivators such as L7/SPA might determine whether an antagonist-bound receptor would be active or not.

The above mentioned corepressors interfere directly with transcriptional activation. Transcriptional inhibition can also be efficiently achieved by preventing nuclear receptor from accessing DNA. TRUP and calreticulin are such proteins whose binding either to the hinge-domain of TR and RAR (TRUP) or to the DNA-binding domain of AR, GR, and RAR (calreticulin) interferes with their DNA binding (101, 102, 103). However, these proteins should not be considered as being real corepressors according to its definition mentioned earlier. Indeed, TRUP and calreticulin prevent transcriptional activation by interfering with receptor binding but not by enhancing basal transcription repression.

The yeast protein Ssn6 was isolated as a negative regulator of the estrogen and progesterone receptors (104). It appeared to repress the ligand-independent activity of ER-AF-1. It is not clear whether Ssn6 should qualify as a nuclear hormone corepressor especially because it affects AF-1 but not AF-2. In addition, there is no study available that could indicate whether Ssn6 fits all the criteria of the corepressor family, and since the steroid hormone receptors are not naturally expressed in yeast, it is unclear whether a similar mechanism would occur in mammals. Interestingly, Ssn6 is involved in glucose-mediated gene repression and requires a partner, Tup1, to achieve full repression (105). Tup1 has been shown to mediate repression by its ability to interact directly with histones H3 and H4 (106). This suggests that repression involves some chromatin components.


    SMRT AND N-CoR MEDIATE TRANSCRIPTIONAL REPRESSION THROUGH THE RECRUITMENT OF A HISTONE DEACETYLASE COMPLEX
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
Immunoprecipitation experiments have revealed that N-CoR and SMRT are components of a cellular complex containing the proteins Sin3A/B and histone deacetylases (107, 108, 109). The N terminus repression domain (SD-1) of SMRT interacts with Sin3A, which in turn associates with the histone deacetylase HDAC-1 through one of its two silencing domains (110). No evidence of a direct interaction between HDAC-1 and SMRT was observed, suggesting that Sin3 acts as a bridging molecule between SMRT and the deacetylase complex. These findings argue that at least part of the silencing mediated by nuclear hormone repressors involves the deacetylation of histones through the recruitment of a histone deacetylase complex (Fig. 2Go).

The importance of histone deacetylation associated to corepression has been highlighted recently in human leukemia (111, 112). Two forms of acute promyelocytic leukemia (APL) are caused by chromosomal translocations that create oncogenic fusion proteins between RAR and either PML (promyelocytic leukemia) or PFLZ (promyelocytic leukemia zinc finger). Both PML-RAR and PFLZ-RAR recruit the corepressor-deacetylase complex through RAR in a ligand-independent fashion. These interactions are abolished with high-dose retinoic acid. However, PFLZ-RAR is also able to associate constitutively and stably with corepressors and deacetylases through the PFLZ moiety, irrespective of the presence of the ligand. This explains why PML-RAR APL patients usually recover after treatment with retinoic acid but not PFLZ-RAR patients. These data strongly suggest that leukemia induced by PML-RAR and PFLZ-RAR is derived from aberrant chromatin deacetylation.

Chromatin modification through acetylation cannot account solely for the repression of transcription mediated by unliganded receptors. Silencing is indeed observed in systems that are devoid of proper chromatin such as transient transfections and in vitro transcription (86, 87, 89). Therefore, alternative silencing pathways must exist and function independently of the recruitment of any histone deacetylase. Early results have suggested that TR silencing is mediated by its direct interaction with the general transcription factor TFIIB and that thyroid hormone is able to decrease this interaction (113). In agreement with these results, TFIIB was recently demonstrated to interact with the corepressors N-CoR and SMRT as well as with Sin3 (110). It appears that TFIIB binds in vitro to the same silencing domain (SD-1) of SMRT as does Sin3 (see above). It is not clear to date whether the binding of TFIIB and Sin3 to SMRT are mutually exclusive. Interestingly, overexpression of SMRT reduces the transcriptional activity of TFIIB tethered to a promoter indicating that their physical interaction is functional. In another study, N-CoR was shown to make simultaneous and noncompetitive contacts with the general transcription factors TFIIB, TAFII32, and TAFII70 (114). In this case the binding of TFIIB with N-CoR can occur in the presence of Sin3B and HDAC-1. The sequestration of TFIIB and TAFII32 by N-CoR inhibits the functional interactions of the two former factors, which is crucial for transcriptional initiation. SMRT contains two silencing domains within its amino-terminal region, namely SD-1 and SD-2, but only SD-1 reportedly interacts with Sin3A or TFIIB (110). Similarly, Sin3A possesses two silencing domains, one of which interacts only with the histone deacetylase HDAC-1. Moreover, the histone deacetylase inhibitor, trichostatin A, has no notable effect on the Sin3A ability to repress transcription. These results suggest that, in addition to the recruitment of either TFIIB or HDACs, other unidentified alternative silencing pathways may exist.


