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Department of Pharmacology and Molecular Toxicology University of Massachusetts Medical School Worcester, Massachusetts 01655-0126
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Both TR and RAR can function as transcriptional repressors in the absence of ligands and potent activators upon binding of ligands (7). DNA-binding assays and functional analysis have demonstrated that the repressor activities of unliganded receptors depend on DNA response elements, as well as on the intact LBD of the receptors (7, 9, 10). In vivo, the TR/RXR heterodimer binds to DNA in the context of chromatin, and nucleosome assembly enhances the transcriptional silencing effect (11). Importantly, the oncogenic activity of v-erbA, a mutated form of TR, is directly linked to transcriptional repression (12, 13). In addition, deletion of the activation domain of RAR converts it into a potent transcriptional repressor, and this mutation was shown to cause defects in cellular differentiation and development (14, 15, 16). Therefore, transcriptional repression by unliganded nuclear receptors appears to play an important role in regulating cell growth and differentiation.
Hormone binding is thought to induce conformational changes that lead
to ligand-dependent transformation of the receptors from repressors to
activators (1). The C terminus of TR, about 20 amino acids, constitutes
the 12th amphipathic helix (helix 12) of the LBD (17, 18, 19), which
functions as a ligand-dependent activation core domain known as the
AF2-AD, 
C, or 4 domain (8, 20, 21, 22). Comparison of the LBD
structures of the unliganded (19) and liganded receptors (17, 18)
reveals a striking difference in the relative position of the helix
12/AF2-AD domain. This positional shift is thought to play an important
role in receptor activation, allowing the liganded receptors to
displace corepressors (8, 23, 24, 25) and to interact with coactivators
(see reviews in Refs. 26–28).
SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors (24, 25) that are distinct from other proteins (29). They were shown to utilize the C-terminal domain for interaction with unliganded receptors (30, 31, 32, 33), and the N-terminal domain for transcriptional repression (25, 30). In this study, we investigate mechanisms of protein-protein interactions between SMRT and nuclear receptors and analyze the modes of repression mediated by SMRT/N-CoR. To do this, we define the interacting surfaces between SMRT and nuclear receptors in binding and functional assays. Next, we compare transcriptional repression mediated by SMRT and N-CoR using transient transfection assays in mammalian cells. Evidence is presented that SMRT and N-CoR interact with additional corepressors, and that histone deacetylation plays a role in SMRT/N-CoR- mediated repression.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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shows the domain structure of TR and
the relative position of individual helices in the LBD as determined by
x-ray crystallography (17, 18). The sequence at the C terminus region
around helices 11 and 12 is also shown for both TR and RAR.
[35S]Methionine-labeled TR or RAR deletion mutants were
hybridized to glutathione S-transferase (GST)-SMRT and
GST-RXR in far-Western analyses in the absence of hormone
(Fig. 1B). The relative strengths of these interactions are summarized
in Fig. 1C.
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Amino-terminal truncation of TR at residue 173, which removes the
DNA-binding domain (DBD), does not affect the interaction with either
SMRT or RXR. Further N-terminal deletion to residue 260, which removes
the first and second helices of the TR LBD, markedly impairs SMRT
association. No interaction with RXR by this mutant was detectable.
Similarly, C-terminal deletion of helix 12 from RAR (1–403) also
increases interaction with SMRT as compared with that of wild type RAR
(1–462). Further deletion to residue 395, which removes part of helix
11, diminishes the enhanced interaction to a level comparable with that
of full-length RAR, and ligand has little effect on the interaction.
Together, these results identify two distinct interacting domains at
the N-terminal hinge and C-terminal helix 11 regions of the receptor
LBD that might act synergistically to promote interaction with SMRT. We
find that the other two RAR isoforms, ß and 
, also interact with
SMRT in a ligand-reversible manner, although the interactions observed
are weaker compared with that with RAR
(Fig. 1D
). The interactions
of both RARß and RAR with RXR were not affected by ligand
treatment.
