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Howard Hughes Medical Institute (W.X., R.M.E.) Gene Expression
Laboratory (W.X., N.N.Y., R.J.L., C.M.S., R.M.E.) The Salk
Institute for Biological Studies La Jolla, California 92037
Department of Pathology (H.H., M.R.S.) University of Southern
California Los Angeles, California 90033
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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and
ß) and steroidogenic factor 1 (SF-1), an additional activation
function (AF-1, or A/B domain) resides in the NH2-terminal
region of the NRs (4, 5, 6, 7). It is possible to exchange the domains
between receptors to create chimeras with predictable altered DNA
and/or ligand binding properties (8). An important conceptual advance for NRs was the isolation and characterization of the orphan receptors whose cognate ligands are either unknown or unnecessary. Most orphan receptors exhibit domain structure similar to that of classic NRs (3, 9, 10, 11). At present, orphan receptors are by far the largest subclass of the family, and ligands and synthetic drugs have been identified for some of these (for review, see Refs. 3, 9, 12).
Recent advances have identified several classes of NR cofactors
that appear to play key roles in transcriptional activation (for
review, see Refs. 13, 14). One well characterized family of
coactivators for NRs are the three related p160 proteins: steroid
receptor coactivator 1 (SRC-1) (15, 16), glucocorticoid receptor
interacting protein 1 (GRIP1)/transcriptional intermediary factor 2
(TIF2) (17, 18, 19), and activator of thyroid and retinoic acid receptors
(ACTR) (20) [also known as p/CIP (p300/CBP interacting protein) (21),
RAC3 (receptor-associated coactivator 3) (22), AIB1 (amplified in
breast cancer 1) (23), and TRAM-1 (thyroid hormone receptor activator
molecule-1)(24)]. Coactivators are targeted to the LBD via specific
receptor interaction domains or RIDs (for review, see Refs. 13, 14).
Both structural and mutational analysis of multiple RIDs revealed a
core LXXLL motif (where L is leucine and X can be any amino acid) that
mediates the direct association. The LXXLL motif-containing -helices
located in the central region of the p160 coactivators function as
protein-protein interaction modules and contact a hydrophobic groove on
the surface of an agonist bound LBD (19, 21, 26, 27, 28). Therefore, the
LBD serves as a molecular switch that recruits activator proteins in
the presence of ligand and releases them in the absence of ligand.
While classical NRs require binding of ligand before they can activate
transcription (16, 18, 19), some receptors display constitutive
activity and bind coactivator in the absence of any apparently added
inducer. For example, orphan receptor CARß apparently functions as a
transcriptional activator and associates with coactivator SRC-1 in the
absence of ligand, while the binding of its ligand androstane
metabolites results in the dissociation of bound coactivators, thus
providing a negative regulatory mechanism for the ligand (29).
Even though human estrogen receptor-related protein 1 and 2 (hERR1 and -2) were the first orphan receptors identified, their properties and mechanisms of transcriptional activation remain to be defined. We now describe the characterization of ligand-independent gene activation by each of these receptors and suggest that members of the p160 family of NR coactivators potentiate this activity.
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, both hERR1 and hERR2
unexpectedly activate transcription through both the ERE and the
palindromic thyroid hormone response element (TREpal) (Fig. 1A) reporters in a hormone- and serum-independent fashion. Under the
same serum-free conditions, other NRs including the ER and TR (Fig. 1A)
and GR (Fig. 1B), activate gene transcription only in the presence of
their cognate ligands. To demonstrate that this constitutive activity
is promoter independent, another series of reporters based on the
glucocorticoid-inducible mammary tumor virus (MTV)-CAT (10) was
used in the cotransfection experiments. To generate 
MTV-ERE-CAT and
MTV-TREpal-CAT (30), the glucocorticoid response element
(GRE) in the MTV sequence was replaced by the ERE or
TREpal, respectively. As shown in Fig. 1B, when this series
of reporters were cotransfected in HeLa cells together with the hERR2
expression plasmid, gene transcription is again activated independently
of exogenous hormones or serum. In addition, similar activation curves
were seen with the ERE-containing Xenopus vitellogenin A2
gene promoter (vitA2 -331/-87CAT) (31) when cotransfected with hERR1
and hERR2 expression vector (data not shown). Induction is specific to
ERE and TRE reporter genes as the two hERRs fail to stimulate MTV, a
reporter carrying the glucocorticoid response element under the same
experimental conditions (Fig. 1B). This hormone-independent
transactivation activity of hERR2 depends upon the amount of the
expression vector transfected into the recipient cells; the activity
increased with the amount of hERR1 or hERR2 expression vector
transfected. Shown in Fig. 2 is a
saturation curve revealing a dose-dependent transactivation
profile.