    CONCLUDING REMARKS
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 
The increasing number of described cofactors adds to the complexity of the transcriptional regulation mediated by nuclear hormone receptors. One of the future challenges will be to determine the specificities of the coregulator family. There is strong evidence that coregulators do not modulate the activity of all nuclear hormone receptors. For instance, it is known that neither SMRT nor N-CoR represses PPAR{gamma} activity although they interact in solution (115). In fact, the PPAR{gamma}/RXR{alpha} heterodimer fails to recruit these corepressors once bound to DNA, at least at the acyl CoA oxidase gene promoter. More interestingly, N-CoR but not SMRT potentiates RevErb repression indicating that these two corepressors do not possess redundant functions. Similarly, the recently described "repressor of estrogen receptor activity" (REA) appears to be selective for the liganded ER (116). Thus, the first level of specificity might be achieved by the selective recruitment of a given cofactor. We now know that some coregulators are part of multisubunit complexes such as DRIP and P/CAF (47, 49, 117). The presence of various accessory proteins within these complexes or alternative subcomplexes will likely influence the specificity of transcription. We have also seen that some coactivators possess a HAT activity. Finally, posttranslational modifications of coregulators or of other components within their complex may as well prove to be important for proper regulation. All these potential levels of regulation increase not only the complexity but also the number of possibilities available for a better tuning of transcriptional control. The active research in the nuclear hormone receptor during the last decade has dramatically changed the simple view of the mechanism of receptor action. More surprises are likely to come in the near future.


    FOOTNOTES
 
Address requests for reprints to: Dr. Walter Wahli, Institut de Biologie Animale, Université de Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland. E-mail: walter.wahli{at}iba.unil.ch

1 Present address: Department of Biological Chemistry, Molecular Biology Institute, University of California, Los Angeles, California 90095. Back

Received for publication July 21, 1999. Revision received September 27, 1999. Accepted for publication October 6, 1999.


    REFERENCES
 TOP
 INTRODUCTION
 DESCRIPTION OF THE NUCLEAR...
 NUCLEAR RECEPTOR COACTIVATORS
 COACTIVATORS, A GROWING FAMILY
 SRC-1/CBP/p300/pCAF: A...
 OTHER POTENTIAL COACTIVATORS
 NUCLEAR RECEPTOR COREPRESSORS
 DISCOVERY OF COREPRESSORS
 SMRT AND N-CoR MEDIATE...
 CONCLUDING REMARKS
 REFERENCES
 

  1. Barettino D, Vivanco Ruiz MM, Stunnenberg HG 1994 Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J 13:3039–3049[Abstract]
  2. Danielian PS, White R, Lees JA, Parker MG 1992 Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J 11:1025–1033[Abstract]
  3. Durand B, Saunders M, Gaudon C, Roy B, Losson R, Chambon P 1994 Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J 13:5370–5382[Abstract]
  4. Saatcioglu F, Bartunek P, Deng T, Zenke M, Karin M 1993 A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor). Mol Cell Biol 13:3675–3685[Abstract]
  5. Tora L, White J, Brou C, Tasset D, Webster N, Scheer E, Chambon P 1989 The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 59:477–487[Medline]
  6. Bocquel MT, Kumar V, Stricker C, Chambon P, Gronemeyer H 1989 The contribution of the N- and C-terminal regions of steroid receptors to activation of transcription is both receptor and cell-specific. Nucleic Acids Res 17:2581–2595[Abstract]
  7. Meyer ME, Gronemeyer H, Turcotte B, Bocquel MT, Tasset D, Chambon P 1989 Steroid hormone receptors compete for factors that mediate their enhancer function. Cell 57:433–442[Medline]
  8. Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C, Brown M 1994 Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 264:1455–1458[Medline]
  9. Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L 1996 Nuclear receptor coactivators and corepressors. Mol Endocrinol 10:1167–1177[Abstract]
