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Cellular and Molecular Medicine (M.S., A.V., C.K.G.) and, Howard
Hughes Medical Institute (T.H., R.M.L., M.G.R.), Graduate Program in
Biology (R.M.L.),University of California, San Diego, La Jolla,
California 92093-0651,
H. Lee Moffitt Cancer Center and
Research Institute (W.Y., E.S.), University of South
Florida,Tampa, Florida 33612,Salk Institute for Biology
(D.A.P.), La Jolla, California 92037
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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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Biochemical studies of cellular proteins that were capable of
interacting with the unliganded thyroid hormone and retinoic acid
receptors led to the identification of a 270-kDa protein, termed N-CoR
(nuclear receptor corepressor), that exhibited several properties
suggesting that it might serve a role as a corepressor (12, 13). N-CoR
interacted with the ligand-binding domains of both the thyroid hormone
and retinoic acid receptors and was released from DNA-bound receptors
by T3 and retinoic acid, respectively. Interaction of N-CoR
with the thyroid hormone and retinoic acid receptors required a region
within the N-terminal end of the ligand-binding domain, termed the CoR
box (12, 13). Mutations within this region of the thyroid hormone and
retinoic acid receptors abolished ligand-independent repression,
suggesting that interaction with N-CoR is required for repression
function. The isolation of cDNAs encoding N-CoR indicated that the
primary transcript can be alternatively spliced to generate several
distinct protein products (13, 14). Western blotting experiments
indicated that the major protein products migrate at approximately 270
kDa, consistent with the forms initially identified to interact with
the retinoic acid and thyroid hormone receptors (12, 13). Functional
analysis of N-CoR deletion mutants indicate that it contains two
distinct C-terminal domains required for interactions with nuclear
receptors (14, 15). Fusion of N-CoR to the DNA- binding domain of GAL4
resulted in a chimeric protein that strongly repressed the
transcription of a promoter containing GAL4-binding sites (13).
Analysis of subregions of N-CoR linked to the GAL4 DNA-binding domain
led to the identification of three distinct regions, termed repressor
domains I, II, and III, that possessed intrinsic repressor activity
(Fig. 1
). Finally, overexpression of the C-terminal
domain of N-CoR lacking repression domains I-III relieves repression by
the unliganded thyroid hormone receptor (16). Based on these
observations, N-CoR was proposed to function as a nuclear receptor
corepressor (12, 13).
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Recent investigations into the mechanisms by which N-CoR might exert repressive effects have suggested a link with members of the Sin3 family of transcriptional corepressors (34a). Sin3 was initially identified by genetic screens for suppresser mutations of a Swi 5 defect in yeast (19, 20). Mammalian homologs of Sin3 were subsequently discovered in the course of investigating mechanisms responsible for transcriptional repression by bHLHZ proteins of the Mad family (21, 22). Members of the Mad family, which are believed to be involved in the induction of terminal differentiation in a wide range of cell types, have previously been demonstrated to act as transcriptional repressors upon heterodimerization with Max (23, 24, 25, 26, 27, 28, 29). The Mad proteins contain an N-terminal region that is required for transcriptional repression. Utilizing this repression domain to identify interacting proteins, mammalian homologs of Sin3 (mSin3A and mSin3B) were identified (21, 22).
Genetic studies in yeast have linked transcriptional repression by Sin3 to the global transcriptional regulator RPD3 (30, 31, 32, 33). A human homolog of RPD3, hdac1, was isolated by virtue of its interaction with trapoxin, a histone deacetylase inhibitor (34). These observations led to the demonstration that RPD3 and hdac1 both posses histone deacetylase activity, suggesting a direct link between histone deacetylation and transcriptional repression.
