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Advances in Brief |
-1 Orphan Receptor1
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-1 shares a high amino acid sequence homology with estrogen receptor . Although estrogens are not ligands of ERR-1, our recent results suggest that toxaphene and chlordane, two organochlorine pesticides with estrogen-like activity, behave as antagonists for this orphan nuclear receptor. The two compounds increased ERR-1-mediated expression of the reporter enzyme ß-galactosidase in a yeast-based assay. The screen was developed by expressing the hERR-1-yeast Gal 4 activation domain fusion protein in yeast cells carrying the ß-galactosidase reporter plasmid, which contains an ERR-1-binding element. In transfection experiments using mammalian cell lines, such as the SK-BR-3 breast cancer cell line, the compounds were found to have an antagonist activity against ERR-1-mediated expression of the reporter chloramphenicol acetyltransferase. In contrast to the findings with ERR-1, the two compounds were found to slightly induce the estrogen receptor -mediated expression of chloramphenicol acetyltransferase in SK-BR-3 cells. In a ligand-independent manner, the ERR-1 activity in SK-BR-3 cells was induced 3-fold by cotransfection with the GRIP1 coactivator expression plasmid. Toxaphene was found to be capable of suppressing the GRIP1 coactivator-induced ERR-1 activity in SK-BR-3 cells. In addition, a stable ERR-1 expressing HepG2 hepatoma cell line was generated, and the aromatase activity in the transfected cell line was found to be twice that in the untransfected cell line. The enzyme aromatase converts androgens to estrogens, and aromatase expression in HepG2 cells is regulated in part by an ERR-1-modulating promoter. A 24-h incubation of an ERR-1-transfected HepG2 cell line with 10 µM toxaphene reduced its aromatase activity to the level in the untransfected cell line. Because toxaphene is not an inhibitor of aromatase, it is thought that the decrease of the aromatase activity in ERR-1 transfected HepG2 cells following toxaphene treatment resulted from a suppression of the aromatase expression by toxaphene acting as the antagonist of ERR-1. Toxaphene and chlordane are among the 12 persistent organic pollutants identified by the United Nations Environment Programme as requiring urgent attention. Their antagonistic effects on ERR-1 should not be overlooked. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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(1)
. Sequence alignment of ERR-1, ER, and ERß revealed high degrees of similarity among the receptors. In the DNA-binding domain, ERR-1 shares 68% amino acid homology with ER and 70% homology with ERß. In the ligand-binding region, the amino acid sequence of ERR-1 shows 36% identity with ER and 34% identity with ERß. However, ERR-1 does not bind to any of the major classes of steroids, including estrogens and androgens (1)
. ERR-1 is an isoform of ERR-1 and was first reported by Yang et al. (2)
. The hERR-1/ERR-1 appears to be widely distributed, although it is most abundant in the brain (1)
, heart (3)
, skeletal muscle (3
, 4)
, and brown adipose tissue (5)
. A role for ERR-1/ERR-1 in bone development (6)
, skeleton formation (4)
, and fat metabolism (5)
has been suggested. Recent studies (7)
from our laboratory have revealed that ERR-1 is expressed in human breast tissue and may modulate aromatase expression/estrogen biosynthesis in this tissue. Aromatase is the enzyme that converts androgens to estrogens (see Fig. 1
). ERR-1 is also thought to modify the activation effect of estrogens on a number of gene promoters by both direct DNA-binding competition and through ER-ERR-1 protein-protein interaction (2
, 8)
.
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-1 is a member of the orphan nuclear receptor family, in that its ligand has not yet been identified. Considering its importance in modulating the synthesis and action of estrogens in cells as well as its roles in other biological processes, attempts were made in this laboratory to search for ligands of ERR-1. Although we have confirmed that estrogens and androgens are not ligands of this receptor, two organochlorine pesticides, toxaphene and chlordane (see Fig. 1
for structures), were found to be antagonists for ERR-1. |
Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Plasmids.
