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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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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(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. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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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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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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(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 72–148 as the minimal ER interaction
domain. This same region is sufficient for interaction with RXR, TR,
RAR, and mCAR (16).
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, [35S]methionine-labeled SHP showed
17ß-estradiol-dependent interaction with a
glutathione-S-transferase (GST)-human ER ligand-binding
domain (LBD) fusion protein (lanes 2–4). This SHP-ER interaction was
as strong as or stronger than interaction of SHP with full-length RXR
(lanes 3–6). 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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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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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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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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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) 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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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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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 pJG4–5 (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, 8H18–34. 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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FOOTNOTES |
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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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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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E. M. Resnick, D. A. Schreihofer, A. Periasamy, and M. A. Shupnik Truncated Estrogen Receptor Product-1 Suppresses Estrogen Receptor Transactivation by Dimerization with Estrogen Receptors alpha and beta J. Biol. Chem., March 15, 2000; 275(10): 7158 - 7166. [Abstract] [Full Text] [PDF]
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 L. Johansson, A. Båvner, J. S. Thomsen, M. Färnegårdh, J.-A. Gustafsson, and E. Treuter The Orphan Nuclear Receptor SHP Utilizes Conserved LXXLL-Related Motifs for Interactions with Ligand-Activated Estrogen Receptors Mol. Cell. Biol., February 15, 2000; 20(4): 1124 - 1133. [Abstract] [Full Text]
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Y.-K. Lee, H. Dell, D. H. Dowhan, M. Hadzopoulou-Cladaras, and D. D. Moore The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression Mol. Cell. Biol., January 1, 2000; 20(1): 187 - 195. [Abstract] [Full Text]
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 J.- A. Gustafsson Novel Aspects of Estrogen Action Reproductive Sciences, January 1, 2000; 7(1_suppl): S8 - S9. [Abstract] [PDF]
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C.-y. Chang, J. D. Norris, H. Gron, L. A. Paige, P. T. Hamilton, D. J. Kenan, D. Fowlkes, and D. P. McDonnell Dissection of the LXXLL Nuclear Receptor-Coactivator Interaction Motif Using Combinatorial Peptide Libraries: Discovery of Peptide Antagonists of Estrogen Receptors alpha and beta Mol. Cell. Biol., December 1, 1999; 19(12): 8226 - 8239. [Abstract] [Full Text] [PDF]
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Y.-K. Lee, K. L. Parker, H.-S. Choi, and D. D. Moore Activation of the Promoter of the Orphan Receptor SHP by Orphan Receptors That Bind DNA as Monomers J. Biol. Chem., July 23, 1999; 274(30): 20869 - 20873. [Abstract] [Full Text] [PDF]
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D. A. Schreihofer, E. M. Resnick, A. Y. Soh, and M. A. Shupnik Transcriptional Regulation by a Naturally Occurring Truncated Rat Estrogen Receptor (ER), Truncated ER Product-1 (TERP-1) Mol. Endocrinol., February 1, 1999; 13(2): 320 - 329. [Abstract] [Full Text]
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H. Zhang, J. S. Thomsen, L. Johansson, J.-A. Gustafsson, and E. Treuter DAX-1 Functions as an LXXLL-containing Corepressor for Activated Estrogen Receptors J. Biol. Chem., December 15, 2000; 275(51): 39855 - 39859. [Abstract] [Full Text] [PDF]
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Y. Luo, C.-p. Liang, and A. R. Tall The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor J. Biol. Chem., June 29, 2001; 276(27): 24767 - 24773. [Abstract] [Full Text] [PDF]
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Y.-K. Lee and D. D. Moore Dual Mechanisms for Repression of the Monomeric Orphan Receptor Liver Receptor Homologous Protein-1 by the Orphan Small Heterodimer Partner J. Biol. Chem., January 18, 2002; 277(4): 2463 - 2467. [Abstract] [Full Text] [PDF]
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T. T. Lu, J. J. Repa, and D. J. Mangelsdorf Orphan Nuclear Receptors as eLiXiRs and FiXeRs of Sterol Metabolism J. Biol. Chem., October 5, 2001; 276(41): 37735 - 37738. [Full Text] [PDF]
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H. Nishigori, H. Tomura, N. Tonooka, M. Kanamori, S. Yamada, K. Sho, I. Inoue, N. Kikuchi, K. Onigata, I. Kojima, et al. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects PNAS, January 16, 2001; 98(2): 575 - 580. [Abstract] [Full Text] [PDF]
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 G. Zollner, P. Fickert, D. Silbert, A. Fuchsbichler, C. Stumptner, K. Zatloukal, H. Denk, and M. Trauner Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G184 - G191. [Abstract] [Full Text] [PDF]
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