Based on the parallels between transcriptional repression by nuclear
receptors and Mad/Max heterodimers, studies have been performed to
determine whether there might be functional interactions between mSin3,
N-CoR, and RPD3. Consistent with this possibility, mSin3 and N-CoR have
recently been found to directly interact in vitro (34a). Two
Sin interaction domains within N-CoR were demonstrated to be capable of
mediating these interactions, an N-terminal SIN interaction domain (SID
1) extending from amino acids 254 to amino acid 312 in repression
domain I and a second domain (SID 2), extending from amino acids 1829
to 1940, in the C terminus of N-CoR (Fig. 1
and Ref. 34a). Evidence
that the interactions between N-CoR and mSin3A/B are relevant to the
repressive activities by nuclear receptors was provided by
microinjection experiments in which cells were injected with antibodies
directed against either N-CoR or the murine Sin3 homologs (34a). These
experiments provided evidence that mSin3A/B and N-CoR were each
required for transcriptional repression by nuclear receptors and by
Mad.
A potential role for RPD3 in repression events was suggested by immunoprecipitation experiments, in which anti-Sin3A/B antibodies coprecipitated RPD3 (R. Eisenman, personal communication). Furthermore, microinjection of anti-RPD3 antibodies relieved repression by the nuclear receptor ligand-binding domain and by Mad (34a). In concert, these observations suggested the existence of a corepressor complex containing N-CoR, mSin3A/B, and RPD3 that is required for transcriptional repression by at least two distinct families of transcription factors.
To further examine the possibility that N-CoR, Sin3A/B, and RPD3 function as components of a corepressor complex in cells, we have performed a series of experiments examining the functional properties of N-CoR deletion mutants and the subnuclear localization of N-CoR and RPD3 using specific antibodies. Paradoxically, marked overexpression of N-CoR relieves, rather than potentiates, the repressive effects of the unliganded retinoic acid receptor. These observations suggest that alterations in the stoichiometry of corepressor function result in inhibition of the repressor complex. At low levels of expression, N-CoR is widely distributed throughout the nucleus in a nonuniform pattern, while at high levels of expression, an additional subpopulation of N-CoR becomes localized to multiple discrete dot structures. This discrete pattern of localization requires the presence of the N-CoR C terminus. RPD3 is also widely distributed throughout the nucleus in a nonuniform pattern. RPD3 and N-CoR appear to partially colocalize, consistent with the possibility that they are involved in the formation of a corepressor complex. RPD3 does not colocalize with N-CoR in the dot structures, however, and RPD3 and N-CoR are independently distributed throughout much of the nucleus. These observations suggest that the interactions between N-CoR and RPD3 may be dynamically regulated and are consistent with biochemical studies of histone deacetylases in yeast that suggest functionally distinct complexes.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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. Domains
involved in transcriptional repression, nuclear receptor interaction,
and mSin3A/B interaction are indicated. In the case of deletion mutants
lacking the extreme amino terminus, a nuclear localization signal was
incorporated into the expression vector to ensure appropriate targeting
of N-CoR derivatives to the nucleus. In addition, to facilitate
immunolocalization of these various derivatives, an epitope (FLAG)-tag
was engineered into the carboxy terminus.
Functional analysis of N-CoR and N-CoR deletion mutants was initially
performed by assessing their effects on the transcriptional properties
of retinoid acid receptor (RAR)/retinoid X receptor (RXR) heterodimers
bound to the DR1 element present in the CRBPII promoter (Fig. 2). On this element, the RAR has been shown to
constitutively repress transcription by RXR in CV1 cells (35, 36). We
have previously demonstrated that N-CoR remains bound to RAR on this
element, even in the presence of retinoic acid (12). As illustrated in
Fig. 2A, several deletion mutants of N-CoR resulted in
ligand-independent derepression of the RAR/RXR heterodimer on the DR1
element, consistent with the possibility that they functioned as
dominant negative inhibitors of endogenous N-CoR function.
Surprisingly, however, overexpression of the full-length N-CoR protein,
rather than potentiating transcriptional repression, also resulted in
increased levels of transcription from the DR1 element (Fig. 2A). This
effect was dependent on the presence of the DR1 elements because
overexpression of N-CoR or N-CoR 1586–2453 had no effect on the
thymidine kinase (TK) promoter containing GAL4-binding sites (Fig. 2B).