  10. Glass CK, Rose DW, Rosenfeld MG 1997 Nuclear receptor coactivators. Curr Opin Cell Biol 9:222–232[CrossRef][Medline]
  11. Torchia J, Glass C, Rosenfeld MG 1998 Co-activators and corepressors in the integration of transcriptional responses. Curr Opin Cell Biol 10:373–383[CrossRef][Medline]
  12. Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR 1996 GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA 93:4948–4952[Abstract/Free Full Text]
  13. Kalkhoven E, Valentine JE, Heery DM, Parker MG 1998 Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J 17:232–243[Abstract/Free Full Text]
  14. Oñate SA, Tsai SY, Tsai MJ, O’Malley BW 1995 Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270:1354–1357[Abstract]
  15. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, Rosenfeld MG 1996 A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85:403–414[Medline]
  16. Yao TP, Ku G, Zhou N, Scully R, Livingston DM 1996 The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci USA 93:10626–10631[Abstract/Free Full Text]
  17. Takeshita A, Yen PM, Misiti S, Cardona GR, Liu Y, Chin WW 1996 Molecular cloning and properties of a full-length putative thyroid hormone receptor coactivator. Endocrinology 137:3594–3597[Abstract]
  18. Heery DM, Kalkhoven E, Hoare S, Parker MG 1997 A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733–736[CrossRef][Medline]
  19. Feng W, Ribeiro RCJ, Wagner R, Nguyen H, Apriletti JW, Fletterick RJ, Baxter JD, Kushner PJ, West BL 1998 Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280:1747–1749[Abstract/Free Full Text]
  20. Henttu PM, Kalkhoven E, Parker MG 1997 AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors. Mol Cell Biol 17:1832–1839[Abstract]
  21. Nolte RT, Wisely GB, Westin S, Cobbs JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV 1998 Ligand binding and coactivator assembly of the peroxisome proliferator-activated receptor-{gamma}. Nature 395:137–143[CrossRef][Medline]
  22. Westin S, Kurokawa R, Nolte RT, Wisely GB, McInerney EI, Rose DW, Milburn MV, Rosenfeld MG, Glass CK 1998 Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators. Nature 395:199–202[CrossRef][Medline]
  23. McInerney EM, Tsai MJ, O’Malley BW, Katzenellenbogen BS 1996 Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. Proc Natl Acad Sci USA 93:10069–10073[Abstract/Free Full Text]
  24. Oñate SA, Boonyaratanakornkit V, Spencer TE, Tsai SY, Tsai M-Y, Edwards DP, O’Malley BW 1998 The steroid receptor coactivator-1 contains multiple receptor interacting and activation domains that cooperatively enhance the activation function 1(AF1) and AF2 domains of steroid receptors. J Biol Chem 273:12101–12108[Abstract/Free Full Text]
  25. Hanstein B, Eckner R, DiRenzo J, Halachmi S, Liu H, Searcy B, Kurokawa R, Brown M 1996 p300 is a component of an estrogen receptor coactivator complex. Proc Natl Acad Sci USA 93:11540–11545[Abstract/Free Full Text]
  26. Chakravarti D, Lamorte VJ, Nelson MC, Nakajima T, Schulman IG, Juguilon H, Montminy M, Evans RM 1996 Role of CBP/p300 in nuclear receptor signalling. Nature 383:99–103[CrossRef][Medline]
  27. Smith CL, Oñate SA, Tsai M-J, O’Malley BW 1996 CREB-binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Proc Natl Acad Sci USA 93:8884–8888[Abstract/Free Full Text]
  28. Janknecht R, Hunter T 1996 Transcription - a growing coactivator network. Nature 383:22–23[CrossRef][Medline]
  29. Janknecht R, Hunter T 1996 Transcriptional control - versatile molecular glue. Curr Biol 6:951–954[Medline]
  30. Shikama N, Lyon J, La Thangue NB 1997 The p300/CBP family: integrating signals with transcription factors and chromatin. Trends Cell Biol 7:230–236[CrossRef]
  31. Blanco JCG, Minucci S, Lu JM, Yang XJ, Walker KK, Chen HW, Evans RM, Nakatani Y, Ozato K 1998 The histone acetylase PCAF is a nuclear receptor coactivator. Genes Dev 12:1638–1651[Abstract/Free Full Text]
  32. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG 1997 The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677–684[CrossRef][Medline]