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. The DBDs of hERR1 and hERR2 were then
swapped with that of hGR to generate chimeric receptor GE1G and GE2G
(Fig. 3A). When the resulting chimeric receptor GE2G was transfected
into HeLa cells, it functioned as a glucocorticoid-dependent activator
of reporter vectors harboring ERE and TRE sequences (Fig. 3B). This
indicates that the DBD of hERR2 is important for response element
recognition but does not embody the dominant constitutive activity of
the parental receptor.
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). The resulting hybrids should recognize the GRE of the MTV-LTR.
When cotransfected with MTV-CAT reporter genes into HeLa cells, GGE1
and GGE2 activated gene transcription through MTV-LTR in the absence of
any exogenous inducers (Fig. 3C, lanes 5 and 7) in contrast to the
parental hGRNX molecule, which activated MTV only in a
hormone-dependent fashion (Fig. 3C, lane 3 and 4). Together, these data
indicate that the LBDs of the hERR1 and hERR2 are in an intrinsically
activated state and that this property is transferable to a
heterologous receptor.
The Intact LBDs of hERR1 and hERR2 Are Essential for
Transcriptional Activation
In the case of the GR and ER, the LBDs function as
a contiguous unit such that disruption of this region by deletion or
insertions leads to loss of hormone binding. Such mutants are expected
to become transcriptionally inactive. In contrast, complete truncation
of the hormone- binding domain can lead to constitutively active
mutants as previously described for both GR and ER (4). Accordingly, a
series of mutations were generated in the LBD of hERR1 to examine their
potential effects on transactivation (Fig. 4). These include a C-terminal truncation
mutant 2681, an internal deletion mutant, 268–373, and a linker
insertion mutant I373 (Fig. 4). Mutant 2681 has the entire LBD deleted
after amino acid position 268 with an addition of six extra amino acids
from the inserted linker. Mutant 268–373 has an in-frame deletion
from amino acid 268 to 373, and mutant I373 contains a linker encoding
five amino acids, PHRWG, inserted in-frame after amino acid 373 without
disrupting any other parts of the molecule. When each of the mutants
was tested, all were transcriptionally silent (Fig. 4). Thus, an intact
LBD is apparently required for the constitutive activation phenotype.
Furthermore, the failure of these mutants in transactivation indicates
that, unlike ER, the putative AF-1 domain in the N terminus of hERR1
and 2 may not contribute to their transcription activity.
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MTV-ERE-Luc) by hERR1 (Fig. 5A) and hERR2 (Fig. 5B) was enhanced
significantly by cotransfection of ACTR, GRIP1, or SRC-1, while these
coactivators did not activate the reporter gene in the absence of hERRs
(Fig. 5A). Among the examined coactivators, GRIP1 exhibited relatively
higher potency as compared with ACTR and SRC-1. In the case of GRIP1,
while the wild-type proteins potentiate the activation of transcription
by hERR1 (Fig. 5D) or by hERR2 (Fig. 5E), a mutant GRIP1 containing
mutations in NR boxes II and III failed to function as a coactivator
(Fig. 5, D and E). In the NR box mutant, the second and third LXXLL
motifs are changed to LXXAA; these mutations are known to disrupt
binding to the hydrophobic pocket created by the carboxyl-terminal AF-2
domain (Ref. 32 and data not shown). In the coactivator transfection
assays, treatment with 17ß-estradiol (E2) had no effect
on either hERR1 or -2 activation (data not shown).
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Ligand-Independent Binding of Coactivators by hERR1 and hERR2
We used a glutathione-S-transferase GST pull-down assay
to determine whether hERR1 and -2 can directly interact with p160
proteins in vitro. As shown in Fig. 6A, while GST does not bind the
full-length hERR1 or hERR2 synthesized in vitro, the
bead-bound GST-ACTR-RID621–821 (20) is able to bind the
hERRs efficiently. The binding between ACTR and hERRs can also be
demonstrated when the LBD of the hERRs, instead of the full-length
proteins, was used (data not shown). In the same GST pull-down assays,
GST-GRIP1563–1121 also bound full-length hERR2 efficiently
(Fig. 6B). No hormone was added either in the synthesis of the proteins
or in the binding reactions, further supporting the notion that
activation of transcription by hERRs is ligand independent.