One possible interpretation of this paradoxical effect of N-CoR might
be that at high levels of expression, N-CoR titrates out additional
components required for the function of a corepressor complex. To
assess this possiblility, transcriptional activity of the
DR1-containing promoter was evaluated over a wide range of N-CoR
expression by transfecting between 10 ng to 5 µg of N-CoR expression
plasmid. At low levels of N-CoR expression (10–100 ng expression
plasmid per well), transcription from the DR1-containing promoter was
reduced, while at 1–5 µg of N-CoR expression plasmid, transcription
was significantly increased (Figs. 2C and 3A). Indeed, when 1–5 µg
of N-CoR expression plasmids were transfected, there was not only an
increase in basal expression from the DR1-containing promoter, but the
transcriptional response to the RAR-specific ligand, TTNPB, was also
significantly increased (Fig. 3A). When evaluated on a
promoter containing two copies of the DR5 element present in the
RARß2 promoter, transfection of 1–5 µg of N-CoR expression plasmid
similarly resulted in a marked increase in promoter activity in the
absence of ligand, consistent with relief of ligand-independent
repression (Fig. 3B).
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). Undifferentiated
ES cells exhibited very high levels of N-CoR. Intriguingly, N-CoR
levels were markedly down-regulated during the in vitro
differentiation of ES cells into embryoid bodies after removal of
leukemia-inhibiting factor (LIF). These observations indicate that
N-CoR levels can be dynamically regulated in cells.
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, transient
expression of epitope-tagged N-CoR in CV1 cells revealed a finely
granular nuclear pattern of staining that was excluded from the
nucleolus. In many cells, N-CoR staining was also observed in a number
of discrete dot structures. The accumulation of N-CoR in these
structures appears to be a consequence of high levels of N-CoR
expression, as parallel experiments using antibodies directed against
the N- or C-terminal regions of the endogenous N-CoR in nontransfected
cells exhibited the identical granular staining pattern as exogenously
expressed N-CoR, but did not stain the discrete dot structures (data
not shown). Furthermore, increased levels of N-CoR expression, achieved
by transfection of increasing amounts of N-CoR expression plasmid, were
correlated with an increase in the number and size of these dot
structures (Fig. 5, panels B-D). A similar pattern of
N-CoR staining was observed in HeLa cells and P19 cells (data not
shown), indicating that localization of N-CoR into these discrete
structures was not cell type-specific. Treatment of cells with retinoic
acid did not alter the staining pattern of N-CoR (data not shown).
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. As illustrated in Fig. 6B, the N-terminal region of N-CoR (amino acids 1–1461)
containing repressor domains 1, 2, and 3 was localized to the nucleus
in a finely granular pattern, but failed to stain the dot-like
structures observed for full-length N-CoR. In contrast, a construct
containing C-terminal amino acids from 758 to 2453 exhibited both the
granular and dot-like patterns of staining (Fig. 5C). Additional
amino-terminal deletion mutants beginning at amino acids 979 and
1586 also exhibited both granular and dot-like patterns of staining
(Fig. 6, D and E). A further N-terminal deletion to amino acid 2218
resulted in a diffuse pattern of staining in both the cytoplasm and
nucleus. An internal region of N-CoR extending from 1586 to 2211 also
failed to exhibit a dot-like staining pattern. Most of the N-CoR
deletion mutants that accumulated in nuclear dot structures were also
observed to relieve repression. However, relief of repression was also
observed for some N-CoR derivatives that did not localize to nuclear
dot structures. For example, N-CoR 1586–2211 did not accumulate in dot
structures but was effective at relieving repression. This may reflect
the fact that N-CoR 4586–2211 retains one of the nuclear receptor
interaction domains (NRI) and would be expected to compete with
endogenous N-CoR for interaction with RAR.
