Coregulator Interactions with the Thyroid Hormone Receptor

Jamie M. R. Moore{ddagger} and R. Kiplin Guy§,

From the {ddagger} Department of Late Stage Formulation Development, Genentech, South San Francisco, California 94080 and the § Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143


    ABSTRACT
 TOP
 ABSTRACT
 TR INTERACTION WITH COREGULATORS
 QUANTITATION OF THE INTERACTIONS...
 CONCLUSIONS
 REFERENCES
 
The thyroid hormone receptor (TR) directly regulates the transcription of thyroid hormone-responsive genes in response to changing levels of thyroid hormone. Mechanistically TR utilizes a complex set of binding interactions, with hormone, response elements, and coregulatory proteins, to provide specific local control of patterns of transcriptional response that are partially responsible for inducing the tissue-selective responses to the circulating hormone. One of the apparently dominant phenomena in the regulation of thyroid hormone responses is the protein interactions between TR and its coregulators. This review summarizes the current state of knowledge with respect to the identity of these coregulators, their interaction with TR, and the consequences of those interactions.


Thyroid hormone controls essential functions in growth, development, and metabolism and is important for normal function of almost all tissues (1, 2). Most of the effects of thyroid hormone (TH)1 are relatively slow in onset and mediated by a family of high affinity receptor proteins known as the thyroid hormone receptors (TRs) that act directly as transcription factors (3). However, recent work has demonstrated that metabolites of thyroid hormone can also exert rapid biological effects through the G-protein-coupled receptors that act through secondary messenger pathways (4). This review focuses on the classic transcription regulation pathways controlled by the TRs.

The TRs belong to the large superfamily of nuclear hormone receptors that regulate gene transcription (58). These proteins control a diverse set of target genes in response to specific physiological signals. Family members include the endocrine receptors, such as the estrogen (ER) and androgen (AR) receptors; the adopted orphan receptors, such as the retinoid X receptor (RXR) and peroxisome proliferator-activated receptor (PPAR); and the orphan receptors, receptors that do not require an endogenous ligand or for which a ligand has yet to be identified, such as steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1) (9, 10).

Like nearly all NRs, TRs contain three major domains (Fig. 1A): a ligand-independent amino-terminal transactivation domain, a central DNA binding domain, and a carboxyl-terminal ligand binding domain that adjusts transactivation in response to ligand. There are two different genes that express different TR subtypes, TR{alpha} and TRß (11). Each transcript can be alternatively spliced generating different isoforms (TR{alpha}1, TR{alpha}2, TRß1, and TRß2), which differ most in the composition of the amino-terminal transactivation domain and the far carboxyl-terminal region of the ligand binding domain. While the isoforms are detectably expressed in almost all tissues they do have isoform-specific patterns of dominant expression. TR{alpha}1 is expressed most heavily in skeletal muscle and brown fat, while TR{alpha}2 is most highly expressed in the brain. TRß1 is the most widely distributed subtype but is most highly expressed in the brain, liver, and kidney. TRß2 is expressed almost exclusively in the pituitary and hypothalamus in adults. While TR{alpha}1, TRß1, and TRß2 bind TH with similar affinity, TR{alpha}2 does not bind to TH and is believed to inhibit the action other TRs.



View larger version (21K):
[in this window]
[in a new window]
 
FIG. 1. TR structure and regulation of gene transcription. A, diagram of the primary structure of the TR subtypes. The majority of the variation is in the A/B and F regions. Note that the one subtype with a highly variant E/F region ({alpha}2) does not bind triiodothyronine and is thought to act mostly through competitive inhibition of the action of the other subtypes. B, mechanism of TR transcriptional control. TR forms a heterodimer complex with RXR that recognizes specific TREs. In the absence of TH, this complex is associated with corepressors that repress transcription of the TRE-regulated gene. Upon binding of TH, TR undergoes a conformational change, releasing corepressors and allowing for the interaction of coactivators required for maximal gene activation. AF, activation function; LBD, ligand binding domain; NTD, amino-terminal transactivation domain; T3, triiodothyronine.

 
A number of transgenic and knock-out mouse models have provided information on TR isoform-specific functions, and these have been reviewed (12, 13). In general, the studies show that the TR{alpha} and TRß isoforms have distinct, non-redundant, and tissue-specific functions. Specifically it has been shown that TR{alpha} is an important regulator of heart function, influencing heart rate and contractility. On the other hand, TRß appears to be a key regulator of hypothalamus-pituitary-thyroid feedback regulation and plasma cholesterol levels (3). One striking feature of the knock-out studies is that deletion of both TR{alpha} and TRß induces only mild hypothyroidism and relatively viable animals, much more so than many of the single knock-outs (1417). This points to the importance of repression of transcription by unliganded TR as a mechanism for thyroid hormone function. To take advantage of these clinical implications, isoform-specific ligands such as the TRß-selective agonist GC-1 have been designed to reduce serum cholesterol levels without deleterious effects on the heart (18).

The TR DNA binding domain recognizes and interacts with short, repeated sequences of DNA found in thyroid hormone-responsive genes, termed the thyroid hormone response elements (TREs) (19). TR can bind to this half-site, AGGTCA, as a monomer, a homodimer, or a heterodimer with the RXR (20). In the absence of thyroid hormone, the TR/RXR heterodimer is associated with corepressor proteins at the TRE (21). These corepressor proteins interact with TR and RXR and recruit large multiprotein complexes containing histone deacetylase activity that maintain the chromatin in a compact state repressing gene activation. Upon binding of thyroid hormone, TR undergoes a conformational change, releasing corepressor proteins and allowing for the interaction with coactivator proteins that enhance TRE-driven gene transcription (Fig. 1B) (22). It is the control of the interactions of the TR with its coregulatory proteins that ultimately defines the transcription of individual genes. Herein we focus on defining TR coregulator interactions by organizing the available data and providing simple conclusions about the potential in vivo affects of TR coregulators.


    TR INTERACTION WITH COREGULATORS
 TOP
 ABSTRACT
 TR INTERACTION WITH COREGULATORS
 QUANTITATION OF THE INTERACTIONS...
 CONCLUSIONS
 REFERENCES
 
Coactivators
The regulation of gene expression by TR involves interaction with a complex network of coregulator proteins (Fig. 1B). These coregulators can either enhance (coactivators) or repress (corepressors) TR-driven gene transcription. Structural, biochemical, and genetic studies have provided a considerable amount of information about TR-coregulator interactions.

