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Section of Microbiology (S.M.Y., M.L.P.) Division of Biological
Sciences University of California at Davis Davis, California
95616
Department of Medicine (V.K.K.C.) University of
Cambridge Level 5, Addenbrooke’s Hospital Cambridge, CB2 2QQ,
United Kingdom
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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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and T3Rß), steroid
receptors, and retinoid receptors (reviewed in Refs. 1–6). All nuclear
hormone receptors contain a variety of motifs involved in DNA binding,
hormone binding, receptor dimerization, and interactions with the
transcriptional machinery (Fig. 1
). On binding to
specific target DNA sequences, nuclear hormone receptors modulate the
expression of adjacent target genes (1, 2, 3, 4, 5, 6). The nature of the
transcriptional response (activation or repression) is dictated by cell
type, promoter context, and hormone status (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In most contexts
T3Rs are transcriptional repressors in the absence of
cognate hormone (T3) and activators in its presence (2, 7, 8, 11, 12, 13, 14, 15).
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A variety of neoplastic and endocrine disorders are the consequence of
aberrations in nuclear hormone receptor function (26, 27, 28, 29, 30, 31). The syndrome
of Resistance to Thyroid Hormone (RTH) is an autosomal dominant human
endocrine disease (reviewed in Refs. 32–34). Individuals with RTH
exhibit a failure to respond to elevated circulating thyroid hormone.
This disorder is associated with diverse mutations at the
T3Rß locus, resulting in the synthesis of abnormal
receptors that are impaired in hormone binding and in transcriptional
activation (35, 36, 37, 38, 39). As a result, the RTH-T3Rs appear to
function as dominant negatives, and interfere with the actions of the
normal T3Rs synthesized from the unaffected
T3R- and ß-alleles (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50). More than 30 different
T3Rß mutations have been associated with the RTH
syndrome.
Nonetheless, the precise mechanism(s) by which RTH-T3Rs act as dominant negatives remains uncertain. In addition, a given RTH-T3R mutation can have very different phenotypic consequences in different individuals or in different tissues in the same individual, suggesting a potential involvement of other factors modulating dominant negative function and the degree of resistance (32, 48, 51, 52, 53, 54). We report here evidence that the RTH syndrome is associated with an aberrant interaction between the RTH-T3Rs and the SMRT/TRAC corepressors and that this corepressor interaction is important in the ability of RTH-T3Rs to act as dominant negative inhibitors. Furthermore, different RTH-T3Rs exhibit distinct corepressor interactions. Conceivably, differential interactions with, expression of, or genetic polymorphisms within the corepressors may contribute to the highly variable presentation observed for RTH disease.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). The truncated T3R species are
likely to the products of translational initiation on internal ATG
codons and have been reported previously for both in vitro
and in vivo expression systems (26, 27, 55).
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). Addition of increasing amounts of
T3 hormone strongly inhibited binding of the
wtT3Rß to GST-SMRT, with a 50% inhibition observed at 56
nM hormone (Fig. 2, and quantified in Fig. 3
and Table 1). This interaction of wtT3Rß
with SMRT closely resembles that observed previously for
wtT3R (11, 14, 15). Note that all three receptor
translation products (p55, p48, and p33) were bound by the GST-SMRT
construct and were released congruently by hormone, indicating that the
use of alternative initiation sites did not alter the interaction of
T3Rß with corepressor (Fig. 2).
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and 3 and are
summarized, along with data for additional mutants, in Table 1. Nine of
the 11 RTH mutants analyzed here associated normally with SMRT in the
absence of hormone (i.e. at levels comparable to
wtT3R). Four RTH mutants in this group of nine (R320L,
M334R, R338W, and R438C) were eventually displaced from SMRT by
T3, but only at hormone levels significantly greater than
those required for the wt receptor/SMRT dissociation. For the remaining
five of these nine mutants (V264D, G344E, G345S, P453A, and P453H),
little or no receptor/SMRT dissociation (less than 50%) was observed
at up to 1 µM T3; notably the P453A and p453H
mutants fail to dissociate from SMRT even though these mutant receptors
are able to bind thyroid hormone (see Discussion).
The last two of the 11 RTH mutants analyzed (
430 M and 432G) were
not only impaired in their dissociation from SMRT in the presence of
T3, but also exhibited a dramatically enhanced SMRT
association at all hormone concentrations (Figs. 2 and 3 and Table 1).