Interaction of Helix 12/AF2-AD Deletion Mutants with SMRT in
Yeast
To further understand the role of helix 12/AF2-AD in interaction
with SMRT, we analyzed interactions between AF2-AD deletion mutants of
RAR and RXR with C-terminal receptor-interacting domain of SMRT in a
yeast two-hybrid system (Fig. 2). The RAR
LBD alone is sufficient to interact with SMRT in a ligand-reversible
manner (Fig. 2A, column 3), but the resulting activity is much weaker
compared with that of full-length RAR (column 9). Similar to the
far-Western results, SMRT and full-length RAR retain some interaction,
even after treatment of the yeast cells with a saturating amount of
ligand. It is unclear whether this obervation reflects an association
between liganded receptors and SMRT or the existence of a small percent
of unliganded receptors after ligand treatment. Deletion of the AF2-AD
domain results in a RAR mutant that stimulates gene expression in
response to hormone treatment in yeast (columns 4 and 10), as opposed
to the dominant negative activity of this mutant observed in mammalian
cells (14). The ligand-dependent activation of RAR403 is more obvious
in the context of full-length receptor (column 10). A similar effect
has been shown in v-erbA, which normally acts as a constitutive
repressor in mammalian cells, but as a ligand-dependent activator in
yeast (34). Cotransformation of the RAR403 mutants with a Gal4
activation domain-SMRT fusion (Gal4 AD-SMRT) strongly induces
ß-galactosidase expression, even in the absence of hormone
(columns 5 and 11). Furthermore, in contrast to the hormone-dependent
dissociation seen with full-length RAR, hormone treatment does not
interrupt these interactions. Similarly, the Gal4 DBD-SMRT fusion
interacts strongly with the Gal4 AD-RAR403 mutants in a
ligand-insensitive manner (columns 6 and 12). These results are
consistent with the enhanced interaction observed in vitro
and indicate that the AF2-AD domain may act as a negative regulatory
element, controlling hormone-sensitive interaction between SMRT and
nuclear receptors.
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). Ligand treatment weakly
activates the Gal4 DBD-RXR LBD fusion (column 1), while
cotransformation with Gal4 AD-SMRT enhances reporter gene expression
(column 2), suggesting that SMRT can interact with RXR in either
absence or presence of ligand. Truncation at residue 443 enhances the
association between RXR and SMRT, and treatment with ligand does not
alter this interaction (columns 4 and 5). These results suggest that
SMRT can interact with RXR and that the AF2-AD domain of RXR also acts
negatively in SMRT association. Furthermore, we observed a significant
interaction between vitamin D3 receptor (VDR) and SMRT in
the absence of hormone, and treatment with ligand reduces the
interaction (column 8). This result is consistent with the recent
finding that VDR also contains intrinsic transcriptional repression
activity (35), suggesting that SMRT might mediate transcriptional
repression by VDR.
Two SMRT Domains Mediate Differential Interactions with Nuclear
Receptors
The finding that two regions of TR are essential for
protein-protein interaction with SMRT suggests that SMRT might also
contain duplicated receptor-interacting domains. Several deletion
mutants of SMRT were used to test this possibility in a far-Western
blot, and the results are summarized in Fig. 3A. The GST fusions of these SMRT mutants
were overexpressed, and the purified proteins (Fig. 3B, lanes 1 and 2)
or crude extracts (lanes 3, 4, and 5) were analyzed for interaction
with 35S-labeled RAR and TR. SMRT(981–1495
) interacts
equally well with both RAR and TR in the absence of ligands. RAR, but
not TR, also interacts with degradation products of SMRT(981–1495).
Similarly, several fast migrating products of SMRT(1086–1291) also
interact well with RAR, but not with TR (lane 4). These results
indicate that RAR and TR may interact differently with SMRT. Consistent
with this speculation, we find that SMRT(982–1291) (lane 2) as well as
SMRT(1086–1291) interact more strongly with RAR than with TR. In
contrast, the C-terminal fragment (1260–1495) interacts better with
TR than wth RAR (lanes 5). All these interactions were found to be
sensitive to hormone treatment (Fig. 3B and data not shown). Together,
these results identify two independent receptor interacting domains
(RID-1 and RID-2) of SMRT that appear to display different affinities
to TR and RAR.