The best studied coactivators belong to the p160 protein family of steroid receptor coactivators (SRCs) (2325). Members of this family include SRC1, (26) SRC2 (GRIP1/TIF2) (27, 28), and SRC3 (AIB1/TRAM1/RAC3/ACTR) (2934). These proteins contain several functional domains including the nuclear receptor interaction domain and activation domains that interact with other coregulatory proteins (Fig. 2). Within the nuclear receptor interaction domain, there are three repeated motifs with the consensus sequence LXXLL, often termed the NR box. In addition there is a unique fourth LXXLL motif found in the extreme carboxyl terminus of an alternatively spliced variant of SRC1, SRC1a. Several investigations have shown that the LXXLL motif is necessary and sufficient for interaction with NR (35, 36). Specifically it has been demonstrated that peptides comprised of LXXLL motifs from the SRC2 family bind to TR with comparable affinities to full-length SRC2 protein (36). Structural characterization of this interaction revealed that the LXXLL motif of SRC2–2 (second NR box of SRC2) binds to a hydrophobic groove in the ligand binding domain of TRß as an {alpha}-helix (37). In addition to the p160 family, several other coactivator proteins have been shown to interact with TR utilizing LXXLL motifs (NR box). The current state of knowledge for individual coactivators is summarized below and in Table I.



View larger version (12K):
[in this window]
[in a new window]
 
FIG. 2. Functional domains of the steroid receptor coactivator family. The primary structure of SRC1 is displayed with some of the important functional domains highlighted. The amino terminus contains highly conserved basic helix loop helix (bHLH) and PAS A/B domains These domains are believed to function as DNA binding domains or protein-protein interaction surfaces for other transcription factors. The central nuclear interaction domain (NID) contains three nuclear receptor interaction motifs, LXXLL (NR boxes), that are known to interact with NR (the nomenclature for NR boxes is such that the most amino-terminal NR box has a -1 appended to the protein name, e.g. SRC1-1, and so on). In addition, SRC1 has two isoforms, SRC1a and SRC1e. SRC1a has an additional NR box at the carboxyl terminus designated SRC1-4 that has been shown to interact with some NRs. In addition there are two activation function domains (AD1 and AD2) that serve as protein-protein interaction surfaces for other coregulator proteins (25).

 

View this table:
[in this window]
[in a new window]
 
TABLE I Coregulator proteins that interact with thyroid hormone receptors

RTH, resistance to thyroid hormone; TSH, thyroid-stimulating hormone; CRABPI, cellular retinoic acid-binding protein I; VDR, vitamin D3 receptor.

 
SRC1—
SRC1 (also known as NcoA-1) was first identified as a coactivator for the progesterone receptor using a yeast two-hybrid system (26) and was subsequently shown to enhance the transcriptional activity of many nuclear receptors (Table I). Specific interactions with TR were established using microinjection assays and mammalian two-hybrid systems (38, 39). These studies demonstrated that the second and third NR boxes (SRC1-2 and SRC1-3) were required for interaction with TR and suggested amino acids residing carboxyl-terminal of the LXXLL motif were critical for specificity. The binding affinities of individual NR boxes from SRC1 for TRß were recently determined using a quantitative method with SRC1-2 > SRC1-3 > SRC1-1 (40).

SRC1 null mice have provided further evidence that SRC1 is a critical coactivator required for TR regulation. Mice deficient in SRC1 exhibit partial resistance to sex steroid hormones and have features of resistance to thyroid hormone such as elevated free TH and thyroid-stimulating hormone (16). However, SRC1 does not globally affect all TH-responsive genes, and its effects appear to vary with TR isoforms. In the liver, SRC1 regulates the lipogenic enzyme Spot 14 but has no impact on malic enzyme or type 1 iodothyronine 5'-deiodinase levels. Similarly in the pituitary, SRC1 is linked to the regulation of thyroid-stimulating hormone but not growth hormone (41). In the heart, SRC-1 modulates both TR{alpha} and TRß effects on heart rate but does not appear to influence other inotropic and chronotropic cardiac genes (41, 42).

SRC2—
SRC2, also known as GRIP-1 (mouse) (28) and TIF-2/NCoA-2 (human), (27) interacts with many NRs including AR, ER, GR, PR, RAR, SF-1, and TR. Yeast two-hybrid systems, mammalian transfection assays, and glutathione S-transferase pull-down assays have demonstrated that SRC2 strongly interacts with TR with relative NR box affinities of SRC2-2 > SRC2-3 > SRC2-1 (36, 43). More quantitatively determined binding affinities of NR box peptides of SRC2 to TR are consistent with these studies and revealed that NR boxes from SRC2 bind with comparatively higher affinities than all of the SRC1 NR box peptides (40).

It has been suggested that SRC1 and SRC2 are functionally redundant based on their high amino acid homology in their carboxyl-terminal domains (50%) and increased expression levels of SRC2 observed in an SRC1 knock-out mouse (4446). Although there is partial functional overlap between these two coactivators, it is clear that they also regulate different pathways. Mice deficient in either SRC1 or SRC2 have distinct phenotypes, and unlike SRC1 null mice SRC2 null mice display normal thyroid function (42, 46). In addition, these coactivators have differential tissue expression levels, potentially linking SRC2 to TR-regulated genes in the liver (47).

SRC3—
The third member of the SRC family was simultaneously discovered by several groups, and hence there are several names associated with SRC3 (p/CIP (mouse homolog) and RAC3, ACTR, AIB-1, and TRAM-1 (human isoforms)) (2934). A far-Western approach combined with glutathione S-transferase pull-down assays established SRC3 as a coactivator for TR (30). In vitro relative affinities of SRC3 NR boxes for TR were recently determined with SRC3-2 > SRC3-1 and SRC3-3. The binding affinities of SRC3 NR box peptides for TR are weaker or comparable to SRC1 NR box peptides (40).

The expression of SRC3 follows a more restricted tissue pattern than the other SRC family members. High levels of SRC3 are found only in the oocytes, mammary gland, hippocampus, olfactory bulbs, smooth muscle, hepatocytes, and vaginal epithelium. Consequently mice deficient in SRC3 have a distinct phenotype of dwarfism, delayed puberty, and abnormal reproductive functions (48). Recent in vivo studies suggest that SRC3 may be involved in regulating TR genes in the liver (47).