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, indirect immunofluoresence staining of RPD3
exhibited an exclusive nuclear staining pattern. RPD3 was excluded from
the nucleolus, but was otherwise widely distributed in a nonuniform
pattern. To determine whether RPD3 and N-CoR were colocalized, confocal
laser scanning microscopy was performed. At high image magnification,
RPD3 was localized to many small, diffuse clusters (Fig. 7A). In
addition to the discrete dot-like structures, N-CoR was also localized
to diffuse clusters, although this pattern was somewhat less distinct
than that observed for RPD3 (Fig. 7C). Examination of cells exhibiting
low, moderate, and high levels of transfected N-CoR expression revealed
similar patterns of staining, with the exception that the discrete dot
pattern was only observed at higher levels of N-CoR expression (data
not shown). Upon merging the images obtained for N-CoR and RPD3 within
the same optical section, some colocalization of the two antibodies was
observed, as evidenced by the yellow staining pattern (Fig. 7B). A
significant fraction of the staining for the two proteins did not
colocalize, however, and several regions were observed that stained
brightly for RPD3, but not N-CoR, or brightly for N-CoR, but not RPD3.
Thus, although these observations are consistent with biochemical
experiments indicating that RPD3 and N-CoR interact, they suggest that
a substantial fraction of these proteins reside in separate
compartments within the nucleus.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Investigation of the mechanisms responsible for transcriptional repression by the retinoic acid and thyroid hormone receptors led to the identification of N-CoR and the related factor SMRT, which were subsequently demonstrated to mediate transcriptional repression by v-Erb A and Rev-erb (12, 13, 15, 18). In contrast, mSin3A/B were identified as putative corepressors of Mad (21, 22). Protein-protein interaction assays and coimmunoprecipitation studies have recently demonstrated that N-CoR and mSin3 A/B are components of a corepressor complex that is required for the repression functions of both Mad and unliganded RAR and thyroid hormone receptor (34a). Intriguingly, Sin3 has been demonstrated previously to inhibit the activity of the progesterone receptor in yeast, suggesting that it may play a more general role in regulating nuclear receptor function (45). Although direct interactions have not yet been established, immunoprecipitation of mSin3 A/B or of N-CoR from cells coprecipitates the histone deacetylase, RPD3. RPD3 appears to be required for repression by unliganded nuclear receptors and Mad because microinjection of anti-RPD3 antibodies into cells reverses their repressive effects (34a).
The link between histone deacetylases and corepressor proteins that directly interact with Mad and unliganded retinoic acid and thyroid hormone receptors suggests an attractive mechanism by which these factors repress the transcription of target genes. It has been well established that nucleosomes play important roles in both positive and negative regulation of transcription (reviewed in Refs. 39, 46, and 47). The dynamic effects of nucleosomes on transcription have been suggested to be due, in part, to the acetylation of lysine residues present in the amino-terminal ends of the core histones (46). Numerous studies have demonstrated that nucleosomes containing hyperacetylated histones are colocalized with actively transcribed regions of the genome (48, 49, 50). Conversely, histone hypoacetylation is associated with heterochromatic regions of DNA that are transcriptionally silent (51, 52). The mechanisms by which the state of histone acetylation influences transcription have not been established, but acetylation of the N-terminal tails of histones H3 and H4 appears to facilitate the association of other transcription factors with nucleosomal DNA (53).
The acetylated state of the core histones is thought to be determined by the competing activities of histone acetylases and deacetylases. In this regard it is intriguing to note that transcriptional activation by liganded nuclear receptors has been demonstrated to require cAMP response element binding protein (CBP) and/or p300 (54, 55, 56, 57). CBP and p300 each posses intrinsic histone acetylase activity (58, 59) and can associate with p/CAF, which also exhibits histone acetylase activity (60). These observations suggest a highly symmetric model in which transcriptional repression is mediated by a complex containing N-CoR, mSin3, and RPD3, which effects local histone deacetylation. Upon binding of activating ligands, this deacetylase-containing complex dissociates from nuclear receptors and is replaced by a coactivator complex containing CBP/p300 and p/CAF, which acetylates histones and facilitates entry of core transcription factors.
