Inhibition of Estrogen Receptor Action by the Orphan Receptor SHP (Short Heterodimer Partner)
Wongi Seol,
Bettina Hanstein1,
Myles Brown and
David D. Moore
Department of Cell Biology (D.D.M.) Baylor College of
Medicine Houston, Texas 77030
Department of Adult
Oncology (W.S., B.H., M.B.) Dana-Farber Cancer Institute
Boston, Massachusetts 02115
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ABSTRACT
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SHP (short heterodimer partner) is an unusual
orphan receptor that lacks a conventional DNA-binding domain. Previous
results have shown that it interacts with several other nuclear hormone
receptors, including the retinoid and thyroid hormone receptors,
and inhibits their ligand-dependent transcriptional activation. Here we
show that SHP also interacts with estrogen receptors and inhibits their
function. In mammalian and yeast two-hybrid systems as well as
glutathione-S-transferase pull-down assays, SHP
interacts specifically with estrogen receptor-
(ER
) in an
agonist-dependent manner. The same assay systems using various
deletion mutants of SHP map the interaction domain with ER
to the
same SHP sequences required for interaction with the nonsteroid hormone
receptors such as retinoid X receptor and thyroid hormone
receptor. In transient cotransfection assays, SHP inhibits
estradiol -dependent activation by ER
by about 5-fold. In contrast,
SHP interacts with ERß independent of ligand and reduces its ability
to activate transcription by only 50%. These data suggest that SHP
functions to regulate estrogen signaling through a direct interaction
with ER
.
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INTRODUCTION
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The nuclear hormone receptor superfamily is a group of
transcription factors that regulate target genes in response to small
hydrophobic compounds such as steroids, thyroid hormone, and retinoids.
The members of this superfamily play a variety of important roles in
development and differentiation by regulating transcription of specific
target genes (1, 2, 3, 4). In general, these proteins bind DNA with high
affinity as dimers. The majority of the type II or nonsteroid
receptors, such as the thyroid hormone receptor (TR), retinoic acid
receptor (RAR), or the orphan receptors, require heterodimerization
with the retinoid X receptor (RXR) for high-affinity binding to their
response elements (2). In contrast, the steroid receptors are generally
thought to bind to their response elements exclusively as homodimers
(e.g. Ref. 1), although the recently described ERß isoform
(5, 6) suggests the possibility of additional interactions.
Estrogen receptor (ER) regulates gene expression in female reproductive
tissues in response to estrogen and is an important target in breast
cancer therapy, as more than half of breast cancers express high levels
of ER and depend on estrogen for growth. Although the ER
and ERß
isoforms recognize the same response elements, ERß binds estrogen
with a lower affinity than ER
and shows weaker transactivation
activity (7). In addition, ERß may activate a different spectrum of
genes in response to certain ligands (8). Both the overlapping
expression patterns of ER
and ß in various tissues and the
possibility of formation of ER
-ERß heterodimers have complicated
the understanding of gene regulation by estrogen. Furthermore, recent
studies suggest that ER function may be modulated by cyclin D1 (9, 10)
and that epidermal growth factor, transforming growth
factor-
, and dopamine (11) elicit estrogen-independent,
ER-dependent gene transcription of estrogen-responsive genes. Thus, ERs
may have functional interactions with a range of other signaling
molecules.
SHP (short heterodimer partner) was initially isolated by yeast
two-hybrid screening (12) based on its interaction with mCAR (13), the
murine homolog of the orphan receptor MB67 (14). Isolation of
full-length cDNA clones revealed that SHP, like the orphan DAX-1 (15),
lacks a conventional DNA-binding domain (12). Both direct biochemical
analysis and results from the yeast two-hybrid system demonstrated that
SHP can interact with the thyroid hormone receptor (TR), RAR, RXR, and
other members of the receptor superfamily. In addition, SHP inhibits
in vitro DNA binding by RAR/RXR heterodimers. In mammalian
cell cotransfections, SHP also inhibits transactivation by RAR, mCAR,
and other receptor superfamily members with which it interacts (12).
These results suggest that the major physiological role of SHP is to
repress signaling by other receptor superfamily members. Additional
support for this hypothesis was provided by the recent demonstration
that SHP itself can act as a direct transcriptional repressor (16). The
receptor interaction and repression domains of SHP were mapped to the
central region and carboxyl terminus, respectively, by both mammalian
and yeast two-hybrid assays (16).