Thyroid Hormone Receptor-associated Protein (TRAP) 220—
The TRAP complex is a large multisubunit complex that has been shown to act as a general coactivator for many transcription factors (49). One of the proteins in this complex, TRAP220 (DRIP205/PBP) interacts with many NRs including ER, PPAR, RAR, RXR, TR, and vitamin D3 receptor through two distinct LXXLL motifs (50). The use of glutathione S-transferase pull-down assays demonstrated that NRs have different affinities for TRAP220 NR boxes. It was shown that RXR strongly interacts with the first NR box of TRAP220 (TRAP220-1), while TR{alpha} prefers the second LXXLL motif (TRAP220-2). In addition, recent in vitro binding assays have revealed that TR isoforms also have unique NR box preferences with TRß more strongly recruiting TRAP220-1 (40). Both homozygous disruption of TRAP220 and conditional hypomorphic expression of TRAP220 are embryonically lethal due to developmental defects in the liver and heart, perhaps indicating a role for this coactivator in thyroid function in these tissues (51).

Peroxisome Proliferator-activated Receptor-{gamma} Coativator-1 (PGC-1)—
PGC-1 is a unique coactivator with tissue-specific expression that can be induced by external stimuli such as exposure to cold temperatures and exercise (52). This coactivator was originally identified as a PPAR-specific coactivator, but it has been subsequently shown to interact with a broader array of NRs and has been linked to important physiological pathways including adaptive thermogenesis and hepatic gluconeogenesis (5254). Several groups have shown that TR can interact with PGC-1 in a ligand-dependent fashion via its one LXXLL motif (40, 55). In addition, it is believed that PGC-1 can also potentiate TR activity in a ligand-independent manner utilizing domains outside of the LXXLL motif in PGC-1 and ligand binding domain of TR (55).

Thyroid Hormone Receptor-binding Protein (TRBP)—
TRBP, also known as PRIP, was identified as a TR coactivator in a yeast two-hybrid system. This coactivator contains one LXXLL motif that interacts fairly strongly with TRß (40, 56). TRBP is believed to be a general coactivator capable of activating several transcriptional factors in addition to NR. Homologous disruption of TRBP leads to embryonic lethality due to failure to develop a normal placenta (57).

p300—
p300/CBP has been termed a cointegrator because of its ability to form intranuclear complexes between nuclear receptors and transcriptional machinery (58). In addition, p300 has intrinsic histone acetyltransferase activity capable of modifying chromatin for gene transcription. Although in vitro binding studies have linked the interaction of p300 with NR, the precise physiological role of this interaction in thyroid signaling is not fully understood. There are some indications this cofactor may be required for myogenesis (59).

Androgen Receptor Activator 70 (ARA70)—
ARA70 contains one LXXLL motif that has been shown to additionally interact with ER, PPAR, and TR (40, 60). Fusions of ARA70 have been associated with radiation-induced thyroid cancers (61). The precise role of ARA70 for TR function has not been elucidated.

Other Coregulators—
There are several other coactivators known to interact with TR including Trip1/Sug1, RAP46/BAG-1, E6-AP, and translocated-in-liposarcoma (TLS). These coactivators do not contain LXXLL motifs, and in many cases the mechanism for activation of TR has not been worked out.

Trip1/Sug1 was identified as thyroid-interacting protein 1 through a yeast two-hybrid system (62). It appears to interact with the ligand binding domain of TR in a ligand-dependent manner. Trip1 may be involved in the removal of ubiquitinated proteins from DNA by recruiting 26 S proteasome and therefore may be important for selectively targeting TR at a TRE for degradation or processing (63).

RAP46/BAG-1 belongs to a family of co-chaperones that contain a conserved carboxyl-terminal domain that can interact and inhibit the action of the molecular chaperone HSP70 (64). It appears that RAP46 uses multiple mechanisms to both enhance and repress transcriptional activity of NR.

E6-AP belongs to the E3 ubiquitin-protein ligase family and can enhance transcriptional activity of AR, ER, GR, PR, RAR, and TR (65). However, it has been shown that the ubiquitin-protein ligase function is not required for activation of NR. The mechanism for E6-AP coactivator function has yet to be defined. Homozygous disruption of E6-AP affects sex steroid signaling but has no readily apparent effects upon thyroid metabolism or signaling.

TLS was identified as a coactivator for RXR and TR using glutathione S-transferase pull-down assays (66). This coactivator belongs to the ribonucleoprotein family of RNA-binding proteins, and it is believed to be involved in RNA processing. Its precise function in TR signaling has not been investigated. Homozygous disruption of TLS has no readily apparent thyroid-related phenotype.

Corepressors
Repression of TR-regulated genes has been shown to be both ligand-independent and ligand-dependent (6769). In the absence of ligand, TR is associated with corepressor proteins such as nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) (70, 71). These proteins contain amino-terminal repression domains and carboxyl-terminal nuclear receptor interaction domains. Within the nuclear receptor interaction domains are repeated motifs, (I/L)XX(I/V)I, termed CoRNR boxes, that are required for interaction with nuclear receptors (21). This motif is analogous to the coactivator motif, and structural studies have demonstrated that the binding site for coactivators and corepressors partially overlap (72).

The mechanism for thyroid hormone-dependent negative regulation of genes has yet to be fully elucidated. Several models have been postulated (73). One of these models suggests that liganded TR can associate with LXXLL-containing coregulators that are capable of repressing gene transcription by directly competing with other known coactivators. Some of these coregulators include receptor interacting protein 140 (RIP140), small heterodimer partner (SHP), and dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region of the X chromosome (DAX) 1.

NCoR and SMRT—
The interaction of NCoR and SMRT with TR has been extensively studied (21, 7476). NCoR and SMRT both contain two nuclear hormone receptor interaction domains (CoRNR domains) that form an extended helical motif. Biochemical and cellular studies have shown that unliganded TR preferentially interacts with NCoR to repress basal transcription of target genes. Specifically it has been shown by several groups that TR interacts strongly with the first CoRNR motif in NCoR (21, 75). This preference is believed to derive from an additional NCoR interaction domain, termed N3, found upstream of CoRNR-1. This domain is not present in SMRT and appears to be specific for TR interaction.