  33. Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y 1996 A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382:319–324[CrossRef][Medline]
  34. Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney E, Mullen T-M, Glass CK, Rosenfeld MG 1998 Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279:703–707[Abstract/Free Full Text]
  35. McKenna NJ, Nawaz Z, Tsai SY, Tsai M-Y, O’Malley BW 1998 Distinct steady-state nuclear receptor coregulators complexes exist in vivo. Proc Natl Acad Sci USA 95:11697–11702[Abstract/Free Full Text]
  36. Zhou G, Cummings R, Li Y, Mitra S, Wilkinson HA, Elbrecht A, Hermes JD, Schaeffer JM, Smith RG, Moller DE 1998 Nuclear receptors have distinct affinities for coactivators: fluorescence resonance energy transfer. Mol Endocrinol 12:1594–1604[Abstract/Free Full Text]
  37. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y 1996 The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87:953–959[Medline]
  38. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O’Malley BW 1997 Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389:194–198[CrossRef][Medline]
  39. Mizzen CA, Allis CD 1998 Linking histone acetylation to transcriptional regulation. Cell Mol Life Sci 54:6–20[CrossRef][Medline]
  40. Bannister AJ, Kouzarides T 1996 The CBP co-activator is a histone acetyltransferase. Nature 384:641–643[CrossRef][Medline]
  41. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM 1997 Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90:569–580[Medline]
  42. Gu W, Roeder RG 1997 Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90:595–606[Medline]
  43. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H 1997 Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 7:689–692[Medline]
  44. Boyes J, Byfield P, Nakatani Y, Ogryzko V 1998 Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 396:594–598[CrossRef][Medline]
  45. Zhang WJ, Bieker JJ 1998 Acetylation and modulation of erythroid Kruppel-like factor (EKLF) activity by interaction with histone acetyltransferases. Proc Natl Acad Sci USA 95:9855–9860[Abstract/Free Full Text]
  46. Rachez C, Suldan Z, Ward J, Chang C-PB, Burakov D, Erdjument-Bromage H, Freedman LP 1998 A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system. Genes Dev 12:1787–1800[Abstract/Free Full Text]
  47. Rachez C, Lemon BD, Suldan Z, Bromleigh V, Gamble M, Naar AM, Erdjument-Bromage H, Tempst P, Freedman LP 1999 Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398:824–828[CrossRef][Medline]
  48. Yuan C-X, Ito M, Fondell JD, Fu Z-Y, Roeder RG 1998 The TRAP220 component of a thyroid hormone receptor-associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand- dependent fashion. Proc Natl Acad Sci USA 95:7939–7944[Abstract/Free Full Text]
  49. Näär AM, Beaurang PA, Zhou S, Abraham S, Solomon W, Tjian R 1999 Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398:828–832[CrossRef][Medline]
  50. Zeiner M, Gehring U 1995 A protein that interacts with members of the nuclear hormone receptor family: identification and cDNA cloning. Proc Natl Acad Sci USA 92:11465–11469[Abstract]
  51. Imhof MO, McDonnell DP 1996 Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors. Mol Cell Biol 16:2594–2605[Abstract]
  52. Forman BM, Tzameli I, Choi H-S, Chen J, Simha D, Seol W, Evans RM, Moore DD 1998 Androstane metabolites bind to and deactivate the nuclear receptor CAR-ß. Nature :612–615
  53. Le Douarin B, Zechel C, Garnier JM, Lutz Y, Tora L, Pierrat P, Heery D, Gronemeyer H, Chambon P, Losson R 1995 The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18. EMBO J 14:2020–2033[Abstract]
  54. Lee JW, Ryan F, Swaffield JC, Johnston SA, Moore DD 1995 Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature 374:91–94[CrossRef][Medline]
  55. vom Baur E, Zechel C, Heery D, Heine MJ, Garnier JM, Vivat V, Le Douarin B, Gronemeyer H, Chambon P, Losson R 1996 Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J 15:110–124[Abstract]
  56. Kim YJ, Bjorklund S, Li Y, Sayre MH, Kornberg RD 1994 A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77:599–608[Medline]