In the present study, we have evaluated the consequences of overexpression of N-CoR and N-CoR deletion mutants and have examined the intracellular distributions of N-CoR and RPD3 in the cell. At low levels of expression, both N-CoR and RPD3 are distributed in the nucleus in a nonuniform, finely granular pattern. Based on images obtained using confocal laser scanning microscopy, a fraction of N-CoR and RPD3 appear to be colocalized, consistent with biochemical evidence for their presence in a corepressor complex. However, a significant fraction of the two proteins also appears to be independently distributed. These observations suggest heterogeneity in the composition of corepressor complexes containing RPD3 and/or the possibility that the formation of mSin3/N-CoR/RPD3 is dynamically regulated. Biochemical evidence for heterogeneity in histone deacetylase complexes has been obtained in yeast, in which two deacetylase complexes have been identified, termed HDA and HDB, that exhibit different sensitivities to deacetylase inhibitors (61).
Overexpression of several regions of N-CoR involved in nuclear receptor or mSin3 interaction resulted in derepression of RAR/RXR heterodimers bound to a DR1 element, consistent with the possibility that they serve as dominant negative inhibitors of endogenous N-CoR activity. Surprisingly, marked overexpression of N-CoR relieved receptor-dependent repression. These observations raised the possibility that active repression by N-CoR might require a specific stoichiometry of corepressor components, and that overexpression of N-CoR might cause redistribution of some of these components away from the target promoter. Localization of N-CoR by indirect immunofluorescence revealed that, when expressed at high levels, a significant fraction of N-CoR was redistributed to discrete dot structures within the nucleus that were not observed for endogenous N-CoR. Localization of overexpressed N-CoR to these structures required an extended region of the N-CoR C terminus, containing the nuclear receptor and C-terminal mSin3 interaction domains. The redistribution of N-CoR to these discrete structures is consistent with the possibility that disruption of corepressor complexes accounts for the relief of repression by unliganded RAR/RXR heterodimers observed after N-CoR overexpression. RPD3 was not colocalized to these structures, consistent with the lack of evidence for a direct interaction between RPD3 and N-CoR or mSin3. Additional studies localizing nuclear receptors, mSin3, and other putative components of the corepressor complex should help resolve the possible function of these discrete structures.
Studies of N-CoR expression in ES cells revealed very high levels in undifferentiated cells and marked down-regulation during their differentation into embryoid bodies. These results are consistent with in situ hybridization studies that indicate very high levels of N-CoR mRNA in embryonic tissues. These levels markedly decline during later stages of development and reach much lower levels in adult tissues (M. G. Rosenfeld, unpublished observation). Thus, N-CoR levels appear to be dynamically regulated during development and differentiation. Such changes in N-CoR expression are likely to have significant effects on repression mediated by nuclear receptors and Mad. Intriguingly, the RAR/RXR heterodimer does not constitutively repress transcription from DR1-containing promoters in several ES cell lines (62). These observations raise the possibility that high levels of N-CoR in ES cells may result in derepression, rather than enhanced repression, if other components of the corepressor complex are limiting. It will be of considerable interest to determine whether the marked variations in levels of N-CoR expression result in significant alterations in patterns of transcriptional repression that might have important consequences for normal programs of growth and development.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Transient Transfection Assays
Transfections were performed in six-well plates by the calcium
phosphate method as described previously (34). If not otherwise
indicated, each well was transfected with 1 µg reporter plasmid and 1
µg N-CoR constructs. The precipitate was washed away with PBS after
12 h, and the media was replaced. The cells were harvested after
an additional 24 h and assayed for luciferase activity.
Indirect Immunofluorescence Analysis
Cells were grown on coverslips in 6-cm dishes and were
transiently transfected with N-CoR constructs as indicated. Cells were
washed after 12 h, after which the media were replaced, and the
cells were incubated for an additional 24 h. Cells were then fixed
in 2% paraformaldehyde in PBS for 45 min at room temperature, washed
in PBS, and permeabilized with 0.1% Triton X-100 for 10 min at room
temperature. Monoclonal FLAG antibody M2 (Kodak, New Haven, CT) (50
µg/ml in PBS, 1% BSA) was added for 1 h at room temperature.