To date there is very little information on repression of specific TR target genes by NCoR. The use of a dominant negative mutant NCoRi, however, has provided information of NCoR effects on TR hepatic target genes (77). This study demonstrated that NCoR represses basal transcription of Spot 14, Bcl-3, glucose 6-phosphate, and 5'-deiodinase. Additionally it appears that NCoR also prevents cellular proliferation of hepatocytes. An increased endogenous level of SMRT in the presence of NCoRi suggests a compensatory role for SMRT. These results provide the first evidence that NCoR represses basal transcription of TR target genes in vivo. Homozygous disruption of NCoR is embryonically lethal without obvious connection to thyroid signaling pathways (78).

RIP140—
RIP140 was originally identified in breast cancer cell lines and isolated using the ligand binding domain of ER (79). It was subsequently shown to be ubiquitously expressed and able to interact with a number of different NRs. RIP140 contains nine LXXLL motifs and is recruited to NR through these domains in a ligand-dependent manner. However, unlike coactivators, RIP140 represses transcriptional activity (8083). Quantitative in vitro binding assays determined that TR strongly interacts with NR box 5 in RIP140 and weakly interacts with the RIP140-3 and RIP140-8 (40). The remaining NR boxes in RIP140 do not interact with TR. Disruption of the RIP140 gene gives mice that are viable but undersized and infertile due to problems with ovulation (84). There was no demonstrated connection between the phenotype and thyroid hormone signaling.

Recently the interaction of TR and RIP140 was linked to the regulation of retinoic acid levels. Studies conducted in P19 embryonic carcinoma cells demonstrated that overexpression of RIP140 suppressed TH induction of cellular retinoic acid-binding protein I, a protein thought to control intracellular retinoic acid levels (85).

DAX-1—
DAX-1 is an orphan nuclear receptor lacking a traditional DNA binding domain. DAX-1 is recruited to nuclear receptors, such as ER, LRH-1, and SF-1, and represses gene transcription (8688). There are four LXXLL-like motifs found in DAX-1. Recently it was shown that TR is also capable of interacting with some of the DAX-1 NR boxes in the presence of TH. Specifically TR strongly interacts with DAX-1-3, while only weak binding was observed with the remaining NR boxes (40).

Studies using mouse Leydig tumor cells explored TR regulation of steroidogenesis and demonstrated that TH can induce expression of steroidogenesis acute regulatory protein and SF-1. Overexpression of DAX-1, however, diminished the TH-mediated responses (89). It remains unclear whether DAX-1 directly interacts with TR to elicit this response or acts indirectly by inhibiting SF-1.

SHP—
SHP is also an orphan nuclear receptor lacking the highly conserved DNA binding domain. It is believed that SHP can interact with a variety of NRs to repress transcriptional activity through an LXXLL motif found in the amino terminus (90, 91). SHP exerts its inhibitory affect through a two-step mechanism (92). The first step is direct interaction of SHP with the activation function-2 of NR where it has been shown to compete with coregulator proteins. The final step requires the autonomous repression function of SHP. A variety of in vivo and in vitro tests have shown that SHP interacts with and represses gene activation of ER, LRH-1, RAR, RXR, SF-1, and TR. The precise physiological response of TR-SHP interaction has not been documented.


    QUANTITATION OF THE INTERACTIONS OF TR AND COREGULATORS
 TOP
 ABSTRACT
 TR INTERACTION WITH COREGULATORS
 QUANTITATION OF THE INTERACTIONS...
 CONCLUSIONS
 REFERENCES
 
The majority of the work discussed in the preceding section has involved indirect or heterogeneous, non-quantitative methods for measuring the interaction of TR with cofactors in the presence or absence of ligands. In general these methods allow one to determine the likelihood of occupancy and the importance of interactions but not to determine relative affinities and thus predict the implications of potential competitions for limiting binding sites. Some work, including our own (40), as summarized above has dealt with the issue of relative affinities and with the change of affinity in response to variations in ligand structure.

To date, these data exist only for TRß with two ligands (triiodothyronine and the TRß-selective agonist GC-1) and for ER{alpha} with estradiol. Carrying out these studies with the full range of NR box structures has allowed the determination of consensus NR box sequences that drive the binding of coregulators by particular NR·ligand pairs. The consensus results of the studies with TR are presented in Fig. 3 along with the ER/estradiol results for comparison. TRß itself requires three distinct residues outside the canonical LXXLL motif of the NR box for strong recruitment of a cofactor: a histidine-proline pair spaced one residue amino-terminal of the first leucine of the motif and a glutamine immediately carboxyl-terminal of the last leucine of the motif. In addition to these defined amino acids, strongly recruited cofactors include within their NR box a hydrophobic amino acid immediately amino-terminal to the LXXLL motif and a series of hydrophilic amino acids after the requisite glutamine. One of the most interesting findings when one compares the results of examining the pattern of cofactor recruitment by TRß when liganded with GC-1 with that just discussed is that the requirement for the histidine-proline pair no longer holds. That is to say that GC-1 still recruits NR box-containing cofactors to TRß, but the molecular mechanism of the recruitment and the pattern of preferred cofactors have changed.



View larger version (9K):
[in this window]
[in a new window]
 
FIG. 3. Determinants of the specificity of the interaction of TR with its coactivators. Shown is a summary of all existing proteomic data concerning the role of the NR box sequences in modulating interaction with the liganded receptors. Representative coregulator peptides are listed for TRß·triiodothyronine (T3), TRß·GC-1, and ER{alpha}·estradiol (E2) with amino acids highlighted in red representing amino acids that convey specificity for each NR·ligand state. {Phi} denotes hydrophobic amino acids, and {zeta} represents hydrophilic amino acids.

 
A major caveat to conclusions drawn from existing work is that all quantitative measurements to date have been garnished from the study of protein-peptide binding using NR box peptides, whereas the qualitative work has mostly been done with either the NR box-containing domain (typically holding one to three NR boxes) or intact protein. While the binding constants determined for peptide and full-length protein have always been in good agreement, some aspects of the interaction, particularly cooperativity, may not be faithfully modeled with the simpler peptide system. This may have particular significance with regard to the interaction of retinoid and thyroid signaling.