  57. Akiyama K, Yokota K, Kagawa S, Shimbara N, DeMartino GN, Slaughter CA, Noda C, Tanaka K 1995 cDNA cloning of a new putative ATPase subunit p45 of the human 26S proteasome, a homolog of yeast transcriptional factor Sug1p. FEBS Lett 363:151–156[CrossRef][Medline]
  58. Rubin DM, Coux O, Wefes I, Hengartner C, Young RA, Goldberg AL, Finley D 1996 Identification of the gal4 suppressor Sug1 as a subunit of the yeast 26S proteasome. Nature 379:655–657[CrossRef][Medline]
  59. Cavaillès V, Dauvois S, Danielian PS, Parker MG 1994 Interaction of proteins with transcriptionally active estrogen receptors. Proc Natl Acad Sci USA 91:10009–10013[Abstract/Free Full Text]
  60. Cavaillès V, Dauvois S, L’Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG 1995 Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 14:3741–3751[Abstract]
  61. L’Horset F, Dauvois S, Heery DM, Cavaillès V, Parker MG 1996 RIP-140 interacts with multiple nuclear receptors by means of two distinct sites. Mol Cell Biol 16:6029–6036[Abstract]
  62. Yoshinaga SK, Peterson CL, Herskowitz I, Yamamoto KR 1992 Roles of SWI1, SWI2, and SWI3 proteins for transcriptional enhancement by steroid receptors. Science 258:1598–1604[Medline]
  63. Kwon H, Imbalzano AN, Khavari PA, Kingston RE, Green MR 1994 Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370:477–481[CrossRef][Medline]
  64. Peterson CL, Dingwall A, Scott MP 1994 Five SWI/SNF gene products are components of a large multisubunit complex required for transcriptional enhancement. Proc Natl Acad Sci USA 91:2905–2908[Abstract]
  65. Chiba H, Muramatsu M, Nomoto A, Kato H 1994 Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res 22:1815–1820[Abstract]
  66. Muchardt C, Yaniv M 1993 A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation by the glucocorticoid receptor. EMBO J 12:4279–4290[Abstract]
  67. Dallas PB, Cheney IW, Liao DW, Bowrin V, Byam W, Pacchione S, Kobayashi R, Yaciuk P, Moran E 1998 p300/CREB binding protein-related protein p270 is a component of mammalian SWI/SNF complexes. Mol Cell Biol 18:3596–3603[Abstract/Free Full Text]
  68. Power RF, Mani SK, Codina J, Conneely OM, O’Malley BW 1991 Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 254:1636–1639[Medline]
  69. Bunone G, Briand P-A, Miksicek RJ, Picard D 1996 Activation of the liganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15:2174–2183[Abstract]
  70. Ignar-Trowbridge DM, Teng CT, Ross KA, Parker MG, Korach KS, McLachlan JA 1993 Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen responsive element. Mol Endocrinol 7:992–998[Abstract]
  71. Aronica SM, Katzenellenbogen BS 1993 Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate and insulin-like growth factor-I. Mol Endocrinol 7:743–752[Abstract]
  72. Kuiper GG, Brinkmann AO 1994 Steroid hormone receptor phosphorylation: is there a physiological role? Mol Cell Endocrinol 100:103–107[CrossRef][Medline]
  73. Mougdil VK 1990 Phosphorylation of steroid hormone receptors. Biochim Biophys Acta 1055:243–258[Medline]
  74. Ali S, Metzger D, Bornert JM, Chambon P 1993 Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J 12:1153–1160[Abstract]
  75. Arnold SF, Melamed M, Vorojeikina DP, Notides AC, Sasson S 1997 Estradiol-binding mechanism and binding capacity of the human estrogen receptor is regulated by tyrosine phosphorylation. Mol Endocrinol 11:48–53[Abstract/Free Full Text]
  76. Migliaccio A, Rotondi A, Auricchio F 1986 Estratiol receptor: phosphorylation on tyrosine in uterus and interaction with anti-phosphotyrosine antibody. EMBO J 5:2867–2872[Abstract]
  77. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P 1995 Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494[Abstract]
  78. Tremblay A, Tremblay GB, Labrie F, Giguère V 1999 Ligand-independent recruitment of SRC-1 to estrogen receptor ß through phosphorylation of activation function AF-1. Mol Cell 3:513–519[Medline]
  79. Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K, Weigel NL, Ingraham HA 1999 Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Mol Cell 3:521–526[Medline]
  80. Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, Pestell RG, Hinds PW, Dowdy SF, Brown M, Ewen ME 1997 Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol 17:5338–5347[Abstract]