For double-staining, cells were incubated with monoclonal FLAG antibody
M2 (50 µg/ml) plus rabbit-mRPD3 antisera (1:50 dilution in PBS, 1%
BSA) for 1 h, followed by five washes in PBS, 0.1% BSA.
Fluorochrome-conjugated secondary antibody (anti-mouse fluorescein
isothiocyante (FITC) affinipure F (ab')2 goat IgG diluted
1:150 was applied for 60 min followed by five washes. Double-stained
cells were incubated for 60 min with fluorochrome-conjugated secondary
antibody (anti-mouse FITC affinipure F (ab')2 goat IgG plus
biotinylated anti-rabbit goat antisera (diluted 1:150), washed five
times in PBS-0.1% BSA, and incubated with Cy3-conjugated streptavidin
(diluted 1:1000), followed by five washes in PBS-0.1% BSA.
Confocal Laser Scanning Microscopy
Fluorescent sections were imaged using a Bio-Rad MRC600 confocal
microscope (Hemel Hempstead, UK) equipped with a krypton/argon laser
and coupled to a Zeiss Axiovert 135 M microscope (Carl
Zeiss, Thornwood, NY) as described (63).
Analysis of N-CoR in ES Cells
D3 ES cells were maintained in an undifferentiated
state by culture in the presence of leukemia-inhibitory factor (LIF).
To induce embryoid body formation, ES cells were transferred to
LIF-deficient media and plated at 1 x 104 cells/ml.
Embryoid bodies formed over the next 5–12 days and exhibited
morphological evidence of hematopoietic development and the development
of contractile cells. Whole-cell extracts were prepared from
undifferentiated ES cells and embryoid bodies as described by Halachmi
et al. (64). N-CoR was purified on a
glutathione-S-transferase (GST)-RAR affinity matrix,
resolved by SDS-PAGE, and transferred to nitrocellulose membranes as
described by Kurokawa et al. (12). N-CoR was detected using
[32P]GST-RAR or anti N-CoR antisera as described
(12).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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M.S. is supported by the Swedish Natural Science Research Counsel scholarship. M.G.R. is an investigator of the Howard Hughes Medical Institute. C.K.G. is supported by NIH Grant 5 RO1CA-52599-07.
Received for publication February 21, 1997. Accepted for publication March 24, 1997.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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 F. Guidez, K. Petrie, A. M. Ford, H. Lu, C. A. Bennett, A. MacGregor, J. Hannemann, Y. Ito, J. Ghysdael, M. Greaves, et al. Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein Blood, October 1, 2000; 96(7): 2557 - 2561. [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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S.-K. Lee, J.-H. Kim, Y. C. Lee, J. Cheong, and J. W. Lee Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors, as a Novel Transcriptional Corepressor Molecule of Activating Protein-1, Nuclear Factor-kappa B, and Serum Response Factor J. Biol. Chem., April 21, 2000; 275(17): 12470 - 12474. [Abstract] [Full Text] [PDF]
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J. A. Grimes, S. J. Nielsen, E. Battaglioli, E. A. Miska, J. C. Speh, D. L. Berry, F. Atouf, B. C. Holdener, G. Mandel, and T. Kouzarides The Co-repressor mSin3A Is a Functional Component of the REST-CoREST Repressor Complex J. Biol. Chem., March 24, 2000; 275(13): 9461 - 9467. [Abstract] [Full Text] [PDF]
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S. Huang and S. J. Brandt mSin3A Regulates Murine Erythroleukemia Cell Differentiation through Association with the TAL1 (or SCL) Transcription Factor Mol. Cell. Biol., March 15, 2000; 20(6): 2248 - 2259. [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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D. Szapary, Y. Huang, and S. S. Simons Jr. Opposing Effects of Corepressor and Coactivators in Determining the Dose-Response Curve of Agonists, and Residual Agonist Activity of Antagonists, for Glucocorticoid Receptor-Regulated Gene Expression Mol. Endocrinol., December 1, 1999; 13(12): 2108 - 2121. [Abstract] [Full Text]