    CONCLUSIONS
 TOP
 ABSTRACT
 TR INTERACTION WITH COREGULATORS
 QUANTITATION OF THE INTERACTIONS...
 CONCLUSIONS
 REFERENCES
 
The work reviewed above shows that the field now has a fairly strong model relating the interaction of particular transcriptional coactivators and corepressors with the liganded TR and explaining how these might affect transcription. The recent emergence of fairly comprehensive quantitative data has allowed one to begin to make predictions about the effects of perturbing these interactions in terms of affected physiology. Likewise a number of studies have monitored the global transcriptional response to THs, particularly triiodothyronine, in a variety of settings. What is missing from the field right now is a comprehensive model relating the changes in cofactor interactions with the activation of particular genes. It is only in such a relational model that the proteomics of this pathway will be fully useful. Hopefully such a model will emerge from ongoing work in the not distant future.


    FOOTNOTES
 
Received, January 7, 2005

Published, January 18, 2005

Published, MCP Papers in Press, January 18, 2005, DOI 10.1074/mcp.R500001-MCP200

1 The abbreviations used are: TH, thyroid hormone; AR, androgen receptor; ARA, androgen receptor activator; CBP, cAMP-response element-binding protein (CREB)-binding protein; DAX, dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region of the X chromosome; ER, estrogen receptor; GR, glucocorticoid receptor; LRH-1, liver receptor homolog 1; NCoR, nuclear receptor corepressor; NR, nuclear hormone receptor; PGC, PPAR{gamma} coactivator; PPAR, peroxisome proliferator-activated receptor; PR, progesterone receptor; RAR, retinoid A receptor; RIP, receptor-interacting protein; RXR, retinoid X receptor; SF-1, steroidogenic factor 1; SHP, small heterodimer partner; SMRT, silencing mediator of retinoid and thyroid hormone receptors; SRC, steroid receptor coactivator; TLS, translocated-in-liposarcoma; TR, thyroid hormone receptor; TRAP, thyroid hormone receptor-associated protein; TRE, thyroid response element; TRBP, thyroid hormone receptor-binding protein. Back

To whom correspondence should be addressed. Tel.: 415-502-7051; Fax: 415-514-0689; E-mail: rguy{at}cgl.ucsf.edu


    REFERENCES
 TOP
 ABSTRACT
 TR INTERACTION WITH COREGULATORS
 QUANTITATION OF THE INTERACTIONS...
 CONCLUSIONS
 REFERENCES
 

  1. Malm, J. (2004) Thyroid hormone ligands and metabolic diseases. Curr. Pharm. Des. 10, 3525 –3532[CrossRef][Medline]

  2. Werner, S. C., Ingbar, S. H., Braverman, L. E., and Utiger, R. D. (2004) Werner & Ingbar’s the Thyroid: a Fundamental and Clinical Text, 9th Ed., Lippincott Williams & Wilkins, Philadelphia

  3. Harvey, C. B., and Williams, G. R. (2002) Mechanism of thyroid hormone action. Thyroid 12, 441 –446[CrossRef][Medline]

  4. Scanlan, T. S., Suchland, K. L., Hart, M. E., Chiellini, G., Huang, Y., Kruzich, P. J., Frascarelli, S., Crossley, D. A., Bunzow, J. R., Ronca-Testoni, S., Lin, E. T., Hatton, D., Zucchi, R., and Grandy, D. K. (2004) 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med. 10, 638 –642[CrossRef][Medline]

  5. Aranda, A., and Pascual, A. (2001) Nuclear hormone receptors and gene expression. Physiol. Rev. 81, 1269 –1304[Abstract/Free Full Text]

  6. Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., and Evans, R. M. (1995) The nuclear receptor superfamily: the second decade. Cell 83, 835 –839[CrossRef][Medline]

  7. Walters, M. R., and Nemere, I. (2004) Receptors for steroid hormones: membrane-associated and nuclear forms. Cell Mol. Life Sci. 61, 2309 –2321[Medline]

  8. Freedman, L. P. (1998) Molecular Biology of Steroid and Nuclear Hormone Receptors. Progress in Gene Expression, p. xvi, Birkhauser, Boston

  9. Gronemeyer, H., Gustafsson, J. A., and Laudet, V. (2004) Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discov. 3, 950 –964[CrossRef][Medline]

  10. Shiau, A. K., Coward, P., Schwarz, M., and Lehmann, J. M. (2001) Orphan nuclear receptors: from new ligand discovery technologies to novel signaling pathways. Curr. Opin. Drug Discov. Dev. 4, 575 –590[Medline]

  11. Lazar, M. A. (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr. Rev. 14, 184 –193[CrossRef][Medline]

  12. Flamant, F., and Samarut, J. (2003) Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol. Metab. 14, 85 –90[CrossRef][Medline]

  13. Brent, G. A. (2000) Tissue-specific actions of thyroid hormone: insights from animal models. Rev. Endocr. Metab. Disord. 1, 27 –33[CrossRef][Medline]

  14. Gothe, S., Wang, Z., Ng, L., Kindblom, J. M., Barros, A. C., Ohlsson, C., Vennstrom, B., and Forrest, D. (1999) Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev. 13, 1329 –1341[Abstract/Free Full Text]

  15. Plateroti, M., Chassande, O., Fraichard, A., Gauthier, K., Freund, J. N., Samarut, J., and Kedinger, M. (1999) Involvement of T3R{alpha}- and ß-receptor subtypes in mediation of T3 functions during postnatal murine intestinal development. Gastroenterology 116, 1367 –1378[Medline]

  16. Gauthier, K., Chassande, O., Plateroti, M., Roux, J. P., Legrand, C., Pain, B., Rousset, B., Weiss, R., Trouillas, J., and Samarut, J. (1999) Different functions for the thyroid hormone receptors TR{alpha} and TRß in the control of thyroid hormone production and post-natal development. EMBO J. 18, 623 –631[Abstract/Free Full Text]

  17. Johansson, C., Gothe, S., Forrest, D., Vennstrom, B., and Thoren, P. (1999) Cardiovascular phenotype and temperature control in mice lacking thyroid hormone receptor-ß or both {alpha}1 and ß. Am. J. Physiol. 276, H2006 –H2012[Medline]

  18. Trost, S. U., Swanson, E., Gloss, B., Wang-Iverson, D. B., Zhang, H., Volodarsky, T., Grover, G. J., Baxter, J. D., Chiellini, G., Scanlan, T. S., and Dillmann, W. H. (2000) The thyroid hormone receptor-ß-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141, 3057 –3064[Abstract/Free Full Text]