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HERR1 and -2 were originally isolated by low-stringency hybridization
probed with the DBD of human ER and were the first two orphan receptors
identified. Indeed, ERR is also an expanding family of proteins; we
have recently cloned the closely related ERR3 gene as a GRIP1
interacting protein (34). While ERRs display significant homology to
the ER (hERR1 has 91% amino acid identity with hERR2, 68% with hER in
DBD), none bind either natural or synthetic estrogens in
vitro (35). In addition, initial ligand screen has ruled out some
other traditional hormones as ERR ligands (N. N. Yang and R.
M. Evans, data not shown). Interestingly, individual ERRs appear to
have unique expression patterns: ERR1 expresses widely in later stages
of mouse embryos, although its expression in the heart, skeletal
muscles, and nervous system is relatively abundant (36). The expression
of ERR2 is restricted to the trophoblast progenitor cells between
embryonic days 6.5 and 7.5. Restricted low levels of ERR2 expression
were also detected in adult mouse tissues (35). The highest expression
of ERR3 occurs around days 11–15 post coitum, a period of very active
organogenesis (34). The restricted patterns of their expression suggest
ERRs have unique potential significance in developmental and
physiological processes. Indeed, ERR1 has been shown to be a
transcriptional regulator of the human lactoferrin (37), the human
medium-chain acyl coenzyme A dehydrogenase (38), thyroid hormone
receptor (TR) (39), and the osteopontin (40) genes. Homologous
recombination studies revealed that ERR2 has an important role in early
embryogenesis where ERR2 null mice die at 10.5 days post coitum due to
placental abnormalities (41).
Although many members of the steroid receptor superfamily are ligand-dependent transcription factors, the results reported here support the notion that some members may manifest constitutive activity in absence of the addition of a specific ligand. Transfection studies indicate that hERR1 and hERR2 have similar DNA binding properties and are effective activators of estrogen and thyroid hormone target genes. The activation of ERE-controlled gene expression by hERR2 is consistent with the previous observation that ERR2 protein is able to bind ERE in vitro as revealed by gel mobility shift assay (42). Whether either hERR1 or -2 manifests any estrogenic or thyroimimetic type properties in vivo is not yet known. Even though the LBDs of hERR1 and hERR2, like classic hormone receptors, harbor transcriptional activation functions, added ligands are apparently not needed to manifest this property. This appears to be a consequence of the ability of the p160 cofactors to be able to directly bind the LBDs in a ligand-independent fashion.
Based upon these studies, we can consider at least four possible, but
not exclusive, models to explain the transcription properties of the
hERRs. First, the hERRs may not be exceptions to the rule that all
receptors are hormone dependent in activation. Rather, the activating
ligands may be produced endogenously by the recipient cells leading to
an apparent constitutive property. In this case, the ligand could
either be secreted and reabsorbed by the cells in an autocrine fashion
or could represent an internal molecule that is not released but is
able to interact with the intracellular receptor directly. Such
intracellular regulatory systems might have value in modulating
metabolic pathways as well as providing direct feedback regulation for
intracellular homeostatic systems. Furthermore, even though hERRs
exhibit transcriptional activity in cell-based assays in the absence of
any exogenously added ligand, this does not exclude the potential
existence of an endogenous ligand that modulates this function. For
example, the orphan receptor LXR manifests some constitutive
activity (high basal) on certain target sequences that can be
substantially potentiated by the addition of ligands such as
24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol (43). In
addition, two other orphan receptors, SF-1 and hepatic nuclear factor 4
(HNF-4), which also display constitutive activity, have recently been
proposed to be further activated by oxysterols and fatty acyl-CoA
thioesters, respectively (44, 45). However, direct binding of the
ligands to the receptor has yet to be confirmed. A second model would
suggest that the receptors are ligand-dependent repressors such that in
the absence of the appropriate inducing molecule, target genes are
constitutively activated. Indeed, we have recently shown that the
constitutive activity of the CAR-ß results from a ligand-independent
recruitment of transcriptional coactivators, while androstane
metabolites bind to and deactivate CAR-ß by promoting coactivator
release from the LBD (29). It remains possible that a mechanism of
potential ligand-mediated receptor deactivation also applies to hERRs.