We have examined the potential role of SHP in estrogen signaling. Here
we report that SHP interacts with ER
, both in vitro and
in yeast and mammalian two-hybrid systems in a ligand-dependent
fashion. As expected from its functional effects with other receptors,
SHP inhibits transactivation by ER
induced by estrogen. Thus we
propose that SHP is a novel inhibitor of ER
activity and may play a
role in modulating cellular responses to estrogen.
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RESULTS
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SHP Interacts with ER
We have shown previously that SHP interacts with RXR and several
of its heterodimer partners, such as RAR, TR, and mCAR, using
two-hybrid, biochemical, and functional assays (12, 16). Unexpectedly,
the same approaches demonstrate that SHP also interacts with human
estrogen receptor
(ER
). In yeast, ER
interacts with
full-length SHP (Table 1
). The pattern
of interaction of ER with a series of SHP deletion mutants (Fig. 1
) previously used to identify SHP
sequences required for interaction with other receptors (16) is quite
similar to that described for RXR, although interaction of ER with the
E1 and W160X mutants is more ligand dependent (Table 1
). These
results identify SHP residues 72148 as the minimal ER interaction
domain. This same region is sufficient for interaction with RXR, TR,
RAR, and mCAR (16).

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Figure 1. Deletion Mutants of SHP
The ER-interacting domain is indicated by a solid box.
The deletion constructs were previously described (16 ).
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The possibility of a direct interaction of SHP with ER was tested
biochemically. As indicated in Fig. 2A
, [35S]methionine-labeled SHP showed
17ß-estradiol-dependent interaction with a
glutathione-S-transferase (GST)-human ER
ligand-binding
domain (LBD) fusion protein (lanes 24). This SHP-ER interaction was
as strong as or stronger than interaction of SHP with full-length RXR
(lanes 36). An analogous, although somewhat weaker, ligand-dependent
interaction was also observed between a GST full-length SHP fusion and
[35S]methionine-labeled full-length hER
(data not
shown). The interaction of rat ERß (rERß) and SHP was also examined
using GST-rERß LBD and [35S]methionine-labeled SHP. A
specific, but ligand-independent and relatively weak interaction was
observed (data not shown). In contrast to these results with ER
isoforms, a GST-human androgen receptor LBD (GST-hAR) fusion protein
did not interact with SHP in either the presence or absence of its
ligand (Fig. 2A
, lanes 7 and 8), and GST-SHP also showed no interaction
with radiolabeled full-length hAR (data not shown).

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Figure 2. In vitro Interaction of GST-Receptor
Fusion Protein with SHP
Full-length murine SHP and various mutants (Fig. 1 ) were radiolabeled
with [35S]methionine by in vitro
translation with pT7lacHisMycSHP. A, Specific interaction of SHP with
GST-human ER . GST-ER LBD, -AR LBD, and -RXR full-length
proteins were expressed in E. coli BL21 strain and
tested for interaction with SHP in the absence and presence of their
cognate ligands (25 ). For ligands, 1 µM of
17ß-estradiol, 9-cis-retinoic acid, and R1881 were
used for ER, RXR, and AR, respectively, and indicated as +. SHP did not
bind to GST protein. About 20% of SHP used in each lane was shown as
INPUT (lane 1). B, Effect of 4-OHT on interaction of SHP with ER.
GST-human ER LBD fusion protein was incubated in the absence or
presence of 10 nM (indicated as 1) or 1 µM
(indicated as 100) 17ß-estradiol (E2). To test whether
SHP can interact with ER in the presence of a partial agonist, 1
µM 4-OHT was incubated with or without 10 nM
estradiol. About 20% of radiolabeled SHP used in each lane was shown
as INPUT (lane 1). c, Mapping of ER-interacting domain of SHP. SHP
products were tested for interaction with a GST fusion to LBD of human
ER in the absence and presence of 1 µM
17ß-estradiol. Tests of SHP proteins with GST alone did not show any
specific interaction.
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As 4-hydroxy-tamoxifen (4-OHT) acts as a partial ER
agonist in
liver, where SHP is highly expressed, the effect of 4-OHT on the
in vitro interaction between SHP and ER
was examined. As
shown in Fig. 2B
, SHP did not bind to ER in the presence of 1
µM 4-OHT (lane 6). Moreover, addition of 1
µM of 4-OHT abolished the hormone-dependent interaction
observed in the presence of 10 nM estradiol (lane 5). These
results indicate that SHP specifically recognizes the
estrogen-bound form of ER
.