  19. Tsai, M. J., and O’Malley, B. W. (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63, 451 –486[CrossRef][Medline]

  20. Umesono, K., Murakami, K. K., Thompson, C. C., and Evans, R. M. (1991) Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65, 1255 –1266[CrossRef][Medline]

  21. Hu, X., and Lazar, M. A. (1999) The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402, 93 –96[CrossRef][Medline]

  22. Ribeiro, R. C., Apriletti, J. W., Wagner, R. L., West, B. L., Feng, W., Huber, R., Kushner, P. J., Nilsson, S., Scanlan, T., Fletterick, R. J., Schaufele, F., and Baxter, J. D. (1998) Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies. Recent Prog. Horm. Res. 53, 351 –394[Medline]

  23. Xu, J., and Li, Q. (2003) Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol. Endocrinol. 17, 1681 –1692[Abstract/Free Full Text]

  24. Stallcup, M. R., Kim, J. H., Teyssier, C., Lee, Y. H., Ma, H., and Chen, D. (2003) The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. J. Steroid Biochem. Mol. Biol. 85, 139 –145[CrossRef][Medline]

  25. Leo, C., and Chen, J. D. (2000) The SRC family of nuclear receptor coactivators. Gene (Amst.) 245, 1 –11[CrossRef][Medline]

  26. Onate, S. A., Tsai, S. Y., Tsai, M. J., and O’Malley, B. W. (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354 –1357[Abstract]

  27. Voegel, J. J., Heine, M. J., Zechel, C., Chambon, P., and Gronemeyer, 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]

  28. Hong, H., Kohli, K., Garabedian, M. J., and Stallcup, M. R. (1997) GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol. Cell. Biol. 17, 2735 –2744[Abstract]

  29. Suen, C. S., Berrodin, T. J., Mastroeni, R., Cheskis, B. J., Lyttle, C. R., and Frail, D. E. (1998) A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity. J. Biol. Chem. 273, 27645 –27653[Abstract/Free Full Text]

  30. Takeshita, A., Cardona, G. R., Koibuchi, N., Suen, C. S., and Chin, W. W. (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]

  31. Anzick, S. L., Kononen, J., Walker, R. L., Azorsa, D. O., Tanner, M. M., Guan, X. Y., Sauter, G., Kallioniemi, O. P., Trent, J. M., and Meltzer, P. S. (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277, 965 –968[Abstract/Free Full Text]

  32. Chen, H., Lin, R. J., Schiltz, R. L., Chakravarti, D., Nash, A., Nagy, L., Privalsky, M. L., Nakatani, Y., and Evans, R. M. (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[CrossRef][Medline]

  33. Li, H., Gomes, P. J., and Chen, J. D. (1997) RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc. Natl. Acad. Sci. U. S. A. 94, 8479 –8484[Abstract/Free Full Text]

  34. Torchia, J., Rose, D. W., Inostroza, J., Kamei, Y., Westin, S., Glass, C. K., and Rosenfeld, M. G. (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677 –684[CrossRef][Medline]

  35. Heery, D. M., Kalkhoven, E., Hoare, S., and Parker, M. G. (1997) A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733 –736[CrossRef][Medline]

  36. Darimont, B. D., Wagner, R. L., Apriletti, J. W., Stallcup, M. R., Kushner, P. J., Baxter, J. D., Fletterick, R. J., and Yamamoto, K. R. (1998) Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 12, 3343 –3356[Abstract/Free Full Text]

  37. Wagner, R. L., Apriletti, J. W., McGrath, M. E., West, B. L., Baxter, J. D., and Fletterick, R. J. (1995) A structural role for hormone in the thyroid hormone receptor. Nature 378, 690 –697[CrossRef][Medline]

  38. McInerney, E. M., Rose, D. W., Flynn, S. E., Westin, S., Mullen, T. M., Krones, A., Inostroza, J., Torchia, J., Nolte, R. T., Assa-Munt, N., Milburn, M. V., Glass, C. K., and Rosenfeld, M. G. (1998) Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev. 12, 3357 –3368[Abstract/Free Full Text]

  39. Northrop, J. P., Nguyen, D., Piplani, S., Olivan, S. E., Kwan, S. T., Go, N. F., Hart, C. P., and Schatz, P. J. (2000) Selection of estrogen receptor ß- and thyroid hormone receptor ß-specific coactivator-mimetic peptides using recombinant peptide libraries. Mol. Endocrinol. 14, 605 –622[Abstract/Free Full Text]

  40. Moore, J. M., Galicia, S. J., McReynolds, A. C., Nguyen, N. H., Scanlan, T. S., and Guy, R. K. (2004) Quantitative proteomics of the thyroid hormone receptor-coregulator interactions. J. Biol. Chem. 279, 27584 –27590[Abstract/Free Full Text]

  41. Takeuchi, Y., Murata, Y., Sadow, P., Hayashi, Y., Seo, H., Xu, J., O’Malley, B. W., Weiss, R. E., and Refetoff, S. (2002) Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T3-regulated transcription of genes in vivo. Endocrinology 143, 1346 –1352

  42. Sadow, P. M., Chassande, O., Gauthier, K., Samarut, J., Xu, J., O’Malley, B. W., and Weiss, R. E. (2003) Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action. Am. J. Physiol. 284, E36 –E46

  43. Ding, X. F., Anderson, C. M., Ma, H., Hong, H., Uht, R. M., Kushner, P. J., and Stallcup, M. R. (1998) Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol. Endocrinol. 12, 302 –313[Abstract/Free Full Text]

  44. Glass, C. K., Rose, D. W., and Rosenfeld, M. G. (1997) Nuclear receptor coactivators. Curr. Opin. Cell Biol. 9, 222 –232[CrossRef][Medline]

  45. Weiss, R. E., Xu, J., Ning, G., Pohlenz, J., O’Malley, B. W., and Refetoff, S. (1999) Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone. EMBO J. 18, 1900 –1904[Abstract/Free Full Text]

  46. Weiss, R. E., Gehin, M., Xu, J., Sadow, P. M., O’Malley, B. W., Chambon, P., and Refetoff, S. (2002) Thyroid function in mice with compound heterozygous and homozygous disruptions of SRC-1 and TIF-2 coactivators: evidence for haploinsufficiency. Endocrinology 143, 1554 –1557[Abstract/Free Full Text]