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).
Consistent with previous observations, full-length as well as N-SMRT
(amino acids 1–981) repress basal transcription strongly and in a
dose-dependent fashion (rows 2 and 3), while C-SMRT (amino acids
982-1495) exhibits minimal repression (row 4) compared with Gal4 DBD
alone (row 1). Further deletion from the C terminus of N-SMRT reveals
that amino acids 743 to 981 are not necessary for repression (row 5),
while deletion to residue 475 reduces the repression effect about
2-fold (row 6). These results suggest that amino acids 475 to 981 may
contribute in part to SMRT repression. Further C-terminal deletion to
residue 337 drastically interferes with repression (row 7), indicating
that the N-terminal boundary of this SMRT repression domain-1 (SRD-1)
is located between amino acids 337 and 475. Truncation from the N
terminus reveals that amino acids 1–134 are dispensable for repression
by SRD-1 (row 8), while further deletion to residue 337 abolishes
repression (row 9), indicating that the C-terminal boundary of the
SRD-1 is within amino acids 134–337. When the SMRT fragment between
amino acids 475 and 981 was tested for repression, we found that this
fragment also strongly repressed basal transcription (row 10). Together
with the observation that amino acids 743–981 are not important for
repression, these results may define amino acids 475–743 as a
second, independent SMRT repression domain (SRD-2).
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, rows 2 and 3), and the two N-CoR domains
corresponding to SRD-1 and SRD-2 also yield 10- to 30-fold repression
(rows 4 and 5), similar to the repression effects observed by SRD-1 and
SRD-2. These two additional N-CoR repression domains are termed N-CoR
repression domain 3 and 4 (NRD-3 and NRD-4), and the two N-terminal
repression domains are called NRD-1 and NRD-2. Together, these results
indicate that both SMRT and N-CoR contain multiple, independent
transcriptional repression domains.
To confirm that lack of repression in some of these SMRT/N-CoR
deletion mutants is not due to lack of appropriate protein expression,
we analyzed the expression of these constructs by both in
vitro translation and Western blot analysis after transient
transfection. We find that all constructs used in this experiment
express approximately equal amounts of Gal4 DBD fusion proteins
in vitro (Fig. 4C) and that the repression-defective mutants
express well in vivo (Fig. 4D). These results indicate that
lack of repression by certain SMRT/N-CoR deletion mutants are not due
to lack of protein expression.
Multiple Mechanisms of Transcriptional Repression by SMRT/N-CoR
The mechanism of transcriptional activation by nuclear receptors
has been shown to require recruitment of coactivators, including
histone acetyltransferases such as CBP/p300 (36, 37, 38, 39). The opposite of
histone acetylation, histone deacetylation, has recently been
implicated in transcriptional repression by unliganded receptors and
the associated corepressors. Several reports have described a
corepressor complex containing a Mad-dependent corepressor mSin3A, a
histone deacetylase HDAC1 or mRPD3, and the nuclear receptor
corepressor SMRT/N-CoR (40, 41, 42, 43, 44, 45, 46, 47, 48). These results suggest that histone
deacetylation may be a mechanism of transcriptional repression by
unliganded receptors.
To confirm the interaction between mSin3A and the defined
repression domains of SMRT and N-CoR, we tested the interactions
between mSin3A and the individual repression domains of SMRT/N-CoR in a
mammalian two-hybrid system. Coexpression of a VP16 AD-mSin3A fusion
with all Gal4 DBD-SMRT/N-CoR repression domain fusions results in weak
reduction of the repression activities (Fig. 5A). Coexpression of VP16 AD-mSin3A with
a Gal4 DBD-HDAC1 fusion also results in partial release of repression
mediated by Gal4 DBD-HDAC1 fusion. However, no activation above the
background level was observed even though a VP16 activation domain was
present. Since the weak interaction between SMRT/N-CoR repression
domain with mSin3A in the two-hybrid system may reflect a dominant
effect of repression over activation, we tested the interaction between
mSin3A and individual SMRT/N-CoR repression domains in vitro
by far-Western analysis. Full-length mSin3A was translated and labeled
in vitro and used as a probe for GST fusions of various SRD
and NRD domains. We find that mSin3A interacts specifically and
consistently with NRD-1 and NRD-4 in this assay (Fig. 5B). In one
experiment, we also detected interaction between SRD-2 and mSin3A (data
not shown). No interaction is observed between SRD-1, NRD-2, and
NRD-3. Therefore, these results suggest that different SMRT and N-CoR
repression domains may repress transcription in a mSin3A-dependent or
-independent manner.