Various deletion mutants of SHP were used to confirm the mapping of the
ER interaction domain of SHP (Fig. 2C
). Consistent with the results
observed in yeast, the pattern of in vitro interactions was
almost identical to that reported for RXR (16). SHP-ER interaction was
retained with several SHP mutants, including W160X, which lack the
I-box or the 9th heptad, as well as internal deletions of either this
region (
E3), or of the more highly conserved signature motif located
near the N terminus of the LBD (
E1). The SHP N-terminal deletion
120 did not show specific interaction in vitro with
GST-ER, relative to GST alone. The smallest protein retaining specific
in vitro interaction was the
N-148 mutant, as observed in
yeast (Fig. 2C
and Table 1
).
To further confirm these results, the interaction of SHP with ER
was
tested using the mammalian two-hybrid system, with GAL4-hER
LBD and
VP16-SHP fusion constructs. Cotransfection of GAL4-ER with VP16 alone
in HepG2 cells showed approximately 5-fold activation by
17ß-estradiol relative to cotransfection of both empty vectors, GAL4
and VP16. However, cotransfection of VP16-SHP fusion with GAL4-ER LBD
increased transactivation to more than 35-fold, or 7-fold greater than
that of the GAL4-ER
LBD with VP16 alone (Fig. 3
). Very similar results were obtained in
transfections using U2-OS cells (data not shown).

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Figure 3. Specific Interaction of ER with SHP in HepG2 Cells
by a Mammalian Two-Hybrid Assay
GAL4-human ER LBD (0.1 µg/well) and VP16-SHP (0.5 µg/well) were
cotransfected by diethylaminoethyl-dextran method (28 ) with TKGH
(0.5 µg/well) and luciferase reporter plasmid containing three copies
of GAL4 DNA-binding element (0.5 µg/well) into HepG2 cells grown in
12-well plates. Fresh media containing either 1 µM
17ß-estradiol or ethanol were added about 16 h after DMSO shock.
Results are expressed relative to luciferase expression with empty
vectors, GAL4 alone plus VP16, in the absence of ligand. The data were
reproducible, and a similar pattern was obtained with transfection of
U2-OS cells.
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Overall, we conclude that SHP specifically interacts with ER in a
ligand-dependent manner, as demonstrated by both yeast and mammalian
two-hybrid systems, and by in vitro assays.
SHP Inhibits Transactivation by ER
SHP inhibits transactivation by RAR, mCAR, and other nuclear
receptors (12). Thus, the effect of SHP on transactivation by human
ER
was tested in transient cotransfections using a luciferase
reporter containing three copies of the vitellogenin estrogen response
element (ERE). As shown in Fig. 4
, A and
B, this reporter was transactivated by approximately 30-fold by ER
in U2-OS cells. However, this transactivation was decreased in a
dose-dependent manner by SHP coexpression, with only approximately 20%
of the response remaining with a 10-fold molar excess of SHP expression
vector (Fig. 4B
). This level of inhibition is similar to that
previously observed with mCAR and RXR, and stronger than that with RAR
(12). As expected, a similar inhibitory effect of SHP on ER
was also
observed in HepG2 cells (data not shown). Consistent with the
relatively weak, ligand-independent interaction of SHP with ERß
observed in vitro, SHP coexpression decreased ERß
transactivation by approximately 50% in either the presence or absence
of ligand (Fig. 4A
).

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Figure 4. Specific Inhibition of ER by SHP
A, Inhibition of transactivation by ER with SHP. Plasmids containing
human ER and rat ERß1 in pCDNA3 vector (25 ng/well) and SHP in
CDM8 vector (250 ng/well) were cotransfected with TKß-gal (125
ng/well) and ERETKluciferase (250 ng/well), a luciferase reporter
plasmid containing three copies of vitellogenin ER response element, into U2-OS cells grown
in 24-well plates. Results are expressed relative to luciferase
activity with pCDNA3 alone without 17ß-estradiol. The data were
reproducible, and a similar pattern was obtained with transfection of
HepG2 cells. B, Dose-dependent inhibition of SHP. Plasmids containing
human ER in pCDNA3 vector (25 ng/well) were cotransfected with 1-,
5-, or 10-fold concentration of SHP in CDM8 vector (25, 125, or 250
ng/well, respectively) in addition to TKß-gal (125 ng/well) and
ERETKluciferase (250 ng/well) into U2-OS cells grown in 24-well plates.