  47. Sadow, P. M., Chassande, O., Koo, E. K., Gauthier, K., Samarut, J., Xu, J., O’Malley, B. W., and Weiss, R. E. (2003) Regulation of expression of thyroid hormone receptor isoforms and coactivators in liver and heart by thyroid hormone. Mol. Cell. Endocrinol. 203, 65 –75[CrossRef][Medline]

  48. Xu, J., Liao, L., Ning, G., Yoshida-Komiya, H., Deng, C., and O’Malley, B. W. (2000) The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 97, 6379 –6384[Abstract/Free Full Text]

  49. Ito, M., and Roeder, R. G. (2001) The TRAP/SMCC/Mediator complex and thyroid hormone receptor function. Trends Endocrinol. Metab. 12, 127 –134[CrossRef][Medline]

  50. Ren, Y., Behre, E., Ren, Z., Zhang, J., Wang, Q., and Fondell, J. D. (2000) Specific structural motifs determine TRAP220 interactions with nuclear hormone receptors. Mol. Cell. Biol. 20, 5433 –5446[Abstract/Free Full Text]

  51. Landles, C., Chalk, S., Steel, J. H., Rosewell, I., Spencer-Dene, B., Lalani el, N., and Parker, M. G. (2003) The thyroid hormone receptor-associated protein TRAP220 is required at distinct embryonic stages in placental, cardiac, and hepatic development. Mol. Endocrinol. 17, 2418 –2435[Abstract/Free Full Text]

  52. Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M., and Spiegelman, B. M. (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829 –839[CrossRef][Medline]

  53. Herzig, S., Long, F., Jhala, U. S., Hedrick, S., Quinn, R., Bauer, A., Rudolph, D., Schutz, G., Yoon, C., Puigserver, P., Spiegelman, B., and Montminy, M. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179 –183[CrossRef][Medline]

  54. Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., Newgard, C. B., and Spiegelman, B. M. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131 –138[CrossRef][Medline]

  55. Wu, Y., Delerive, P., Chin, W. W., and Burris, T. P. (2002) Requirement of helix 1 and the AF-2 domain of the thyroid hormone receptor for coactivation by PGC-1. J. Biol. Chem. 277, 8898 –8905[Abstract/Free Full Text]

  56. Ko, L., Cardona, G. R., and Chin, W. W. (2000) Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator. Proc. Natl. Acad. Sci. U. S. A. 97, 6212 –6217[Abstract/Free Full Text]

  57. Antonson, P., Schuster, G. U., Wang, L., Rozell, B., Holter, E., Flodby, P., Treuter, E., Holmgren, L., and Gustafsson, J. A. (2003) Inactivation of the nuclear receptor coactivator RAP250 in mice results in placental vascular dysfunction. Mol. Cell. Biol. 23, 1260 –1268[Abstract/Free Full Text]

  58. Kalkhoven, E. (2004) CBP and p300: HATs for different occasions. Biochem. Pharmacol. 68, 1145 –1155[CrossRef][Medline]

  59. De Luca, A., Severino, A., De Paolis, P., Cottone, G., De Luca, L., De Falco, M., Porcellini, A., Volpe, M., and Condorelli, G. (2003) p300/cAMP-response-element-binding-protein (‘CREB’)-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor. Biochem. J. 369, 477 –484[CrossRef][Medline]

  60. Heinlein, C. A., Ting, H. J., Yeh, S., and Chang, C. (1999) Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor {gamma}. J. Biol. Chem. 274, 16147 –16152[Abstract/Free Full Text]

  61. Rabes, H. M. (2001) Gene rearrangements in radiation-induced thyroid carcinogenesis. Med. Pediatr. Oncol. 36, 574 –582[CrossRef][Medline]

  62. Lee, J. W., Ryan, F., Swaffield, J. C., Johnston, S. A., and Moore, D. D. (1995) Interaction of thyroid-hormone receptor with a conserved transcriptional mediator. Nature 374, 91 –94[CrossRef][Medline]

  63. Fraser, R. A., Rossignol, M., Heard, D. J., Egly, J. M., and Chambon, P. (1997) SUG1, a putative transcriptional mediator and subunit of the PA700 proteasome regulatory complex, is a DNA helicase. J. Biol. Chem. 272, 7122 –7126[Abstract/Free Full Text]

  64. Cato, A. C., and Mink, S. (2001) BAG-1 family of cochaperones in the modulation of nuclear receptor action. J. Steroid Biochem. Mol. Biol. 78, 379 –388[CrossRef][Medline]

  65. Nawaz, Z., Lonard, D. M., Smith, C. L., Lev-Lehman, E., Tsai, S. Y., Tsai, M. J., and O’Malley, B. W. (1999) The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily. Mol. Cell. Biol. 19, 1182 –1189[Abstract/Free Full Text]

  66. Powers, C. A., Mathur, M., Raaka, B. M., Ron, D., and Samuels, H. H. (1998) TLS (translocated-in-liposarcoma) is a high-affinity interactor for steroid, thyroid hormone, and retinoid receptors. Mol. Endocrinol. 12, 4 –18[Abstract/Free Full Text]

  67. Harvey, C. B., Stevens, D. A., Williams, A. J., Jackson, D. J., O’Shea, P., and Williams, G. R. (2003) Analysis of thyroid hormone responsive gene expression in osteoblastic cells. Mol. Cell. Endocrinol. 213, 87 –97[CrossRef][Medline]

  68. Haas, M. J., Mreyoud, A., Fishman, M., and Mooradian, A. D. (2004) Microarray analysis of thyroid hormone-induced changes in mRNA expression in the adult rat brain. Neurosci. Lett. 365, 14 –18[CrossRef][Medline]

  69. Moeller, L. C., Dumitrescu, A. M., Walker, R. L., Meltzer, P. S., and Refetoff, S. (2005) Thyroid hormone responsive genes in cultured human fibroblasts. J. Clin. Endocrinol. Metab. 90, 936 –943[Abstract/Free Full Text]

  70. Hu, X., and Lazar, M. A. (2000) Transcriptional repression by nuclear hormone receptors. Trends Endocrinol. Metab. 11, 6 –10[CrossRef][Medline]

  71. Sachs, L. M. (2004) Corepressor requirement and thyroid hormone receptor function during Xenopus development. Vitam. Horm. 68, 209 –230[Medline]