All recombinant DNA and plasmid construction experiments were performed according to standard procedures, and the sequences and orientation of inserted DNA fragments in plasmid constructs were verified by standard DNA sequencing. The pLacZi-3S1 reporter plasmid was prepared by inserting three tandem copies of S1 into the pLacZi reporter plasmid (7)
. S1 is the ERR-1-binding region that is situated between promoters 1.3 and II in the human aromatase gene (9)
A yeast expression plasmid for ADGAL4-hERR1 fusion protein, i.e., pACT2-hERR1, was isolated from the MATCHMAKER mammary gland cDNA expression library using S1 as bait. To construct mammalian expression plasmids for human ERR1 (pSG5-hERR1) and human ER (pSG5-hER), we amplified the coding regions of hERR1 and hER by PCR with EcoRI sites at both ends, and the PCR products were inserted into the EcoRI site of pSG5 vector. The pSG5-GRIP1 was kindly provided by Dr. M. R. Stallcup (University of Southern California, Los Angeles, CA; Ref. 10
).
Yeast Assays.
The procedure for yeast assay was kindly provided by Dr. K. Gaido at the Chemical Industry Institute of Toxicology (Research Triangle Park, NC). The yeast one-hybrid hERR1-S1 reporter strain was prepared by cotransforming the YM4271 yeast strain with linearized pLacZi-3S1 and pACT2-hERR1 plasmids. All of the test compounds in our experiments were dissolved in DMSO and added to the yeast culture with a solvent concentration of 0.1%. The yeast reporter strain hERR1-S1 was grown overnight in 25 ml of SD/-leu media with shaking (300 rpm) at 30°C. The culture was diluted 1:1 with the culture medium the next morning. When A600 nm reached 1, the culture was diluted to an A600 nm of 0.03 with SD/-leu medium, and 50 µM CuSO4 was added. A 5-ml aliquot of diluted yeast was incubated with test chemicals (1:1000 dilution) overnight at 30°C with shaking. Following overnight incubation, the culture was diluted to an A600 nm of 0.25, and 100 µl of yeast culture were added per well of a 96-well microtiter plate (in triplicate). The cell density was measured at A590 nm using a Microplate reader. One hundred µl of assay buffer were added to each well. The assay buffer contained 2 mg/ml o-nitrophenyl-ß-D-galactopyranoside in Z-buffer [60 mM Na2HPO4·7H2O, 40 mM NaH2PO4·H2O, 10 mM KCl, and 1 mM MgSO4·7H2O (pH 7.0)], 0.1% SDS, 50 mM ß-mercaptoethanol, and 200 units/ml oxalyticase. The ß-galactosidase activity was measured at A420 nm. To calculate Miller units, we used the following formula: [A420/(A590 of 1:10 dilution of cells x length of incubation)] x 1000.
Cell Transient Transfection and CAT Assay.
Lipofectin (Life Technologies, Inc.) was used as the mammalian cell transfection agent according to the manufacturer’s instructions. The cotransfection experiments were performed 20–24 h after seeding. Approximately 4 x 105 cells were plated per 60-mm tissue culture dish using 10 µg of the test plasmid and 3 µg of the plasmid pSV-ß-Gal, which was used to normalize the transfection efficiency. After 16-h incubation, medium containing Lipofectin and DNA was removed, and the cells were cultured in growth medium (containing 5% charcoal-/dextran-treated fetal bovine serum instead of the regular fetal bovine serum) and treated with test compounds. After 48-h incubation, the cells were washed twice with 5 ml of PBS and harvested from the plates by scraping, pelleted by centrifugation, resuspended in 0.25 M Tris-HCl (pH 8.0), and disrupted by freeze-thawing four times. Aliquots of the lysate were used for assay of ß-galactosidase activity (11)
. CAT activity in the cell extracts containing an equal amount of ß-galactosidase activity from each sample was determined by the liquid scintillation counting method (12)
. Briefly, the appropriate amount of cell extracts was incubated in a reaction containing [14C]chloramphenicol and n-butyryl-CoA. The reaction products were extracted with a small volume of xylene. The xylene phase was mixed with scintillant and counted in a scintillation counter. The CAT activity was expressed as relative activity compare to that of the pUMSVOCAT construct (activity set at 1.0) and shown as means ± SE of three independent transient transfection experiments performed for each reaction containing three triplicates.