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, lane 2), but not that of C-SMRT
lacking the repression domains (lane 3), repressed basal expression
from a mouse RARß2 promoter approximately 2-fold in comparison to the
empty vector (lane 1). The same result is evident with two minimal
response elements in the context of a thymidine kinase promoter in the
absence of hormone (Fig. 5A). As expected, hormone treatment enhanced
transcription from these promoters, while overexpression of full-length
SMRT reduced slightly this ligand-dependent activation. C-SMRT enhances
the ligand-dependent activation from these promoters (Fig. 5B). These
results suggest that SMRT may, at least under certain circumstances,
facilitate transcriptional repression of natural promoters.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The hinge region of TR was originally shown to interact directly with the RID-2 region of N-CoR (25). Our results indicate that TR requires an additional C-terminal region for efficient association with SMRT. Nested deletion analyses suggest that helix 11 of the TR LBD plays an important role in stabilizing SMRT association, presumably by cooperating with the N-terminal helix 1–2 region. The interaction of SMRT with either the N terminus or C terminus of the LBD alone is very weak but detectable, suggesting that these two potential interacting surfaces may act synergistically to promote protein-protein interactions and to ensure appropriate recruitment of the corepressors. Similarly, two independent regions in the receptor have been shown to act synergistically for interaction with N-CoR (32, 49, 50). It has recently been shown that a receptor dimer is required for interaction with SMRT/N-CoR and that SMRT/N-CoR may contribute to receptor-specific transcriptional repression (51). Furthermore, an antagonist of the transcriptional activation by RXR homodimer was shown to promote association with the corepressor SMRT (52). Together, these studies suggest that SMRT and N-CoR may utilize similar but distinct mechanisms for interaction with nuclear receptors.
We cannot exclude the possibility that the tight association with SMRT by the AF2-AD deletion mutants may weaken hormone binding to the receptor, but the ability of RAR403 to respond to ligand treatment in yeast cells indicates that this mutation does not eliminate the receptor’s hormone-binding capability, consistent with previous observations (14, 53). Therefore, the inability of hormone to dissociate corepressors is likely due to the lack of certain conformational changes that would normally take place in the presence of the AF2-AD. It is possible that the assumed shift of AF2-AD upon hormone binding is a prerequisite for additional structural changes that are important for corepressor dissociation. Alternatively, the shift of helix 12 may mask or compete with certain interacting surfaces required for binding corepressors. The fact that the AF2-AD deletion creates a mutant that binds tighter to the corepressors favors this model. We suspect that helix 11 could constitute such an interacting surface, since disruption of this helix eliminates the enhanced interaction resulting from deletion of AF2-AD. Our results suggest that AF2-AD may act to balance the association between nuclear receptors and the corepressors, by preventing overassociation of unliganded receptors with corepressors, thereby facilitating ligand-dependent dissociation of corepressors.
Nested deletion analysis reveals two distinct subdomains in SMRT that are capable of independent interaction with nuclear receptors. These two receptor- interacting domains, RID-1 and RID-2, interact differently with TR and RAR. The N-terminal RID-1 region interacts more strongly with RAR, and it contains a glutamine-rich domain, while the C-terminal RID-2 region interacts better with TR and contains a putative helical domain analogous to that identified previously in N-CoR (25). The different receptor-interacting properties of these two domains suggest that SMRT may utilize distinct mechanisms for interaction with different receptors. The RID-2 region in N-CoR has been shown to interact directly with the hinge region of TR (25), and therefore it is reasonable to predict that the N-terminal RID-1 region might interact with the C-terminal region of the LBD.