Results are expressed relative to luciferase activity with pCDNA3 alone
without 17ß-estradiol. The data were reproducible and a similar
pattern was obtained with transfection of HepG2 cells. c, No effect of
SHP on transactivation by AR. Plasmids containing human AR with SV 40
promoter (0.05 µg/well) and SHP in CDM8 vector (0.5 µg/well) were
cotransfected with TKß-gal (0.25 µg/well) and luciferase reporter
plasmid MMTV promoter (0.5 µg/well) into U2-OS cells grown in 24-well
plates. Results are expressed relative to luciferase activity with
empty vector alone without a ligand of AR, R1881. In all experiments, 1
µM of appropriate cognate ligands were added about
16 h after transfection, and cells were incubated for one more day
before harvest for assays.
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4-OHT acted as a partial agonist with ER
but not ERß in U2-OS
cells. Somewhat unexpectedly, SHP also decreased this activation of
ER
, although this effect was much weaker than that observed with
estradiol- activated ER
. The basis for this inhibition is unknown,
but it suggests that the partial agonist activity of 4-OHT in these
cells may be due, in part, to a weak, but direct, activation of the ER
LBD.
In striking contrast to the results with ER
, SHP showed no effect on
transactivation of the mouse mammary tumor promoter (MMTV) promoter by
the AR (Fig. 4C
). This lack of effect is consistent with the lack of
apparent in vitro interaction between SHP and AR (Fig. 2A
)
and clearly demonstrates that SHP is not a general inhibitor of all
members of the nuclear hormone receptor superfamily.
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DISCUSSION
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The results described here confirm and significantly extend
previous indications that SHP can interact with a number of nuclear
receptor superfamily members (12, 16). Based on the presumption that
the type I steroid receptors act as homodimers (notwithstanding the
ability of ERß to heterodimerize with ER
) the addition of ER
to
the list of SHP partners is surprising.
At least superficially, the interactions of SHP
with its partners appear similar to those of RXR with its partners, but
with opposite consequences. In contrast to RXR, SHP generally inhibits
transactivation by the superfamily members with which it interacts.
Direct interaction with SHP also blocks, rather than stimulates, DNA
binding by RAR/RXR heterodimers and other SHP targets (12). This latter
finding led to the suggestion that the inhibitory effects of SHP are a
simple consequence of the inhibition of DNA binding (12). However,
further studies have demonstrated additional complexities in the
interactions of SHP with its partners. Thus, the mapping results
described here confirm the previous conclusion that the interaction of
SHP with its partners involves sequences quite distinct from the more
C-terminal subdomain that is involved in both ER homodimerization (17, 18) and RXR heterodimerization (19). When combined with the additional
demonstration that SHP has the capacity to act directly as a
transcriptional repressor (16), a somewhat more complex alternative
mechanism for its inhibitory effects is suggested. In this model,
inhibition could be a consequence of the recruitment of the SHP
repressor activity to response elements via a novel SHP-receptor
interaction, which would differ significantly from standard receptor
homodimer or heterodimer interactions.
This latter model may account for the inhibitory effect of SHP on
ER
. Steroid receptors have a potent dimerization function associated
with their DNA-binding domains and are able to bind their response
elements and transactivate even in the absence of their LBDs. Thus,
based on the well-documented modular nature of the ER, interaction of
SHP with the ER LBD should not preclude the homodimerization of the
DNA- binding domain, and therefore should not block DNA binding.
Indeed, we have so far been unable to demonstrate an inhibitory effect
of SHP on DNA binding by ER
in vitro using conditions in
which binding by RAR/RXR heterodimers is strongly decreased. While this
negative result may not reflect the results in vivo, it is
most consistent with the model in which the inhibition of ER
transactivation by SHP is a consequence of the action of the SHP
repressor domain, rather than an inhibition of DNA binding. This model
is also supported by cotransfection results with SHPW160X, which
contains the interaction domain but not the repression domain and shows
little inhibitory effect on ER
transactivation (data not shown). At
least one of its predictions has not been borne out, however, since we
have been unable to demonstrate the existence of a multimeric
DNA-ER-SHP complex using standard gel shift approaches. The similar
failure to demonstrate an analogous DNA-SF1-DAX-1 complex (20) suggests
either that the interactions of SHP (or the closely related DAX-1) with
their receptor targets may be rather transient, or that other technical
issues may preclude the identification of such complexes in
vitro.
Regardless of the mechanism of the inhibitory effect, it could have a
significant impact on ER
function. SHP is most abundantly expressed
in liver and adrenal gland, with lower expression in other tissues
(Refs. 12, 21 and H-S. Choi, unpublished data). In contrast, ER
has generally been considered to function in reproductive tissues such
as uterus and breast. However, ER
is also active in liver, where its
expression is regulated by GH and various ligands of the nuclear
hormone receptors such as T3 and dexamethasone (22, 23).