These mutants bound to GST-SMRT in the absence or presence of
T3 at levels some 8- to 10-fold greater than that seen with
wtT3Rß or the other RTH mutants (note the change in
ordinate in Fig. 3); equal inputs of receptor were employed
in all experiments. All mutant and wt receptors were transcribed and
translated at equal efficiencies, utilizing identical conditions, and
therefore represent equal specific activities. Additionally, the
enhanced binding observed for mutants 430 M and 432G was
consistently seen in multiple experiments utilizing different
preparations of receptor and of GST-SMRT. Intriguingly, both of these
mutants represent single amino acid deletions mapping to the same
-helix of the receptor and present clinically in a similar fashion
(see Discussion).
We conclude that a common hallmark of the RTH receptors analyzed here is an aberrant interaction with corepressor. The phenotypes of these RTH mutants could be divided into three general categories: 1) normal levels of SMRT association, but requiring higher than normal levels of T3 for dissociation, 2) normal levels of SMRT association, but with little or no T3-mediated dissociation observed under the conditions employed, and 3) a dramatically elevated level of SMRT association at all hormone concentrations tested.
Altered Corepressor Association Correlates with the Dominant
Negative Properties of the RTH Mutants
We next tested the transcriptional properties of representative
RTH mutants from the categories defined above, using transient
transfections of CV-1 cells. We initially introduced the various
receptor mutants individually (Fig. 4A). In the absence
of hormone, all five receptors tested functioned as repressors,
inhibiting reporter gene expression some 50% relative to that seen in
the absence of exogenous T3R. As expected, addition of 100
nM T3 converted the wtT3Rß from a
repressor into a strong transcriptional activator (Fig. 4A). In
contrast, the R320L mutant exhibited an impaired ability to activate
reporter gene expression in the presence of 100 nM
T3, and the G345S, 432G, and P453A mutants functioned as
constitutive repressors unable to induce significant activation of the
reporter in response to T3 (Fig. 4A).
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).
The G345S and 432G mutants were strong dominant negatives in this
cotransfection assay and significantly inhibited the functions of the
wt receptor in a dose-dependent manner. In contrast, the R320L mutant
acted only as a weak inhibitor of wtT3Rß at 100
nM T3. We retested the dominant negative
properties of R320L at a range of hormone concentrations (Fig. 4C).
Consistent with the effects of hormone on the
SMRT/R320L-T3R association in vitro, the R320L
mutant functioned in cells as a strong dominant negative at low
T3 concentrations (i.e. at hormone levels that
fail to displace SMRT) but lost dominant negative activity at higher
T3 concentrations (presumably reflecting the release of
SMRT). We conclude that the RTH-T3Rs that exhibited a
strong constitutive association with SMRT in vitro
manifested the strongest dominant negative phenotypes, whereas the
mutant receptor that could be partially dissociated from SMRT by
T3 exhibited weaker, T3-sensitive dominant
negative properties.
Exogenously Introduced SMRT Derivatives Can Interfere with the
Dominant Negative Phenotype of the RTH-T3Rs
The N terminus of SMRT is required for transcriptional repression,
whereas the C terminus contains the domains necessary for
T3R association (Fig. 5A and Refs. 11–15).
As a consequence, ectopic expression of an N-terminally truncated SMRT
(N-SMRT) interferes with the wtT3R-mediated repression
observed in the absence of hormone (Refs. 11 and 14 and Fig. 5D),
presumably by displacing endogenous full-length SMRT from the receptor
(Fig. 5C). In contrast, expression of N-SMRT has little or no effect
on the transcriptional activation observed for wtT3Rß in
the presence of T3 (Fig. 5D and Ref.14), conditions in
which endogenous SMRT is not bound to the wt receptor (Fig. 5A). If the
dominant negative actions of the RTH-T3Rs reflect a
hormone-resistant association with SMRT (Fig. 5B), cointroduction of a
N-SMRT deletion should counteract the dominant negative RTH
phenotype and partially restore the thyroid hormone response (Fig. 5C).
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432G mutant (which exhibited
both a very strong dominant negative phenotype in vivo and
an enhanced association with SMRT in vitro). As before,
introduction of the 432G mutant severely inhibited
T3-mediated gene activation by wtT3Rß (Fig. 5D). However, these dominant negative properties of the 432G mutant
were strongly counteracted by the cointroduction of the N-SMRT
derivative, resulting in significant restoration of reporter gene
activation by the wtTR3 (Fig. 5D). These effects were
proportional to the amount of N-SMRT expression vector introduced
and were not observed for an empty pSG5 vector (Fig. 5D and data not
shown).