A third model is that hERRs may be activated by agents other than
steroid hormones. Indeed, a number of steroid receptors including
ER, ERß, and SF-1 have been shown to be activated by nonsteroid
agents such as growth factors, protein kinase A, and dopamine
(for review, see Ref. 46), and the AF-1 domain of these NRs appears to
be the target. It has been shown recently that the mitogen-activated
protein kinase-mediated phosphorylation of the AF-1 domain of
ERß and SF-1 promotes ligand-independent recruitment of NR
coactivators (7, 47). Indeed, most if not all, of the members of the NR
family are phosphoproteins (for review, see Ref. 46). However, two
pieces of evidence seem to go against the possibility that the
phosphorylation mechanism also applies to hERRs: 1) Unlike ERs, the
constitutive activation property of hERRs can be destroyed by
truncations, deletions, and insertional mutations in the LBD,
indicating that the putative AF-1 domain may not contribute the
transcription activity of the hERRs; 2) The transactivation activity of
hERRs can be observed in serum-free conditions. The fourth
possibility is that some receptors do not bind classic ligands and,
rather, represent a subgroup of the gene family that have evolved as
hormone-independent transcription factors. Interestingly, classical NRs
undergo conformational changes after hormone binding, and the resulting
conformation allows them to interact with transcriptional coactivators
via the LXXLL motif (26, 28, 32, 48). Mutation of this motif blocks ERR
activation. The coactivator binding with hERR1 and -2 would appears to
reflect a similar conformation to that of an activated receptor. How
this is achieved in the absence of ligand is unknown. Therefore, it
will be of interest to investigate the structural features of hERRs
that enable their constitutive interaction with coactivators. In either
case, these orphan receptors provide a unique opportunity to further
investigate the diverse mechanisms by which the NRs may contribute to
endocrine function.
The fact that hERRs can activate synthetic ERE-controlled genes raises several interesting questions. Is the ERE a natural response element of hERRs? And if so, what is the role of ERRs, relative to ER, in gene regulation. Alternatively, do hERRs have other perfect or imperfect response elements? For the role of hERRs in ERE-controlled gene expression, one possible regulatory mechanism could involve the formation of ER-ERR heterodimers, which may have a different level of activity from ER-ER homodimers. Indeed, cotransfection of hERR1 increased estrogen-dependent activation mediated by the ERE in the lactoferrin promoter, suggesting that heterodimerization between ERRs and ER could play a role in the attenuation or potentiation of estrogen-dependent transcription (37). On the other hand, ERR1 has been shown to bind a monomeric response element (38, 39, 49, 50), and the technique of selected and amplified binding (SAAB) (51) predicts that ERR1 can bind a response element containing a single consensus half-site, 5'-TNAAGGTCA-3' (ERRE). Indeed, most of the previously characterized ERR1 response elements in the promoters of its responsive genes are this single core element (38, 39, 49, 50). We observed that all three ERR family members can activate gene transcription when tk-ERRE-Luc was used as a reporter (W. Xie and R. M. Evans, data not shown). Interestingly, in some promoters, such as those of the oxytocin, PRL, and lactoferrin genes, a putative ERRE overlaps a known ERE (for review, see Ref. 49). Therefore, it is conceivable that ERRs may play a role as transcriptional modulators whose contribution to promoter activity could be determined both by the context of the ERE or ERRE within a complex hormone response element and by potential interactions between ERRs and other nuclear hormone receptors.
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MATERIALS AND METHODS |
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160–1825 (V. Giguere, unpublished data). The construct
with the correct orientation was named pRShERR1–1. To generate
pRShERR1, a SacII-ATtIII fragment of pRShERR1–1
was inserted into a BamHI and ATtIII-digested
pRShGR214 (10) vector. To generate pRShERR2, the coding sequence of the
hERR2 (35) was prepared as a KpnI-BamHI fragment
and ligated into the same pair of enzymes digested vector of
pRSER1825 (30). In the assays of coactivators, the coding sequences of
hERR1 or hERR2 were released from pRShERR1 or pRShERR2 as an
Asp718-BamHI fragment, or an
EcoRI-BamHI fragment, respectively, and cloned
into the same enzyme-digested pCMX-PL2 expression vector (20) to
generate pCMX-hERR1 and pCMX-hERR2 constructs. To generate the NX
mutants, NotI and XhoI sites were introduced into
the cDNA sequence of hERR1 and hERR2 by site-directed mutagenesis as
described previously (8).