Recently, interest in ER
function in the liver has been
significantly heightened by results suggesting that the
cardioprotective effects of estrogen are based, at least in part, on
its effects on liver gene expression. For example, the demonstration of
ER
- mediated transactivation of low density lipoprotein (LDL)
receptor promoter in transiently transfected HepG2 cells (24) suggests
that direct effects of SHP on ER
transactivation could have quite
significant physiological consequences. Further work will be required
to identify the most important targets of ER
in the liver and the
role of SHP in modulating cellular responses to estrogen.
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MATERIALS AND METHODS
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Plasmids
Construction of pT7lacHisMyc murine SHP full length and the
various deletion mutants of murine SHP were reported previously
(16).
The GAL4-ER
and B42-ER
were constructed by insertion of the ER
cDNA digested with EcoRI from pGEX-hER
LBD cDNA into
pCMX-GAL4 DBD (DNA binding domain) and pJG45 (25) treated with
EcoRI, respectively. ERß was isolated from rat prostate
cDNA library by PCR and inserted in pCDNA3 vector (Invitrogen, San
Diego, CA). Sequencing confirmed that this isolate is identical to the
ERß clone reported previously (6).
In Vitro Interaction
[35S]methionine-labeled proteins were prepared by
in vitro translation using pT7lacHisMyc vectors containing
cDNAs coding for full-length SHP and deletion mutants (16) and the
TNT-coupled transcriptional translation system with conditions as
described by the manufacturer (Promega, Madison, WI). GST fusion
proteins containing the LBD of human ER
or human AR, or the
full-length human RXR
(GST-ER, -AR, and -RXR) were expressed
in the E. coli BL21 strain and purified using
glutathione-sepharose affinity chromatography as suggested by the
vendor (Pharmacia, Piscataway, NJ). In vitro protein-protein
interaction assays were carried out as described (26).
Yeast Two-Hybrid Assay
For the yeast two-hybrid system (25, 27), LexA-murine SHP full
length and deletion (16) and B42-human ER
and -human RXR
LBD
fusion plasmids were cotransformed into Saccharomyces
cerevisiae EGY48 strain containing the ß-galactosidase (ß-gal)
reporter plasmid, 8H1834. Characterization of ß-gal expression on
plates was carried out as described (28). Similar results were obtained
in more than two similar experiments with independently isolated
transformants.
Cell Culture and Transfections
HepG2 and U2-OS cells were propagated in DMEM plus 10% FBS. For
transfection of HepG2 cells, cells were grown in 12-well plates with
medium supplemented with 10% charcoal-stripped serum for 24 h and
transfected as described (29) using the
diethylaminoethyl-dextran/chloroquine method followed by dimethyl
sulfoxide (DMSO) treatment. Transfections included indicated amounts of
plasmids expressing proteins of interest and 0.5 µmg/well of both
TKGH (30) and a reporter plasmid containing a luciferase gene
and GAL4-binding elements. Approximately 16 h after DMSO
treatment, 1 µM 17ß-estradiol was added
with fresh medium, and cells were incubated for 1 day.
For transfection of U2-OS cells, the calcium phosphate method (29) or
superfect transfection reagent (Qiagen, Valencia, CA) was used with
cells grown in 24-well plates. A plasmid containing a luciferase gene
and vitellogenin ERE was used as a reporter and TKß-galactosidase as
the internal control plasmid. Approximately 16 h after
transfection, a final concentration of 1 µM
17ß-estradiol, 4-OHT, or R1881 was added with fresh medium, and cells
were incubated for one more day. Luciferase was assayed as described by
the manufacturer (Promega), and the results were normalized using
either GH or ß-gal expression from the internal control plasmids.
Similar results were obtained in more than two similar experiments.
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ACKNOWLEDGMENTS
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AR mammalian expression vector and GST-AR plasmid were gifts
from Dr. Z. Sun (Boston, MA).
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FOOTNOTES
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Address requests for reprints to: David D. Moore, Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: moore{at}bcm.tmc.edu
This work was supported by NIH Grants RO1 DK-46546 to D.D.M. and RO1
CA-57374 to M.B. W.S. was supported by a Helen Hay Whitney
Foundation fellowship.
1 Present address: Molekulargenetisches Labor der
Universitäts-Frauenklinik im, BMFZ, Gebäude 23.12.04,
Univeritäts skr. 1, 40225 Düsseldorf, Germany. 
Received for publication February 10, 1998.
Revision received June 24, 1998.
Accepted for publication October 2, 1998.
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