Artificial Mutants of RTH-T3Rs That Are
Impaired in SMRT Association Are Also Impaired in Dominant-Negative
Function
Although several distinct receptor domains interact with
corepressor, a conserved amino acid sequence in the receptor
ligand-binding domain is particularly important for corepressor
association (Fig. 1 and Refs. 11–15). Receptors bearing mutations in
this conserved sequence are impaired for corepressor association
in vitro and for transcriptional repression in
vivo, but retain the ability to activate transcription (Refs. 11
and 14 and data not shown). To ask whether impairment of SMRT
association results in impairment of the RTH dominant negative
phenotype, we engineered analogous SMRT-association disruptive (sad)
mutations into four of our representative RTH mutant clones (R320L,
G345S, 432G, and P453A). When tested in vitro, these
RTH-T3Rsad mutants were all significantly
reduced in their ability to bind to GST-SMRT relative to the parental
receptors (Fig. 6A). The residual SMRT binding displayed
by the T3Rsad proteins (Fig. 6A) has been noted
before and is likely mediated by additional points of contact between
SMRT and receptor that are not altered in this mutagenesis scheme
(14).
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to Fig. 4B). Little or
no inhibition of T3-mediated reporter gene activation was
detected when T3Rsad versions of R320L, G345S,
432G, or p453A were introduced at 1:1 or 5:1 ratios relative to
wtT3R (Fig. 6B). This contrasts with the strong inhibition
of wtT3Rß activation observed for the cointroduction of
the unmodified G345S, 432G, or P453A mutants (Fig. 6B, last
lane, and Fig. 4B). Note that repression of the reporter gene in
the absence of hormone, mediated by the unmodified
wtT3Rß, is still observed in Fig. 6B, confirming that the
defects in transcriptional repression are specific for the receptors
bearing the sad mutations. The analogous sad
mutant form of the wtT3Rß fails to repress, but retains
the ability to activate, transcription when introduced individually
into CV-1 cells (data not shown), indicating that the sad
lesion does not abolish receptor expression, nuclear localization, or
DNA binding. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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and -ß (40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50). However, many features of RTH remain poorly understood, and its precise molecular mechanism remains elusive. Various models by which RTH-receptors could function as dominant negatives have been proposed, including 1) the formation of inactive dimers between RTH-T3Rs and wtT3Rs, 2) a competition between RTH and wt receptors for essential cofactors, or 3) a competition between RTH and wt receptors for DNA-binding sites. This complexity is paralleled by the clinical phenotype of RTH syndrome, which varies in its severity and characteristics from kindred to kindred. Thus, the known biochemical properties of the RTH receptors do not invariably predict the severity of the disease state, and individuals with the same genetic lesion can display different symptoms (32, 33, 34, 48, 49, 51, 52). It has been suggested that additional, independently inherited factors may be involved in RTH (32, 49, 53, 54).
We therefore asked whether the recently elucidated SMRT/N-CoR family of corepressors might be involved in the pathogenesis of RTH. In this manuscript, we present evidence that RTH-T3Rß mutants are indeed altered in their interactions with SMRT and that these alterations in corepressor association appear to play a role in the dominant negative properties of the RTH receptors and may therefore influence the clinical manifestations of the disease.
RTH Mutant Receptors Exhibit Defects in
T3-Mediated Dissociation from Corepressor
Wild type T3Rß binds to SMRT in the absence of
T3 but dissociates on binding hormone, a process paralleled
by a conversion of the receptor from a transcriptional repressor to an
activator (11, 12, 13, 14, 15). The RTH-T3Rs analyzed here share this
ability to associate with SMRT in the absence of T3 but are
notably impaired in the ability to dissociate from corepressor on
addition of hormone. Four of the RTH mutants tested required higher
than normal levels of hormone to dissociate from SMRT, whereas seven
others failed to dissociate significantly from SMRT at even 1
µM hormone. Given the strong transcriptional silencing
properties of SMRT (11, 14), the RTH-T3R/SMRT complexes
would be predicted to repress transcription under hormone conditions in
which wtT3Rß activates, a prediction consistent with the
dominant negative properties of the RTH mutants. Indeed, the RTH
receptors that were constitutively bound to SMRT exhibited strong,
hormone-refractory dominant negative properties in our transfection
studies. In contrast, an RTH-receptor (R320L) that exhibited impaired,
but detectable, release of corepressor at high hormone concentrations
displayed a similarly hormone-labile dominant negative phenotype.