For the construction of hERR1 mutants, the C-terminal truncated
hERR1–2681 was generated by digesting pRShERR1 with SmaI
and Eco47III enzymes, which recognize two unique sites in the
ligand-binding region of hERR1. Ligation of the larger fragment
resulted in a plasmid coding for hERR1 that stops at amino acid
position 268. Six extra amino acids were added upon the sequence before
it runs into a stop codon. The in-frame internal deletion mutant
hERR1-268–373 was created by inserting an oligo linker coding for
ClaI recognition site (CATCGATG) into the SmaI
and Eco47III enzymes’ double-digested pRShERR1 fragment. The linker
was ligated with the larger fragment. The linker restores the reading
frame; therefore, 268–373 encodes an hERR1 protein with the
sequence between amino acid 268 and 374 in the LBD replaced by a
sequence of four amino acids, Pro-Ile-Glu-Gly. HERR1-I373 was generated
by inserting an oligo linker with ClaI recognition site
(CCCATCGATGGG) into the Eco47III site in the LBD. The resulting hERR1
mutant protein, therefore, has four extra amino acid residues,
Pro-His-Arg-Trp, inserted between amino acid 372 and 373.
MMTV-LUC, MTV-ERE-LUC, and MTV-TREpal-LUC (30), tk-ERE-Luc
and tk-TREpal-Luc (52), MTV-CAT, MTV-CAT,
MTV-ERE-CAT, and MTV-TREpal-CAT (10), and expression
vectors pSG5-GRIP1 (32), pCMX-ACTR, pCMX-SRC-1a (20),
tk-(MH100)4(UAS)-Luc (29), and pRShTR (8) were described
previously.
Bacterial expression vector for GST-GRIP1 fusion protein, pGEX.2TK.GRIP1563–1121, was made by inserting a PCR-amplified GRIP1 fragment into BamHI/EcoRI sites of pGEX.2TK (Pharmacia). pGEX-ACTR-RID 621–821 was described before (20).
Cell Culture and Transient Transfection
CV-1 cells and HeLa cells were maintained in phenol red-free
DMEM supplemented with 10% FBS (Gemini Bio-Products, Inc.). The serum
condition after transfection is presented in the figure legends.
Calcium phosphate precipitation-based (
Figs. 1–4) or liposome-based
(Figs. 5 and 6) transient transfections were performed as described
previously (8, 17, 20). Total DNA used in each transfection was
adjusted to the same amount by adding the appropriate amount of empty
expression vectors. Luciferase assays (30, 34) or CAT assay (10) on
cell extracts were performed 48 h after transfection. Data shown
represent the mean and SD for three or four transfected
cultures.
In vitro transcription and translation of proteins and GST pull-down assays were performed as described previously (20, 53). The cDNAs of hERR1 and 2 were subcloned into pCMX vector (20) to generate vectors for in vitro transcription and translation.
Mammalian two-hybrid assays were performed as described previously (20). pCMX-VP16-L-hERR1 and pCMX-VP16-L-hERR2 were constructed by cloning LBDs from hERRs into the pCMX-VP16 vector.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by grants from NIH. M.R.S is supported by NIH Grant DK-43093. W.X. is supported by the California Breast Cancer Research Program (5FB-0117). R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute for Biological Studies and March of Dimes Chair in Molecular and Developmental Biology.
1 Present address: Endocrine Research, Lilly Research Laboratories,
Eli Lilly & Co., Indianapolis, Indiana 46285. 
Received for publication July 9, 1999. Revision received August 12, 1999. Accepted for publication August 19, 1999.