  81. Zwijsen RM, Wientjens E, Klompmaker R, van der Sman J, Bernards R, Michalides RJ 1997 CDK-independent activation of estrogen receptor by cyclin D1. Cell 88:405–415[Medline]
  82. Zwijsen RML, Buckle RS, Hijmans EM, Loomans CJM, Bernards R 1998 Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev 12:3488–3498[Abstract/Free Full Text]
  83. McMahon C, Suthiphongchai T, DiRenzo J, Ewen ME 1999 P/CAF associates with cyclin D1 and potentiates its activation of the estrogen receptor. Proc Natl Acad Sci USA 96:5382–5387[Abstract/Free Full Text]
  84. Drouin J 1993 Repression of transcription by nuclear receptors. In: Parker MG (ed) Steroid Hormone Action. IRL Press, New York, vol 2:118–140
  85. Johnson AD 1995 The price of repression. Cell 81:655–658[Medline]
  86. Baniahmad A, Kohne AC, Renkawitz R 1992 A transferable silencing domain Is present in the thyroid hormone receptor, in the v-erbA oncogene product and in the retinoic acid receptor. EMBO J 11:1015–1023[Abstract]
  87. Damm K, Thompson CC, Evans RM 1989 Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature 339:593–597[CrossRef][Medline]
  88. Graupner G, Wills KN, Tzukerman M, Zhang X-K, Pfahl M 1989 Dual regulatory role for thyroid-hormone receptors allows control of retinoic- acid receptor activity. Nature 340:653–656[CrossRef][Medline]
  89. Sap J, Munoz A, Schmitt J, Stunnenberg H, Vennsträm B 1989 Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product. Nature 340:242–244[CrossRef][Medline]
  90. Wong J, Shi Y-B, Wolffe AP 1995 A role for nucleosome assembly in both silencing and activation of the Xenopus TRßA gene by the thyroid hormone receptor. Genes Dev 9:2696–2711[Abstract]
  91. Chen JD, Evans RM 1995 A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454–457[CrossRef][Medline]
  92. Härlein AJ, Näär AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Sädersträm M, Glass CK, Rosenfeld MG 1995 Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397–404[CrossRef][Medline]
  93. Kurokawa R, Sädersträm M, Härlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK 1995 Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377:451–454[CrossRef][Medline]
  94. Zamir I, Dawson J, Lavinsky RM, Glass CK, Rosenfeld MG, Lazar MA 1997 Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc Natl Acad Sci USA 94:14400–14405[Abstract/Free Full Text]
  95. Lin BC, Hong SH, Krig S, Yoh SM, Privalsky ML 1997 A conformational switch in nuclear hormone receptors is involved in coupling hormone binding to corepressor release. Mol Cell Biol 17:6131–6138[Abstract]
  96. Mangelsdorf DJ, Umesono K, Kliewer SA, Borgmayer U, Ong ES, Evans RM 1991 A direct repeat in the cellular retinol-binding protein type II gene confers differential regulation by RXR and RAR. Cell 66:555–561[Medline]
  97. Umesono K, Murakami KK, Thompson CC, Evans RM 1991 Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin-D3 receptors. Cell 65:1255–1266[Medline]
  98. Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld MG, Heyman RA, Glass CK 1994 Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature 371:528–531[CrossRef][Medline]
  99. Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, Del-Rio AL, Ricote M, Ngo S, Gemsch J, Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld MG, Rose DW 1998 Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA 95:2920–2925[Abstract/Free Full Text]
  100. Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB 1997 The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 11:693–705[Abstract/Free Full Text]
  101. Burns K, Duggan B, Atkinson EA, Famulski KS, Nemer M, Bleackley RC, Michalak M 1994 Modulation of gene expression by calreticulin binding to the glucocorticoid receptor. Nature 367:476–480[CrossRef][Medline]
  102. Burris TP, Nawaz Z, Tsai M-Y, O’Malley BW 1995 A nuclear hormone repector-associated protein that inhibits transactivation by the thyroid hormone and retinoic acid receptors. Proc Natl Acad Sci USA 92:9525–9529[Abstract]