Two RTH Mutations Appear to Uncouple SMRT Dissociation from Hormone
Binding
The failure of most of our RTH mutants to release from SMRT in the
presence of T3 could be attributed to the impaired
affinities of the mutant receptors for this hormone. For example, the
R338W mutant exhibits a 10-fold reduction in affinity for
T3 relative to wtT3Rß and requires some
6-fold more hormone for SMRT dissociation; similarly the G345S mutant
is virtually unable to bind hormone in vitro and fails to
significantly dissociate from SMRT at even 1 µM
T3. However, two striking exceptions were noted to this
general correlation between affinity for T3 and SMRT
release. The P453A and P453H mutants are only mildly impaired in
hormone binding in vitro (possessing even higher affinities
for T3 than the R338W mutant), yet fail to dissociate from
SMRT at any hormone concentration tested. Protease sensitivity assays
(56) confirm that the P453A and P453H mutant receptors are indeed
occupied by hormone at these T3 concentrations that fail to
displace SMRT (data not shown). Notably, the P453A and P453H mutants
represent different amino acid substitutions at the same codon, in a
region of the receptor that is proposed to undergo a conformational
change on binding hormone (57, 58). Codon 453 may therefore define a
receptor domain critical for corepressor release after hormone binding,
and lesions at this site may confer RTH by preventing SMRT dissociation
in a manner independent of hormone occupancy.
Consistent with these concepts, mutants at codon 453 possess dominant negative properties that are relatively refractory to T3 (48). This region of the receptor has been suggested to operate as a hinge, permitting a C-terminal tail of the receptor to rotate from an exposed position in the absence of hormone to a new position nested against the body of the receptor in the presence of hormone (57, 58). Our preliminary evidence, employing protease sensitivity as a probe of structure, supports the concept that this hinge function may be impaired in the P453A and P453H mutants (B. Lin, S. Yoh, and M. L. Privalsky, manuscript in preparation).
It should be noted that the hormone concentrations required for
inhibition of T3R/SMRT binding in our GST assay were higher
than the association constants (Ka) for T3
reported for the same receptors (Table 1). This phenomenon was
consistently observed in multiple assays, and was also seen for
wtT3R,-ß, and for retinoic acid receptors.
Intriguingly, analogous discrepancies exist between the Ka
values of these receptors and the significantly higher hormone
concentrations required for transcriptional activation in transient
transfection assays (e.g. Refs. 47 and 48). These
differences may simply be technical in origin, i.e. due to
sequestration of hormone by components of the transfection/binding
assays (47). On the other hand, this phenomenon may reflect a
physiologically relevant process. For example, SMRT association may
alter the affinity of T3Rs for hormone, analogous to the
effects reported for heterodimer formation with retinoid X receptor
(59, 60).
Two RTH Mutants Also Exhibit Dramatically Enhanced Levels of SMRT
Association
Two of the nine RTH mutants analyzed (430 M and 432G) were
not only impaired in T3-mediated dissociation from SMRT,
but also exhibited a strongly elevated association with SMRT even in
the absence of hormone. Consistent with this enhanced SMRT binding, the
430 M and 432G mutants exert dominant negative phenotypes that
are among the strongest observed for any of RTH mutants tested; this is
particularly evident with certain promoters and under high hormone
concentrations (48). Notably, these two, independently derived
mutations represent in-frame, single-codon deletions that map to an
-helical domain in the T3Rß C terminus (based on the
crystallographic model of T3R; Ref.57). This helix
appears to play important roles in the conformational changes
associated with hormone binding, in transcriptional activation, and in
dimer formation with other receptors, but has not been previously
identified as a direct contact site for corepressor. It appears that by
shortening or rotating this region by one amino acid residue, the
binding of corepressor can be greatly enhanced, either by directly
affecting an interaction surface or by a more indirect effect on the
global conformation of the receptor C terminus.
Corepressor Association Appears to be Required for the Dominant
Negative Actions of the RTH-T3Rs
Correlating with their dominant negative properties, all 11 RTH
mutants interacted with corepressor under hormone conditions in which
the wtT3R does not. Furthermore, mutations introduced into
RTH-T3Rs that disrupt SMRT association, or transfection of
N-SMRT derivatives that interfere with SMRT function, disrupted the
dominant negative phenotype. These results strongly implicate
corepressors in the ability of RTH-T3Rs to act as dominant
negative inhibitors of the T3 response. In these
properties, the RTH-T3Rß mutants closely parallel
v-Erb A, an oncogenic allele of T3R that both
acts as a dominant negative allele and exhibits hormone-independent
corepressor association (11, 14). The ability of v-Erb A to
repress gene transcription and to function in oncogenesis closely
correlates with SMRT association (11, 14). However, it should be noted
that corepressors are a diverse family of protein factors, and the
dominant negative properties observed for v-Erb A and for
RTH-T3Rs may be mediated by SMRT itself, N-CoR, or some, as
yet unidentified, corepressor-like entity.
A Correlation May Exist between the SMRT Association Properties of
RTH-T3Rs in Vitro and the Clinical
Manifestations of RTH
Clinically, RTH has been broadly divided into a pituitary form
(PRTH) characterized by a predominant pituitary resistance but
preserved peripheral response to T3, vs. a
generalized form (GRTH) characterized by T3 resistance at
the level of both pituitary and peripheral tissues (reviewed in Refs.