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J. Keay, J. T. Bridgham, and J. W. Thornton The Octopus vulgaris Estrogen Receptor Is a Constitutive Transcriptional Activator: Evolutionary and Functional Implications Endocrinology, August 1, 2006; 147(8): 3861 - 3869. [Abstract] [Full Text] [PDF]
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Z. Zhang, K. Chen, J. C. Shih, and C. T. Teng Estrogen-Related Receptors-Stimulated Monoamine Oxidase B Promoter Activity Is Down-Regulated by Estrogen Receptors Mol. Endocrinol., July 1, 2006; 20(7): 1547 - 1561. [Abstract] [Full Text] [PDF]
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 W. Zhou, Z. Liu, J. Wu, J.-h. Liu, S. M. Hyder, E. Antoniou, and D. B. Lubahn Identification and Characterization of Two Novel Splicing Isoforms of Human Estrogen-Related Receptor {beta} J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 569 - 579. [Abstract] [Full Text] [PDF]
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S. J. Han, F. J. DeMayo, J. Xu, S. Y. Tsai, M.-J. Tsai, and B. W. O'Malley Steroid Receptor Coactivator (SRC)-1 and SRC-3 Differentially Modulate Tissue-Specific Activation Functions of the Progesterone Receptor Mol. Endocrinol., January 1, 2006; 20(1): 45 - 55. [Abstract] [Full Text] [PDF]
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S. J. Han, J. Jeong, F. J. DeMayo, J. Xu, S. Y. Tsai, M.-J. Tsai, and B. W. O'Malley Dynamic Cell Type Specificity of SRC-1 Coactivator in Modulating Uterine Progesterone Receptor Function in Mice Mol. Cell. Biol., September 15, 2005; 25(18): 8150 - 8165. [Abstract] [Full Text] [PDF]
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J. Seely, K. S. Amigh, T. Suzuki, B. Mayhew, H. Sasano, V. Giguere, J. Laganiere, B. R. Carr, and W. E. Rainey Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor {alpha} Endocrinology, August 1, 2005; 146(8): 3605 - 3613. [Abstract] [Full Text] [PDF]
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J. B. Barry and V. Giguere Epidermal Growth Factor-Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor {alpha} Cancer Res., July 15, 2005; 65(14): 6120 - 6129. [Abstract] [Full Text] [PDF]
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E. Bonnelye and J. E. Aubin Estrogen Receptor-Related Receptor {alpha}: A Mediator of Estrogen Response in Bone J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3115 - 3121. [Abstract] [Full Text] [PDF]
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 D Liu, Z Zhang, and C T Teng Estrogen-related receptor-{gamma} and peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} regulate estrogen-related receptor-{alpha} gene expression via a conserved multi-hormone response element J. Mol. Endocrinol., April 1, 2005; 34(2): 473 - 487. [Abstract] [Full Text] [PDF]
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C. P. Cheung, S. Yu, K. B. Wong, L. W. Chan, F. M. M. Lai, X. Wang, M. Suetsugi, S. Chen, and F. L. Chan Expression and Functional Study of Estrogen Receptor-Related Receptors in Human Prostatic Cells and Tissues J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1830 - 1844. [Abstract] [Full Text] [PDF]
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J. Kallen, J.-M. Schlaeppi, F. Bitsch, I. Filipuzzi, A. Schilb, V. Riou, A. Graham, A. Strauss, M. Geiser, and B. Fournier Evidence for Ligand-independent Transcriptional Activation of the Human Estrogen-related Receptor {alpha} (ERR{alpha}): CRYSTAL STRUCTURE OF ERR{alpha} LIGAND BINDING DOMAIN IN COMPLEX WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR COACTIVATOR-1{alpha} J. Biol. Chem., November 19, 2004; 279(47): 49330 - 49337. [Abstract] [Full Text] [PDF]
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K. Stokes, B. Alston-Mills, and C. Teng Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor {alpha}-mediated transactivation activity in mammary gland cells J. Mol. Endocrinol., October 1, 2004; 33(2): 315 - 334. [Abstract] [Full Text] [PDF]
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S. Sanyal, J. Matthews, D. Bouton, H.-J. Kim, H.-S. Choi, E. Treuter, and J.-A. Gustafsson Deoxyribonucleic Acid Response Element-Dependent Regulation of Transcription by Orphan Nuclear Receptor Estrogen Receptor-Related Receptor {gamma} Mol. Endocrinol., February 1, 2004; 18(2): 312 - 325. [Abstract] [Full Text] [PDF]