  103. Dedhar S, PSR, Shago M, Hagesteijn C-YL, Yang H, Filmus J, Hawley RG, Bruchovsky N, Cheng H, Matusik RJ, Giguère V 1994 Inhibition of nuclear hormone receptor activity by calreticulin. Nature 367:480–483[CrossRef][Medline]
  104. McDonnell DP, Vegeto E, O’Malley BW 1992 Identification of a negative regulatory function for steroid receptors. Proc Natl Acad Sci USA 89:10563–10567[Abstract]
  105. Keleher CA, Redd MJ, Schultz J, Carlson M, Johnson AD 1992 Ssn6-Tup1 is a general repressor of transcription in yeast. Cell 68:709–719[Medline]
  106. Edmondson DG, Smith MM, Roth SY 1996 Repression domain of the yeast global repressor Tup1 interacts directly with histones H3 and H4. Genes Dev 10:1247–1258[Abstract]
  107. Alland L, Muhle R, Hou HJ, Potes J, Chin L, Schreiber-Agus N, DePinho RA 1997 Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387:49–55[CrossRef][Medline]
  108. Heinzel T, Lavinsky RM, Mullen TM, Sädersträm M, Laherty CD, Torchia J, Yang W-M, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG 1997 A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43–48[CrossRef][Medline]
  109. Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL, Evans RM 1997 Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 89:373–380[Medline]
  110. Wong C-W, Privalsky ML 1998 Transcriptional repression by the SMRT-mSin3 corepressor: multiple interactions, multiple mechanisms, and a potential role for TFIIB. Mol Cell Biol 18:5500–5510[Abstract/Free Full Text]
  111. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG 1998 Fusion proteins of the retinoic acid receptor-{alpha} recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818[CrossRef][Medline]
  112. Lin RJ, Nagy L, Inoue S, Shao W, Miller WHJ, Evans RM 1998 Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811–814[CrossRef][Medline]
  113. Baniahmad A, Ha I, Reinberg D, Tsai S, Tsai M-Y, O’Malley BW 1993 Interaction of human thyroid hormone receptor ß with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. Proc Natl Acad Sci USA 90:8832–8836[Abstract]
  114. Muscat GEO, Burke LJ, Downes M 1998 The corepressor N-CoR and its variants RIP13a and RIP13Æ1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70. Nucleic Acids Res 26:2899–2907[Abstract/Free Full Text]
  115. Zamir I, Zhang J, Lazar MA 1997 Stoichiometric and steric princliples governing repression by nuclear hormone receptors. Genes Dev 11:835–846[Abstract]
  116. Montano M, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS 1999 An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci USA 96:6947–6952[Abstract/Free Full Text]
  117. Ogryzko VV, Kotani T, Zhang X, Schiltz RL, Howard T, Yang X-J, Howard BH, Quin J, Nakatani Y 1998 Histone-like TAFs within the PCAF histone acetylase complex. Cell 94:35–44[Medline]
  118. Voegel JJ, Heine MJ, Zechel C, Chambon P, Grone-meyer H 1996 TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 15:3667–3675[Abstract]
  119. Voegel JJ, Heine MJS, Tini M, Vivat V, Chambon P, Gronemeyer H 1998 The coactivator TIF2 contains three nuclear receptor-binding motifs and mediates transactivation through CBP binding-dependent and -independent pathways. EMBO J 17:507–519[Abstract/Free Full Text]
  120. Leers J, Treuter E, Gustafsson J-Å 1998 Mechanistic principles in NR box-dependent interaction between nuclear hormone receptors and the coactivator TIF2. Mol Cell Biol 18:6001–6013[Abstract/Free Full Text]
  121. Webb P, Nguyen P, Shinsaki J, Anderson C, Feng W, Nguyen MP, Chen D, Huang S-M, Subramanian S, McInerney E, Katsenellenbogen BS, Stallcup MR, Kushner PJ 1998 Estrogen receptor activation function 1 works by binding p160 coactivator proteins. Mol Endocrinol 12:1605–1618[Abstract/Free Full Text]
  122. Li H, Gomes PJ, Chen JD 1997 RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci USA 94:8479–8484[Abstract/Free Full Text]
  123. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS 1997 AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968[Abstract/Free Full Text]
  124. Suen C-S, Berrodin TJ, Mastroeni R, Cheskis BJ, Lyttle CR, Frail DE 1998 A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity. J Biol Chem 273:27645–27653[Abstract/Free Full Text]