32–34). Despite these different clinical manifestations, receptors
isolated from PRTH and GRTH are often similar or identical to one
another in their biochemical properties. It is therefore interesting
that the RTH-T3Rs that display a highly elevated SMRT
association (430 M and 432G) in the current study were both
isolated from patients presenting with PRTH. It is possible that this
constitutively elevated SMRT association may play a role peculiar to
the PRTH phenotype. However, the converse did not appear to be true:
not all PRTH-T3R mutants also displayed elevated SMRT
association in vitro (e.g. R338W).
Notably, none of the experiments described here were performed in different tissues or in the genetic background of the original patients. Therefore, our results do not address whether alterations in corepressor, rather than in receptor, may also contribute to the RTH syndrome. It is tempting to speculate that differences in corepressor expression, perhaps coupled to genetic polymorphisms at the corepressor loci, might account for the variable resistance of the RTH syndrome in different individuals of the same kindred. Similarly, differences in corepressor expression in different tissues could contribute to the varying organ-specific effects of RTH. Clearly, however, RTH is a complex clinical disease and is associated not only with a failure to activate expression of certain genes in response to hormone, as tested here, but also as a failure to suppress expression of others, most notably that of pituitary TSH (32, 33, 34). Further work will be necessary to determine the contributions of corepressors or related factors to these different manifestations of this endocrine disorder.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Assay of the SMRT/T3Rs Interaction
in Vitro
GST-SMRT (identical to the GST-TRAC-1 construct described
previously) was isolated from transformed Escherichia coli
and was immobilized by binding to glutathione agarose, as previously
described (14). 35S-Labeled receptors were synthesized by
in vitro transcription from pSG5 templates using T7 RNA
polymerase, coupled to in vitro translation using rabbit
reticulocyte lysates (TNT kit, Promega, Madison, WI). Each receptor was
subsequently mixed with approximately 2 µg immobilized GST-SMRT
(bound to 20 µl glutathione-agarose) in 200–400 µl HEMG buffer
(14) containing 10 mg/ml BSA and a protease inhibitor cocktail
(Complete, Boehringer-Mannheim, Indianapolis, IN). T3
hormone (or an equivalent volume of ethanol carrier) was included in
the binding reactions where indicated. The binding reactions were
incubated for 60–90 min at 4 C with gentle rocking, and the agarose
matrix was subsequently washed with 4 x 1 ml changes of HEMG
buffer. Bound proteins were eluted in 35 µl of 50 mM
Tris-Cl (pH 7.6) containing 10 mM glutathione, resolved by
SDS-PAGE, and visualized by autoradiography (14). Quantification of the
binding experiments were performed with a Molecular Biosystems Storm
phosphoimaging system (Sunnyvale, CA).
Transient Transfections
For calcium phosphate transfections, CV-1b cells (2 x
105 per 60-mm plate) were propagated overnight at 37 C in a
5% CO2 atmosphere in DMEM containing 10% heat-inactivated
FBS and penicillin-streptomycin (GIBCO/BRL, Gaithersburg, MD). The
cells were subsequently transferred to hormone-depleted medium and
incubated an additional 6 h. Calcium phosphate/DNA precipitates,
prepared by standard protocol (62), were then added, and the cells were
incubated for an additional 16–18 h. Typically, each plate received 1
µg pCH110-lacZ (employed as an internal standard), 1 µg
of a DR4-luciferase reporter (63), various combinations of empty pSG5,
pSG5-T3Rß, or pSG5-N-SMRT (as indicated), and
sufficient pUC18 or pUC19 to bring the total DNA to 10 µg. After an
overnight incubation with precipitate, the cells were washed and
transferred to fresh medium lacking or containing T3. The
cells were harvested 30 h later and lysed in 100 µl Reporter
Lysis Buffer (Promega) per plate. Luciferase activity was determined by
mixing 30 µl of extract with 100 µl Promega luciferase reagent in
an MGM luminometer (MGM Instruments, Cambridge, MA); ß-galactosidase
activity was determined by colorimetric assay (14, 64).