Functional analysis of the transcriptional repression activities of SMRT and N-CoR reveals two independent domains that are capable of repressing basal transcription. Together, there appear to be four independent repression domains in N-CoR and two in SMRT. These repression domains could act independently, and some repress basal transcription as efficiently as the full-length protein, suggesting that these domains might act redundantly and possibly through different mechanisms. Sequence comparison of these repression domains gives little clue as to possible mechanisms of repression. However, within SRD-1 and the corresponding NRD-3, four potential repeated motifs sharing a consensus sequence of GSITQGTPA have been identified (32). In addition, two other potential repeats with a consensus sequence of KGHVI•YEG are noted. These motifs are well conserved between SMRT and N-CoR, suggesting that they might contribute to repression.
Recently, several papers reported that mSin3A and the histone deacetylase HDAC1 form a ternary complex with SMRT and N-CoR (42, 46). These results indicate that SMRT and N-CoR, while interacting with unliganded receptors, can also interact with additional corepressors such as mSin3A and mSin3B (54), as well as the histone deacetylases HDAC1 (55) and mRPD3 (56). The recruitment of histone deacetylase to target promoters by unliganded receptors through SMRT, N-CoR, and mSin3 suggests that deacetylation of histones or other factors may play a role in transcriptional repression, perhaps by establishing an unfavorable chromatin structure for transcriptional activation (41). Our results suggest weak two-hybrid interactions between SMRT/N-CoR and mSin3A, or between mSin3A and HDAC1, even though a VP16 activation domain was present. Alternatively, these results may suggest that the repression activity of the corepressor complex is dominant over that of the VP16 activation domain. An in vitro protein-protein interaction assay detects association of mSin3A with NRD-1 and NRD-4, but not with other repression domains. Although our results are consistent with recent reports, our data also suggest the possibility of other repression mechanisms.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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were generated by
appropriate restriction enzyme digestion and/or PCR amplification from
the parental expression construct pCMX-hTRß and pCMX-hRAR (57).
The GST-SMRT deletion constructs were generated by enzyme digestion at
indicated residues from the parental construct GST-SMRT. The Gal4 DBD
fusions of individual repression domains of SMRT and N-CoR were
generated by PCR amplification and were subsequently transferred to
pGEX vector for expression of GST fusion proteins. The VP16 AD-mSin3A
construct was created by subcloning the ScaI (at residue 56)
to BglII fragment of mSin3A (58) into the pCMX-VP16 vector.
Detailed information regarding these plasmids is available upon
request.
Far-Western Analysis
GST fusion proteins were separated by denaturing protein gels
(SDS-PAGE) and electroblotted onto nitrocellulose filters in transfer
buffer (25 mM Tris-HCl, pH 8.3; 192 mM glycine;
0.01% SDS). After denaturation in 6 M guanidine
hydrochloride (GnHCl), the proteins were renatured by stepwise dilution
of GnHCl to 0.187 M in HB buffer (25 mM HEPES,
pH 7.7; 25 mM NaCl; 5 mM MgCl2; 1
mM dithiothreitol). The filters were then saturated in
blocking buffer (5% nonfat milk, then 1% milk in HB buffer plus
0.05% NP40) at 4 C overnight or at 37 C for 1 h. In
vitro translated 35S-labeled proteins were diluted
into hybridization buffer (20 mM HEPES, pH 7.7; 75
mM KCl; 0.1 mM EDTA; 2.5 mM
MgCl2; 0.05% NP40; 1% milk; 1 mM
dithiothreitol), and the filters were allowed to hybridize overnight at
4 C. After three washes (5 min each) with the hybridization buffer, the
bound proteins were detected by autoradiography.
Yeast Two-Hybrid Assay
The yeast two-hybrid assay was carried out in the Y190 yeast
strain (59). The Gal4 DBD fusion constructs were generated in either
the pAS or pGBT vector (CLONTECH, Palo Alto, CA), and the Gal4 AD
fusion constructs were in the pGAD or pACT vector (CLONTECH). The
ß-galactosidase activities were determined with the
O-nitrophenyl ß-D-galactopyranoside (Sigma,
St. Louis, MO) liquid assay as previously described (30).