Overexpression of ERR-1 in HepG2 Cells by Stable cDNA Transfection.
The hERR1 cDNA was generated by PCR with the EcoRI restriction site at both ends and then ligated into the mammalian expression vector, pHß. The orientation and sequence of the cDNA was confirmed by dideoxy sequencing.
HepG2 cells were divided into each well of a six-well plate at 1 x 105 cells/well and incubated overnight at 37°C and 5% CO2 in Eagle’s MEM with nonessential amino acids, sodium pyruvate, and 10% fetal bovine serum. The next day, cell culture medium was changed to Opti-MEM. Before transfection, 10 µg of pHß-hERR1 plasmid DNA were mixed with 20 µl of Lipofectin and incubated at room temperature for 15 min. The cells were incubated with the DNA mixture for 16 h. The medium was then changed with fresh complete medium, and the culture was incubated at 37°C and 5% CO2 for 48 h before the selection with G418. The selection was started with 500 µg/ml G418, and the concentration of G418 was gradually increased to 1000 µg/ml over 2 weeks. Individual colonies were picked and subcultured into 25-cm2 flasks.
Aromatase Assay.
Cells were washed twice with serum-free cell culture medium before assay for aromatase activity. The substrate, 1ß-[3H]N-androst-4-ene-3,17-dione (specific activity, 17.4 Ci/mmol) was dissolved in serum-free cell culture medium. Cells were incubated with the assay mixture containing 500 nM progesterone (5 reductase inhibitor) and 100 nM [3H] androstenedione. After a 2-h incubation, 1 ml of culture medium was withdrawn from each well. The culture medium was mixed with an equal volume of chloroform to extract unused substrate. The aqueous phase was treated with dextran-treated charcoal and centrifuged, and the amount of the product, tritiated water, was determined using a scintillation counter. The protein concentration was determined using the method of Bradford (13)
after dissolving cells with 0.5 N NaOH. The tritiated water release assay for human aromatase expressed in mammalian cells has been previously validated by the product isolation assay (14)
.
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Results |
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-1 by Yeast One-Hybrid Assay.-1 and ER had significant homology, we decided to examine whether ERR-1 interacts with a series of endocrine disrupters that are known to have estrogen-like activity. Using the yeast one-hybrid assay, toxaphene and chlordane were found to be ligands of ERR-1 (Fig. 2)
. Following incubation with toxaphene or chlordane, the reporter ß-galactosidase activity in yeast transformed with pACT2-hERR-1 and pLacZi-3S1 increased in a dose-dependent manner. The inductive effect of toxaphene was greater than that of chlordane. These results suggest that the toxaphene- or chlordane-bound form of ERR-1 has a higher affinity to the reporter plasmid pLacZ-S1 than the ligand-free form. In the same analysis, we have found that, at concentrations up to 10 µM, aminoglutethimide, biochanin, bisphenol A, CdCl2, chrysin, coumestrol, diethylstilbestrol, dieldrin, 7,8-dihydroxyflavone, endosulfan, genistein, kepone, narigenin, nonyl-phenol, phenol red, dichlorodiphenyltrichloroethane, and tamoxifen are not ligands of ERR-1. As indicated by cell transfection assays (see following paragraphs), these compounds did not affect the activity of ERR-1. As shown in Fig. 1
, dieldrin and endosulfan have structures resemble to those of toxaphene and chlordane, but these compounds are not the ligands of ERR-1. These results indicate that ERR-1 recognizes toxaphene and chlordane in a rather specific manner.