  125. Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW 1997 TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J Biol Chem 272:27629–27634[Abstract/Free Full Text]
  126. Treuter E, Albrektsen T, Johansson L, Leers J, Gustafsson J-Å 1998 A regulatory role for RIP140 in nuclear receptor activation. Mol Endocrinol 12:864–881[Abstract/Free Full Text]
  127. Lee C-H, Chinpaisal C, Wei L-N 1998 Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol Cell Biol 18:6745–6755[Abstract/Free Full Text]
  128. Yeh S, Chang C 1996 Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci USA 93:5517–5521[Abstract/Free Full Text]
  129. Piña B, Berger SL, Marcus G, Silverman N, Agapite J, Guarente L 1993 ADA3: a gene identified by resistence to GAL4-VP16, with properties similar to and different from those of ADA2. Mol Cell Biol 13:5981–5989[Abstract]
  130. Eggert M, Mows CC, Tripier D, Arnold R, Michel J, Nickel J, Schmidt S, Beato M, Renkawitz R 1995 A fraction enriched in a novel glucocorticoid receptor-interacting protein stimulates receptor-dependent transcription in vitro. J Biol Chem 270:30755–30759[Abstract/Free Full Text]
  131. Lee JW, Choi HS, Gyuris J, Brent R, Moore DD 1995 Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol 9:243–254[Abstract]
  132. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM 1998 A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839[Medline]
  133. Castillo G, Brun RP, Rosenfeld JK, Hauser S, Won Park C, Troy AE, Wright ME, Spiegelman BM 1999 An adipogenic cofactor bound by the differentiation domain of PPAR{gamma}. EMBO J 18:3676–3687[Abstract/Free Full Text]
  134. Baniahmad C, Nawaz Z, Baniahmad A, Gleeson MA, Tsai MJ, O’Malley BW 1995 Enhancement of human estrogen receptor activity by SPT6: a potential coactivator. Mol Endocrinol 9:34–43[Abstract]
  135. Bortvin A, Winston F 1996 Evidence that Spt6p controls chromatin structure by a direct interaction with histones. Science 272:1473–1476[Abstract]
  136. Le Douarin B, Nielsen AL, Garnier JM, Ichinose H, Jeanmougin F, Losson R, Chambon P 1996 A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. EMBO J 15:6701–6715[Abstract]
  137. Neigeborn L, Carlson M 1984 Genes affecting the regulation of SUC2 gene expression by glucose repression in Saccharomyces cerevisiae. Genetics 108:845–858[Abstract/Free Full Text]
  138. Stern M, Jensen R, Herskowitz I 1984 Five SWI genes are required for expression of the HO gene in yeast. J Mol Biol 178:853–868[Medline]
  139. Ichinose H, Garnier JM, Chambon P, Losson R 1997 Ligand-dependent interaction between the estrogen receptor and the human homologues of SWI2/SNF2. Gene 188:95–100[CrossRef][Medline]
  140. Moilanen A-M, Poukka H, Karvonen U, Häkli M, Jänne OA, Palvimo J 1998 Identification of a novel RING finger protein as a coregulator in steroid receptor-mediated gene transcription. Mol Cell Biol 18:5128–5139[Abstract/Free Full Text]
  141. Huibregtse JM, Scheffner M, Beaudenon S, Howley PM 1995 A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc Natl Acad Sci USA 92:2563–2567[Abstract]
  142. Huang N, vom Baur E, Garnier J-M, Lerouge T, Vonesch J-L, Lutz Y, Chambon P, Losson R 1998 Two distinct nuclear receptor interacting domains in NSD1, a novel SET protein that exhibits characteristics of both corepressors and coactivator. EMBO J 17:3398–3412[Abstract/Free Full Text]
  143. Sande S, Privalsky ML 1996 Identification of TRACs, a family of co-factors that associate with, and modulate the activity of nuclear hormone receptors. Mol Endocrinol 10:813–825[Abstract]
  144. Park EJ, Schroen DJ, Yang M, Li H, Li L, Chen JD 1999 SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor. Proc Natl Acad Sci USA 96:3519–3524[Abstract/Free Full Text]
  145. Zamir I, Harding HP, Atkins GB, Härlein A, Glass CK, Rosenfeld MG, Lazar MA 1996 A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Mol Cell Biol 16:5458–5465[Abstract]
  146. Schultz J, Carlson M 1987 Molecular analysis of SSN6, a gene functionally related to the SNF1 protein kinase of Saccharomyces cerevisiae. Mol Cell Biol 7:3637–3645[Medline]