Cell Culture and Transient Transfection
African green monkey kidney CV-1 cells were grown in DMEM
supplemented with 10% resin-charcoal stripped FBS, 50 U/ml penicillin
G, and 50 µg/ml streptomycin sulfate at 37 C in 5% CO2.
One day before transfection, cells were plated in a 24-well culture
dish at a density of 50,000 cells per well. Transfection was performed
by standard calcium phosphate precipitation (57). All transfection
experiments were performed in triplicate and were replicated at least
once. Twelve hours after transfection, cells were washed with PBS and
refed fresh medium containing indicated amounts of ligands. After
30 h, cells were harvested for ß-galactosidase and luciferase
assay as described previously (30). The relative luciferase activities
are arbitrary light units normalized to the ß-galactosidase
activities.
In Vitro Translation and Western Blot
In vitro transcription/translation reactions were
carried out in rabbit reticulocyte lysates using the TNT T7 Quick
coupled transcription/translation system (Promega, Madison, WI).
[35S]Methionine (Amersham, Arlington Heights, IL) was
added during the translation reactions, which were performed at 30 C
for 90 min. The translated reactions were analyzed by SDS-PAGE,
followed by autoradiography. For Western blot analysis, transfected
cells were lysed in SDS-sample buffer, and the extracts were separated
by SDS-PAGE. The gels were transferred onto nitrocellulose membranes,
blocked with nonfat milk, and hybridized with anti-Gal4 DBD monoclonal
antibody according to manufacturer’s recommendation (Santa Cruz
Biotechnology, Santa Cruz, CA). The filters were washed and incubated
with horseradish peroxidase-conjugated anti-mouse IgG secondary
antibody and developed by enhanced chemiluminescent reaction
(Amersham).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by an American Society of Hematology Junior Faculty Scholar Award and the USAMRMC Breast Cancer Research Program Idea Award BC961877 (to J.D.C.) and an Arthritis Foundation postdoctoral fellowship (to D.J.S.).
Received for publication May 20, 1997. Revision received August 29, 1997. Accepted for publication September 5, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A. Marimuthu, W. Feng, T. Tagami, H. Nguyen, J. L. Jameson, R. J. Fletterick, J. D. Baxter, and B. L. West TR Surfaces and Conformations Required to Bind Nuclear Receptor Corepressor Mol. Endocrinol., February 1, 2002; 16(2): 271 - 286. [Abstract] [Full Text] [PDF]
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S.-H. Hong, Z. Yang, and M. L. Privalsky Arsenic Trioxide Is a Potent Inhibitor of the Interaction of SMRT Corepressor with Its Transcription Factor Partners, Including the PML-Retinoic Acid Receptor {alpha} Oncoprotein Found in Human Acute Promyelocytic Leukemia Mol. Cell. Biol., November 1, 2001; 21(21): 7172 - 7182. [Abstract] [Full Text] [PDF]
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 G. B. Potter, G. M.J. Beaudoin III, C. L. DeRenzo, J. M. Zarach, S. H. Chen, and C. C. Thompson The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor Genes & Dev., October 15, 2001; 15(20): 2687 - 2701. [Abstract] [Full Text] [PDF]
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 K.-h. Lin and Y.-h. Wu shen-liang chen Impaired Interaction of Mutant Thyroid Hormone Receptors Associated with Human Hepatocellular Carcinoma with Transcriptional Coregulators Endocrinology, February 1, 2001; 142(2): 653 - 662. [Abstract] [Full Text] [PDF]
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S.-H. Hong and M. L. Privalsky The SMRT Corepressor Is Regulated by a MEK-1 Kinase Pathway: Inhibition of Corepressor Function Is Associated with SMRT Phosphorylation and Nuclear Export Mol. Cell. Biol., September 1, 2000; 20(17): 6612 - 6625. [Abstract] [Full Text]