Lipofections were performed using 3 x 104 to 5 x 104 cells seeded per 1 cm-well in 24-well microtiter plates. Lipofectin reagent (GIBCO/BRL) was diluted 10-fold into serum-free medium, incubated 30–45 min at room temperature, then mixed with the DNA and incubated an additional 10 min. Typically, 300 ng pCH110, 100 ng DR4-luciferase reporter, and 100 ng pSG5-T3R construct were employed per well, with sufficient pUC19 DNA to bring the total DNA concentration to 1 µg. The cells were overlayed with the DNA and Lipofectin mixture, incubated 6 h at 37 C, subsequently incubated 18 h with medium containing 20% FBS, and then incubated 24–48 h in medium containing 10% FBS with or without hormone. Cells were lysed and assayed for luciferase and ß-galactosidase activity in a similar manner as that described for the calcium phosphate method.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by Public Health Services/NIH Grant R37 CA-53394.
Received for publication September 19, 1996. Revision received January 27, 1996. Accepted for publication January 27, 1996.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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fusion mRNA encodes a funcionally altered RAR. Cell 66:675–684[CrossRef][Medline]
ligand-binding domain
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W. Wan, B. Farboud, and M. L. Privalsky Pituitary Resistance to Thyroid Hormone Syndrome Is Associated with T3 Receptor Mutants that Selectively Impair {beta}2 Isoform Function Mol. Endocrinol., June 1, 2005; 19(6): 1529 - 1542. [Abstract] [Full Text] [PDF]
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 R. Kumar, A. E. Gururaj, R. K. Vadlamudi, and S. K. Rayala The Clinical Relevance of Steroid Hormone Receptor Corepressors Clin. Cancer Res., April 15, 2005; 11(8): 2822 - 2831. [Abstract] [Full Text] [PDF]
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S. Lee and M. L. Privalsky Heterodimers of Retinoic Acid Receptors and Thyroid Hormone Receptors Display Unique Combinatorial Regulatory Properties Mol. Endocrinol., April 1, 2005; 19(4): 863 - 878. [Abstract] [Full Text] [PDF]
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 M. L. Goodson, B. A. Jonas, and M. L. Privalsky Alternative mRNA Splicing of SMRT Creates Functional Diversity by Generating Corepressor Isoforms with Different Affinities for Different Nuclear Receptors J. Biol. Chem., March 4, 2005; 280(9): 7493 - 7503. [Abstract] [Full Text] [PDF]
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J. Lado-Abeal, A. M. Dumitrescu, X.-H. Liao, R. N. Cohen, J. Pohlenz, R. E. Weiss, M.-C. Lebrethon, A. Verloes, and S. Refetoff A De Novo Mutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor {beta} Gene Perpetuates Resistance to Thyroid Hormone J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1760 - 1767. [Abstract] [Full Text] [PDF]
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K. Kawai, S. Sasaki, H. Morita, T. Ito, S. Suzuki, H. Misawa, and H. Nakamura Unliganded Thyroid Hormone Receptor-{beta}1 Represses Liver X Receptor {alpha}/Oxysterol-Dependent Transactivation Endocrinology, December 1, 2004; 145(12): 5515 - 5524. [Abstract] [Full Text] [PDF]
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 M. Akaike, W. Che, N.-L. Marmarosh, S. Ohta, M. Osawa, B. Ding, B. C. Berk, C. Yan, and J.-i. Abe The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor {gamma}1 (PPAR{gamma}1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPAR{gamma}1 Transcriptional Activation: Involvement in Flow-Induced PPAR{gamma} Activation in Endothelial Cells Mol. Cell. Biol., October 1, 2004; 24(19): 8691 - 8704. [Abstract] [Full Text] [PDF]
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 M. Malartre, S. Short, and C. Sharpe Alternative splicing generates multiple SMRT transcripts encoding conserved repressor domains linked to variable transcription factor interaction domains Nucleic Acids Res., September 1, 2004; 32(15): 4676 - 4686. [Abstract] [Full Text] [PDF]
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M. Agostini, M. Gurnell, D. B. Savage, E. M. Wood, A. G. Smith, O. Rajanayagam, K. T. Garnes, S. H. Levinson, H. E. Xu, J. W. R. Schwabe, et al. Tyrosine Agonists Reverse the Molecular Defects Associated with Dominant-Negative Mutations in Human Peroxisome Proliferator-Activated Receptor {gamma} Endocrinology, April 1, 2004; 145(4): 1527 - 1538. [Abstract] [Full Text] [PDF]
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B. Farboud, H. Hauksdottir, Y. Wu, and M. L. Privalsky Isotype-Restricted Corepressor Recruitment: a Constitutively Closed Helix 12 Conformation in Retinoic Acid Receptors {beta} and {gamma} Interferes with Corepressor Recruitment and Prevents Transcriptional Repression Mol. Cell. Biol., April 15, 2003; 23(8): 2844 - 2858. [Abstract] [Full Text] [PDF]