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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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 S. Nimkarn, B. I. Cerame, J.-Q. Wei, M. I. New, R. C. Wilson, M. Dumic, R. Zunec, L. Brkljacic, and V. Skrabic Congenital Adrenal Hyperplasia without Demonstrable Genetic Mutations--Authors' Response J. Clin. Endocrinol. Metab., August 1, 1999; 84(8): 2976a - 2977. [Full Text]
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T. Kakizawa, T. Miyamoto, K. Ichikawa, A. Kaneko, S. Suzuki, M. Hara, T. Nagasawa, T. Takeda, J.-i. Mori, M. Kumagai, et al. Functional Interaction between Oct-1 and Retinoid X Receptor J. Biol. Chem., July 2, 1999; 274(27): 19103 - 19108. [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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T. Miyamoto, T. Kakizawa, and K. Hashizume Inhibition of Nuclear Receptor Signalling by Poly(ADP-Ribose) Polymerase Mol. Cell. Biol., April 1, 1999; 19(4): 2644 - 2649. [Abstract] [Full Text] [PDF]
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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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A. Z. Chaudhry, A. D. Vitullo, and R. M. Gronostajski Nuclear Factor I-mediated Repression of the Mouse Mammary Tumor Virus Promoter Is Abrogated by the Coactivators p300/CBP and SRC-1 J. Biol. Chem., March 12, 1999; 274(11): 7072 - 7081. [Abstract] [Full Text] [PDF]
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T. Nomura, M. M. Khan, S. C. Kaul, H.-D. Dong, R. Wadhwa, C. Colmenares, I. Kohno, and S. Ishii Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor Genes & Dev., February 15, 1999; 13(4): 412 - 423. [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. Logie, M. Nichols, K. Myles, J. W. Funder, and A. F. Stewart Positive and Negative Discrimination of Estrogen Receptor Agonists and Antagonists Using Site-Specific DNA Recombinase Fusion Proteins Mol. Endocrinol., August 1, 1998; 12(8): 1120 - 1132. [Abstract] [Full Text]
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M. Kullmann, J. Schneikert, J. Moll, S. Heck, M. Zeiner, U. Gehring, and A. C. B. Cato RAP46 Is a Negative Regulator of Glucocorticoid Receptor Action and Hormone-induced Apoptosis J. Biol. Chem., June 5, 1998; 273(23): 14620 - 14625. [Abstract] [Full Text] [PDF]
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F. Guidez, S. Ivins, J. Zhu, M. Soderstrom, S. Waxman, and A. Zelent Reduced Retinoic Acid-Sensitivities of Nuclear Receptor Corepressor Binding to PML- and PLZF-RARalpha Underlie Molecular Pathogenesis and Treatment of Acute Promyelocytic Leukemia Blood, April 15, 1998; 91(8): 2634 - 2642. [Abstract] [Full Text] [PDF]
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B. L. Wagner, J. D. Norris, T. A. Knotts, N. L. Weigel, and D. P. McDonnell The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor Mol. Cell. Biol., March 1, 1998; 18(3): 1369 - 1378. [Abstract] [Full Text]
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C. Underhill, M. S. Qutob, S.-P. Yee, and J. Torchia A Novel Nuclear Receptor Corepressor Complex, N-CoR, Contains Components of the Mammalian SWI/SNF Complex and the Corepressor KAP-1 J. Biol. Chem., December 15, 2000; 275(51): 40463 - 40470. [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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L.-N. Song, B. Huse, S. Rusconi, and S. S. Simons Jr. Transactivation Specificity of Glucocorticoid Versus Progesterone Receptors. ROLE OF FUNCTIONALLY DIFFERENT INTERACTIONS OF TRANSCRIPTION FACTORS WITH AMINO- AND CARBOXYL-TERMINAL RECEPTOR DOMAINS J. Biol. Chem., June 29, 2001; 276(27): 24806 - 24816. [Abstract] [Full Text] [PDF]
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