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R. N. Cohen, A. Putney, F. E. Wondisford, and A. N. Hollenberg The Nuclear Corepressors Recognize Distinct Nuclear Receptor Complexes Mol. Endocrinol., June 1, 2000; 14(6): 900 - 914. [Abstract] [Full Text]
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J.-P. Renaud, J. M. Harris, M. Downes, L. J. Burke, and G. E .O. Muscat Structure-Function Analysis of the Rev-erbA and RVR Ligand-Binding Domains Reveals a Large Hydrophobic Surface That Mediates Corepressor Binding and a Ligand Cavity Occupied by Side Chains Mol. Endocrinol., May 1, 2000; 14(5): 700 - 717. [Abstract] [Full Text]
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J. Yu, C. Angelin-Duclos, J. Greenwood, J. Liao, and K. Calame Transcriptional Repression by Blimp-1 (PRDI-BF1) Involves Recruitment of Histone Deacetylase Mol. Cell. Biol., April 1, 2000; 20(7): 2592 - 2603. [Abstract] [Full Text]
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K. Busch, B. Martin, A. Baniahmad, J. A. Martial, R. Renkawitz, and M. Muller Silencing Subdomains of v-ErbA Interact Cooperatively with Corepressors: Involvement of Helices 5/6 Mol. Endocrinol., February 1, 2000; 14(2): 201 - 211. [Abstract] [Full Text]
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C. K. Glass and M. G. Rosenfeld The coregulator exchange in transcriptional functions of nuclear receptors Genes & Dev., January 15, 2000; 14(2): 121 - 141. [Full Text]
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Z. Yang, S.-H. Hong, and M. L. Privalsky Transcriptional Anti-repression. THYROID HORMONE RECEPTOR beta -2 RECRUITS SMRT COREPRESSOR BUT INTERFERES WITH SUBSEQUENT ASSEMBLY OF A FUNCTIONAL COREPRESSOR COMPLEX J. Biol. Chem., December 24, 1999; 274(52): 37131 - 37138. [Abstract] [Full Text] [PDF]
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V. Perissi, L. M. Staszewski, E. M. McInerney, R. Kurokawa, A. Krones, D. W. Rose, M. H. Lambert, M. V. Milburn, C. K. Glass, and M. G. Rosenfeld Molecular determinants of nuclear receptor-corepressor interaction Genes & Dev., December 15, 1999; 13(24): 3198 - 3208. [Abstract] [Full Text]
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B. S. Johnson, R. A. S. Chandraratna, R. A. Heyman, E. A. Allegretto, L. Mueller, and S. J. Collins Retinoid X Receptor (RXR) Agonist-Induced Activation of Dominant-Negative RXR-Retinoic Acid Receptor alpha 403 Heterodimers Is Developmentally Regulated during Myeloid Differentiation Mol. Cell. Biol., May 1, 1999; 19(5): 3372 - 3382. [Abstract] [Full Text] [PDF]
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U. Dressel, D. Thormeyer, B. Altincicek, A. Paululat, M. Eggert, S. Schneider, S. P. Tenbaum, R. Renkawitz, and A. Baniahmad Alien, a Highly Conserved Protein with Characteristics of a Corepressor for Members of the Nuclear Hormone Receptor Superfamily Mol. Cell. Biol., May 1, 1999; 19(5): 3383 - 3394. [Abstract] [Full Text] [PDF]
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 P. J. Malloy, J. W. Pike, and D. Feldman The Vitamin D Receptor and the Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Endocr. Rev., April 1, 1999; 20(2): 156 - 188. [Abstract] [Full Text]
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C. E. Robinson, X. Wu, Z. Nawaz, S. A. Onãte, and J. M. Gimble A Corepressor and Chicken Ovalbumin Upstream Promoter Transcriptional Factor Proteins Modulate Peroxisome Proliferator-Activated Receptor-{gamma}2/Retinoid X Receptor {alpha}-Activated Transcription from the Murine Lipoprotein Lipase Promoter Endocrinology, April 1, 1999; 140(4): 1586 - 1593. [Abstract] [Full Text]
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E.-J. Park, D. J. Schroen, M. Yang, H. Li, L. Li, and J. D. Chen SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor PNAS, March 30, 1999; 96(7): 3519 - 3524. [Abstract] [Full Text] [PDF]