  72. Xu, H. E., Stanley, T. B., Montana, V. G., Lambert, M. H., Shearer, B. G., Cobb, J. E., McKee, D. D., Galardi, C. M., Plunket, K. D., Nolte, R. T., Parks, D. J., Moore, J. T., Kliewer, S. A., Willson, T. M., and Stimmel, J. B. (2002) Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR{alpha}. Nature 415, 813 –817[CrossRef][Medline]

  73. Lazar, M. A. (2003) Thyroid hormone action: a binding contract. J. Clin. Investig. 112, 497 –499[Abstract/Free Full Text]

  74. Cohen, R. N., Wondisford, F. E., and Hollenberg, A. N. (1998) Two separate NCoR (nuclear receptor corepressor) interaction domains mediate corepressor action on thyroid hormone response elements. Mol. Endocrinol. 12, 1567 –1581[Abstract/Free Full Text]

  75. Makowski, A., Brzostek, S., Cohen, R. N., and Hollenberg, A. N. (2003) Determination of nuclear receptor corepressor interactions with the thyroid hormone receptor. Mol. Endocrinol. 17, 273 –286[Abstract/Free Full Text]

  76. Hu, X., Li, Y., and Lazar, M. A. (2001) Determinants of CoRNR-dependent repression complex assembly on nuclear hormone receptors. Mol. Cell. Biol. 21, 1747 –1758[Abstract/Free Full Text]

  77. Feng, X., Jiang, Y., Meltzer, P., and Yen, P. M. (2001) Transgenic targeting of a dominant negative corepressor to liver blocks basal repression by thyroid hormone receptor and increases cell proliferation. J. Biol. Chem. 276, 15066 –15072[Abstract/Free Full Text]

  78. Jepsen, K., Hermanson, O., Onami, T. M., Gleiberman, A. S., Lunyak, V., McEvilly, R. J., Kurokawa, R., Kumar, V., Liu, F., Seto, E., Hedrick, S. M., Mandel, G., Glass, C. K., Rose, D. W., and Rosenfeld, M. G. (2000) Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102, 753 –763[CrossRef][Medline]

  79. Treuter, E., Albrektsen, T., Johansson, L., Leers, J., and Gustafsson, J. A. (1998) A regulatory role for RIP140 in nuclear receptor activation. Mol. Endocrinol. 12, 864 –881[Abstract/Free Full Text]

  80. Subramaniam, N., Treuter, E., and Okret, S. (1999) Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids. J. Biol. Chem. 274, 18121 –18127[Abstract/Free Full Text]

  81. Cavailles, V., Dauvois, S., L’Horset, F., Lopez, G., Hoare, S., Kushner, P. J., and Parker, M. G. (1995) Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 14, 3741 –3751[Abstract]

  82. Mellgren, G., Borud, B., Hoang, T., Yri, O. E., Fladeby, C., Lien, E. A., and Lund, J. (2003) Characterization of receptor-interacting protein RIP140 in the regulation of SF-1 responsive target genes. Mol. Cell. Endocrinol. 203, 91 –103[CrossRef][Medline]

  83. Miyata, K. S., McCaw, S. E., Meertens, L. M., Patel, H. V., Rachubinski, R. A., and Capone, J. P. (1998) Receptor-interacting protein 140 interacts with and inhibits transactivation by, peroxisome proliferator-activated receptor {alpha} and liver-X-receptor {alpha}. Mol. Cell. Endocrinol. 146, 69 –76[CrossRef][Medline]

  84. White, R., Leonardsson, G., Rosewell, I., Ann Jacobs, M., Milligan, S., and Parker, M. (2000) The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility. Nat. Med. 6, 1368 –1374[CrossRef][Medline]

  85. Wei, L. N., and Hu, X. (2004) Receptor interacting protein 140 as a thyroid hormone-dependent, negative co-regulator for the induction of cellular retinoic acid binding protein I gene. Mol. Cell. Endocrinol. 218, 39 –48[CrossRef][Medline]

  86. Suzuki, T., Kasahara, M., Yoshioka, H., Morohashi, K., and Umesono, K. (2003) LXXLL-related motifs in Dax-1 have target specificity for the orphan nuclear receptors Ad4BP/SF-1 and LRH-1. Mol. Cell. Biol. 23, 238 –249[Abstract/Free Full Text]

  87. Zhang, H., Thomsen, J. S., Johansson, L., Gustafsson, J. A., and Treuter, E. (2000) DAX-1 functions as an LXXLL-containing corepressor for activated estrogen receptors. J. Biol. Chem. 275, 39855 –39859[Abstract/Free Full Text]

  88. Achermann, J. C., Meeks, J. J., and Jameson, J. L. (2001) Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol. Cell. Endocrinol. 185, 17 –25[CrossRef][Medline]

  89. Manna, P. R., Tena-Sempere, M., and Huhtaniemi, I. T. (1999) Molecular mechanisms of thyroid hormone-stimulated steroidogenesis in mouse Leydig tumor cells. Involvement of the steroidogenic acute regulatory (StAR) protein. J. Biol. Chem. 274, 5909 –5918[Abstract/Free Full Text]

  90. Seol, W., Choi, H. S., and Moore, D. D. (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272, 1336 –1339[Abstract]

  91. Seol, W., Chung, M., and Moore, D. D. (1997) Novel receptor interaction and repression domains in the orphan receptor SHP. Mol. Cell. Biol. 17, 7126 –7131[Abstract]

  92. Lee, Y. K., and Moore, D. D. (2002) Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J. Biol. Chem. 277, 2463 –2467[Abstract/Free Full Text]

  93. Sadow, P. M., Koo, E., Chassande, O., Gauthier, K., Samarut, J., Xu, J., O’Malley, B. W., Seo, H., Murata, Y., and Weiss, R. E. (2003) Thyroid hormone receptor-specific interactions with steroid receptor coactivator-1 in the pituitary. Mol. Endocrinol. 17, 882 –894[Abstract/Free Full Text]

  94. Lee, K. C., Li, J., Cole, P. A., Wong, J., and Kraus, W. L. (2003) Transcriptional activation by thyroid hormone receptor-ß involves chromatin remodeling, histone acetylation, and synergistic stimulation by p300 and steroid receptor coactivators. Mol. Endocrinol. 17, 908 –922[Abstract/Free Full Text]