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 K. Jepsen and M. G. Rosenfeld Biological roles and mechanistic actions of co-repressor complexes J. Cell Sci., February 15, 2002; 115(4): 689 - 698. [Abstract] [Full Text] [PDF]
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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. A. Phillips, P. Rotman-Pikielny, J. Lazar, S. Ando, P. Hauser, M. C. Skarulis, F. Brucker-Davis, and P. M. Yen Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5142 - 5147. [Abstract] [Full Text] [PDF]
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 P. M. Yen Physiological and Molecular Basis of Thyroid Hormone Action Physiol Rev, July 1, 2001; 81(3): 1097 - 1142. [Abstract] [Full Text] [PDF]
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A. Aranda and A. Pascual Nuclear Hormone Receptors and Gene Expression Physiol Rev, July 1, 2001; 81(3): 1269 - 1304. [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. Reutrakul, P. M. Sadow, S. Pannain, J. Pohlenz, G. A. Carvalho, P. E. Macchia, R. E. Weiss, and S. Refetoff Search for Abnormalities of Nuclear Corepressors, Coactivators, and a Coregulator in Families with Resistance to Thyroid Hormone without Mutations in Thyroid Hormone Receptor {beta} or {alpha} Genes J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3609 - 3617. [Abstract] [Full Text]
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 L. J. BURKE and A. BANIAHMAD Co-repressors 2000 FASEB J, October 1, 2000; 14(13): 1876 - 1888. [Abstract] [Full Text]
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 A. Antebi, W.-H. Yeh, D. Tait, E. M. Hedgecock, and D. L. Riddle daf-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans Genes & Dev., June 15, 2000; 14(12): 1512 - 1527. [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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S. Ercan-Fang, H. L. Schwartz, C. N. Mariash, and J. H. Oppenheimer Quantitative Assessment of Pituitary Resistance to Thyroid Hormone from Plots of the Logarithm of Thyrotropin Versus Serum Free Thyroxine Index J. Clin. Endocrinol. Metab., June 1, 2000; 85(6): 2299 - 2303. [Abstract] [Full Text]
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B. Altincicek, S. P. Tenbaum, U. Dressel, D. Thormeyer, R. Renkawitz, and A. Baniahmad Interaction of the Corepressor Alien with DAX-1 Is Abrogated by Mutations of DAX-1 Involved in Adrenal Hypoplasia Congenita J. Biol. Chem., March 10, 2000; 275(11): 7662 - 7667. [Abstract] [Full Text] [PDF]
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M. Gurnell, J. M. Wentworth, M. Agostini, M. Adams, T. N. Collingwood, C. Provenzano, P. O. Browne, O. Rajanayagam, T. P. Burris, J. W. Schwabe, et al. A Dominant-negative Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Mutant Is a Constitutive Repressor and Inhibits PPARgamma -mediated Adipogenesis J. Biol. Chem., February 25, 2000; 275(8): 5754 - 5759. [Abstract] [Full Text] [PDF]
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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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E. Y. Huang, J. Zhang, E. A. Miska, M. G. Guenther, T. Kouzarides, and M. A. Lazar Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway Genes & Dev., January 1, 2000; 14(1): 45 - 54. [Abstract] [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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P.-Y. Chien, M. Ito, Y. Park, T. Tagami, B. D. Gehm, and J. L. Jameson A Fusion Protein of the Estrogen Receptor (ER) and Nuclear Receptor Corepressor (NCoR) Strongly Inhibits Estrogen-Dependent Responses in Breast Cancer Cells Mol. Endocrinol., December 1, 1999; 13(12): 2122 - 2136. [Abstract] [Full Text]
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J. Pohlenz, R. E. Weiss, P. E. Macchia, S. Pannain, I. T. Lau, H. Ho, and S. Refetoff Five New Families with Resistance to Thyroid Hormone not Caused by Mutations in the Thyroid Hormone Receptor {beta} Gene J. Clin. Endocrinol. Metab., November 1, 1999; 84(11): 3919 - 3928. [Abstract] [Full Text]
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 N. J. McKenna, R. B. Lanz, and B. W. O’Malley Nuclear Receptor Coregulators: Cellular and Molecular Biology Endocr. Rev., June 1, 1999; 20(3): 321 - 344. [Abstract] [Full Text]
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 S. M. Thacher, S. Nagpal, E. S. Klein, T. Arefieg, G. Krasinski, D. DiSepio, C. Agarwal, A. Johnson, R. L. Eckert, and R. A. S. Chandraratna Cell Type and Gene-specific Activity of the Retinoid Inverse Agonist AGN 193109: Divergent Effects from Agonist at Retinoic Acid Receptor {{gamma}} in Human Keratinocytes Cell Growth Differ., April 1, 1999; 10(4): 255 - 262. [Abstract] [Full Text]