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S.-H. Hong and M. L. Privalsky Retinoid Isomers Differ in the Ability to Induce Release of SMRT Corepressor from Retinoic Acid Receptor-alpha J. Biol. Chem., January 29, 1999; 274(5): 2885 - 2892. [Abstract] [Full Text] [PDF]
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C.-W. Wong and M. L. Privalsky Components of the SMRT Corepressor Complex Exhibit Distinctive Interactions with the POZ Domain Oncoproteins PLZF, PLZF-RARalpha , and BCL-6 J. Biol. Chem., October 16, 1998; 273(42): 27695 - 27702. [Abstract] [Full Text] [PDF]
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C.-W. Wong and M. L. Privalsky Transcriptional Silencing Is Defined by Isoform- and Heterodimer-Specific Interactions between Nuclear Hormone Receptors and Corepressors Mol. Cell. Biol., October 1, 1998; 18(10): 5724 - 5733. [Abstract] [Full Text]
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R. N. Cohen, F. E. Wondisford, and A. N. Hollenberg Two Separate NCoR (Nuclear Receptor Corepressor) Interaction Domains Mediate Corepressor Action on Thyroid Hormone Response Elements Mol. Endocrinol., October 1, 1998; 12(10): 1567 - 1581. [Abstract] [Full Text]
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C.-W. Wong and M. L. Privalsky Transcriptional Repression by the SMRT-mSin3 Corepressor: Multiple Interactions, Multiple Mechanisms, and a Potential Role for TFIIB Mol. Cell. Biol., September 1, 1998; 18(9): 5500 - 5510. [Abstract] [Full Text]
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S.-H. Hong, C.-W. Wong, and M. L. Privalsky Signaling by Tyrosine Kinases Negatively Regulates the Interaction between Transcription Factors and SMRT (Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor) Corepressor Mol. Endocrinol., August 1, 1998; 12(8): 1161 - 1171. [Abstract] [Full Text]
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H. Li and J. D. Chen The Receptor-associated Coactivator 3 Activates Transcription through CREB-binding Protein Recruitment and Autoregulation J. Biol. Chem., March 6, 1998; 273(10): 5948 - 5954. [Abstract] [Full Text] [PDF]
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 G.A. MCARTHUR, C.D. LAHERTY, C. QUEVA, P.J. HURLIN, L. LOO, L. JAMES, C. GRANDORI, P. GALLANT, Y. SHIIO, W.C. HOKANSON, et al. The Mad Protein Family Links Transcriptional Repression to Cell Differentiation Cold Spring Harb Symp Quant Biol, January 1, 1998; 63(0): 423 - 434. [Abstract] [PDF]
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S. M. Yoh and M. L. Privalsky Transcriptional Repression by Thyroid Hormone Receptors. A ROLE FOR RECEPTOR HOMODIMERS IN THE RECRUITMENT OF SMRT COREPRESSOR J. Biol. Chem., May 11, 2001; 276(20): 16857 - 16867. [Abstract] [Full Text] [PDF]
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X. Feng, Y. Jiang, P. Meltzer, and P. M. Yen Transgenic Targeting of a Dominant Negative Corepressor to Liver Blocks Basal Repression by Thyroid Hormone Receptor and Increases Cell Proliferation J. Biol. Chem., April 27, 2001; 276(18): 15066 - 15072. [Abstract] [Full Text] [PDF]
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X. Wu, H. Li, E.-J. Park, and J. D. Chen SMRTe Inhibits MEF2C Transcriptional Activation by Targeting HDAC4 and 5 to Nuclear Domains J. Biol. Chem., June 22, 2001; 276(26): 24177 - 24185. [Abstract] [Full Text] [PDF]
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J. C. Ghosh, X. Yang, A. Zhang, M. H. Lambert, H. Li, H. E. Xu, and J. D. Chen Interactions that determine the assembly of a retinoid X receptor/corepressor complex PNAS, April 30, 2002; 99(9): 5842 - 5847. [Abstract] [Full Text] [PDF]
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