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 D. Sumi and L. J. Ignarro Estrogen-related receptor {alpha}1 up-regulates endothelial nitric oxide synthase expression PNAS, November 25, 2003; 100(24): 14451 - 14456. [Abstract] [Full Text] [PDF]
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D. Liu, Z. Zhang, W. Gladwell, and C. T. Teng Estrogen Stimulates Estrogen-Related Receptor {alpha} Gene Expression through Conserved Hormone Response Elements Endocrinology, November 1, 2003; 144(11): 4894 - 4904. [Abstract] [Full Text] [PDF]
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 Q. Xu and C. Lee Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences Nucleic Acids Res., October 1, 2003; 31(19): 5635 - 5643. [Abstract] [Full Text] [PDF]
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S. N. Schreiber, D. Knutti, K. Brogli, T. Uhlmann, and A. Kralli The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor alpha (ERRalpha ) J. Biol. Chem., March 7, 2003; 278(11): 9013 - 9018. [Abstract] [Full Text] [PDF]
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T. Suzuki, M. Kasahara, H. Yoshioka, K.-i. Morohashi, and K. Umesono LXXLL-Related Motifs in Dax-1 Have Target Specificity for the Orphan Nuclear Receptors Ad4BP/SF-1 and LRH-1 Mol. Cell. Biol., January 1, 2003; 23(1): 238 - 249. [Abstract] [Full Text]
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E. A. Ariazi, G. M. Clark, and J. E. Mertz Estrogen-related Receptor {alpha} and Estrogen-related Receptor {gamma} Associate with Unfavorable and Favorable Biomarkers, Respectively, in Human Breast Cancer Cancer Res., November 15, 2002; 62(22): 6510 - 6518. [Abstract] [Full Text] [PDF]
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R. J. Kraus, E. A. Ariazi, M. L. Farrell, and J. E. Mertz Estrogen-related Receptor alpha 1 Actively Antagonizes Estrogen Receptor-regulated Transcription in MCF-7 Mammary Cells J. Biol. Chem., June 28, 2002; 277(27): 24826 - 24834. [Abstract] [Full Text] [PDF]
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B. Borud, T. Hoang, M. Bakke, A. L. Jacob, J. Lund, and G. Mellgren The Nuclear Receptor Coactivators p300/CBP/Cointegrator-Associated Protein (p/CIP) and Transcription Intermediary Factor 2 (TIF2) Differentially Regulate PKA-Stimulated Transcriptional Activity of Steroidogenic Factor 1 Mol. Endocrinol., April 1, 2002; 16(4): 757 - 773. [Abstract] [Full Text] [PDF]
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D. Lu, Y. Kiriyama, K. Y. Lee, and V. Giguere Transcriptional Regulation of the Estrogen-inducible pS2 Breast Cancer Marker Gene by the ERR Family of Orphan Nuclear Receptors Cancer Res., September 1, 2001; 61(18): 6755 - 6761. [Abstract] [Full Text] [PDF]
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P. Coward, D. Lee, M. V. Hull, and J. M. Lehmann 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma PNAS, July 5, 2001; (2001) 151244398. [Abstract] [Full Text] [PDF]
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 G. B. Tremblay, T. Kunath, D. Bergeron, L. Lapointe, C. Champigny, J.-A. Bader, J. Rossant, and V. Giguère Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR{beta} Genes & Dev., April 1, 2001; 15(7): 833 - 838. [Abstract] [Full Text]
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J. M. Hall, C.-y. Chang, and D. P. McDonnell Development of Peptide Antagonists That Target Estrogen Receptor {beta}-Coactivator Interactions Mol. Endocrinol., December 1, 2000; 14(12): 2010 - 2023. [Abstract] [Full Text]
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Z. Zhang and C. T. Teng Estrogen Receptor-related Receptor alpha 1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene J. Biol. Chem., June 30, 2000; 275(27): 20837 - 20846. [Abstract] [Full Text] [PDF]
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S. S. Koh, D. Chen, Y.-H. Lee, and M. R. Stallcup Synergistic Enhancement of Nuclear Receptor Function by p160 Coactivators and Two Coactivators with Protein Methyltransferase Activities J. Biol. Chem., January 5, 2001; 276(2): 1089 - 1098. [Abstract] [Full Text] [PDF]
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P. Coward, D. Lee, M. V. Hull, and J. M. Lehmann 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma PNAS, July 17, 2001; 98(15): 8880 - 8884. [Abstract] [Full Text] [PDF]
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