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R. E. Weiss and S. Refetoff Editorial: Treatment of Resistance to Thyroid Hormone--Primum Non Nocere J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 401 - 404. [Full Text]
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C. J. McCabe, N. J. Gittoes, M. C. Sheppard, and J. A. Franklyn Thyroid Receptor {alpha}1 and {alpha}2 Mutations in Nonfunctioning Pituitary Tumors J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 649 - 653. [Abstract] [Full Text]
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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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T. Tagami, W.-X. Gu, P. T. Peairs, B. L. West, and J. L. Jameson A Novel Natural Mutation in the Thyroid Hormone Receptor Defines a Dual Functional Domain That Exchanges Nuclear Receptor Corepressors and Coactivators Mol. Endocrinol., December 1, 1998; 12(12): 1888 - 1902. [Abstract] [Full Text]
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J. D. Safer, R. N. Cohen, A. N. Hollenberg, and F. E. Wondisford Defective Release of Corepressor by Hinge Mutants of the Thyroid Hormone Receptor Found in Patients with Resistance to Thyroid Hormone J. Biol. Chem., November 13, 1998; 273(46): 30175 - 30182. [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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Y. Liu, A. Takeshita, S. Misiti, W. W. Chin, and P. M. Yen Lack of Coactivator Interaction Can Be a Mechanism for Dominant Negative Activity by Mutant Thyroid Hormone Receptors Endocrinology, October 1, 1998; 139(10): 4197 - 4204. [Abstract] [Full Text] [PDF]
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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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M. Yamaguchi, M. Nakamoto, H. Honda, T. Nakagawa, H. Fujita, T. Nakamura, H. Hirai, S. Narumiya, and A. Kakizuka Retardation of skeletal development and cervical abnormalities in transgenic mice expressing a dominant-negative retinoic acid receptor in chondrogenic cells PNAS, June 23, 1998; 95(13): 7491 - 7496. [Abstract] [Full Text] [PDF]
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R. J. Clifton-Bligh, F. de Zegher, R. L. Wagner, T. N. Collingwood, I. Francois, M. Van Helvoirt, R. J. Fletterick, and V. K. K. Chatterjee A Novel TR{beta} Mutation (R383H) in Resistance to Thyroid Hormone Syndrome Predominantly Impairs Corepressor Release and Negative Transcriptional Regulation Mol. Endocrinol., May 1, 1998; 12(5): 609 - 621. [Abstract] [Full Text]
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T. Tagami, P. Kopp, W. Johnson, O. K. Arseven, and J. L. Jameson The Thyroid Hormone Receptor Variant {alpha}2 Is a Weak Antagonist because It Is Deficient in Interactions with Nuclear Receptor Corepressors Endocrinology, May 1, 1998; 139(5): 2535 - 2544. [Abstract] [Full Text] [PDF]
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A. Baniahmad, U. Dressel, and R. Renkawitz Cell-Specific Inhibition of Retinoic Acid Receptor-{alpha} Silencing by the AF2/{tau}c Activation Domain Can Be Overcome by the Corepressor SMRT, But Not by N-CoR Mol. Endocrinol., April 1, 1998; 12(4): 504 - 512. [Abstract] [Full Text]
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T. Tagami and J. L. Jameson Nuclear Corepressors Enhance the Dominant Negative Activity of Mutant Receptors That Cause Resistance to Thyroid Hormone Endocrinology, February 1, 1998; 139(2): 640 - 650. [Abstract] [Full Text] [PDF]
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S.-H. Hong, G. David, C.-W. Wong, A. Dejean, and M. L. Privalsky SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha ) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia PNAS, August 19, 1997; 94(17): 9028 - 9033. [Abstract] [Full Text] [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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C. T. Baumann, P. Maruvada, G. L. Hager, and P. M. Yen Nuclear Cytoplasmic Shuttling by Thyroid Hormone Receptors. MULTIPLE PROTEIN INTERACTIONS ARE REQUIRED FOR NUCLEAR RETENTION J. Biol. Chem., March 30, 2001; 276(14): 11237 - 11245. [Abstract] [Full Text] [PDF]
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D.-J. Jung, S.-K. Lee, and J. W. Lee Agonist-dependent Repression Mediated by Mutant Estrogen Receptor alpha That Lacks the Activation Function 2 Core Domain J. Biol. Chem., September 28, 2001; 276(40): 37280 - 37283. [Abstract] [Full Text] [PDF]
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M. G. Rosenfeld and C. K. Glass Coregulator Codes of Transcriptional Regulation by Nuclear Receptors J. Biol. Chem., September 28, 2001; 276(40): 36865 - 36868. [Full Text] [PDF]
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