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-1, we incubated these compounds with the SK-BR-3 breast cancer cell line that was transfected with the ERR-1 expression plasmid pSG5-ERR-1 and a CAT reporter plasmid containing the aromatase genomic fragment that contains promoter I.3 and the ERR-1-regulating element, S1 (9)
. These two chemicals were found to have antagonistic activity against ERR-1-mediated expression of the reporter CAT (Fig. 3A)
, following a dose-dependent manner. As a control, the CAT activity in the cells transfected with only the expression vector (pSG5) was not changed by treatment with toxaphene or chlordane at 10 µM, the highest concentration used in ERR-1 transfected cells (Fig. 3B)
. In contrast to the findings with ERR-1, the two compounds were found to slightly induce the ER-mediated expression of CAT in SK-BR-3 cells (Fig. 3A)
. A weak induction of ER activity by these compounds was reported previously (15)
.
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-1-GRIP1 Coactivator Interaction.-1 activity in SK-BR-3 cells was induced 3-fold by cotransfection with the GRIP1 coactivator expression plasmid. Toxaphene was found to be capable of suppressing GRIP1 coactivator-induced ERR-1 activity in SK-BR-3 cells (Fig. 4)
. The coactivators of nuclear receptors such as GRIP1 are normally found to bind to the receptor at the ligand-binding domain (16)
. The nuclear receptor-coactivator interaction is normally in an agonist-dependent fashion, and antagonist would disrupt the interaction. Our results support the conclusion that toxaphene is an antagonist of ERR-1, and toxaphene may suppress ERR-1 activity by disrupting the interaction of ERR-1 with coactivators such as GRIP1. Because toxaphene was found to be cytotoxic at concentrations of >10 µM, the highest concentration of toxaphene used in our studies was 10 µM.
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-1-mediated Mechanism.-1-modulating promoter I.3 (7
, 17)
. Aromatase activity was found to increase to 128% of the control cells (i.e., cells transfected with the vector pSG5) when SK-BR-3 cells were transiently transfected with the expression plasmid pSG5-hERR1. However, aromatase activity in cells transfected with pSG5-hERR-1 and incubated with 10 µM toxaphene for 24 h was found to be 86% of that in vector-transfected cells incubated with toxaphene. These results suggest that toxaphene treatment can eliminate the inductive effect of aromatase expression by ERR-1. To confirm the results generated with SK-BR-3 cells, we have prepared a HepG2 hepatoma cell line stably expressing ERR-1. This cell line expresses aromatase and has a higher transfection efficiency in the cDNA transfection experiments than SK-BR-3 cell line. As shown in Fig. 5
, aromatase activity in the transfected cell line was found to be 191% that in untransfected cell line. A 24-h incubation of these cells with 10 µM toxaphene reduced aromatase activity to the level of untransfected cells. Because toxaphene is not an inhibitor of aromatase,5
the decrease of aromatase activity is thought to result from a reduction of aromatase expression. Furthermore, because aromatase expression in HepG2 cells is driven by ERR-1-regulated promoters I.3 and II as well as promoter I.4, which is not regulated by ERR-1,6
and toxaphene is an ERR-1 modulator, toxaphene treatment could suppress only the ERR-1-regulating promoters. Because chlordane is an inhibitor of aromatase,5
we did not perform the aromatase suppression experiments using chlordane.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-1 by ligand binding assays. We have demonstrated the interaction using molecular biology techniques that have been successfully used to identify ligands for a few orphan receptors (18, 19, 20)
. Our findings are similar to those for the interaction of androstane metabolites with nuclear receptor CAR-ß (18)
. ERR-1 is constitutively active without ligand, possibly from a ligand-independent recruitment of transcriptional coactivators. We have found that the CAT activity is significantly higher in cells cotransfected with both ERR-1 and coactivator such as GRIP1 than that in cells transfected with ERR-1 only (Fig. 4)
. Our results obtained with toxaphene suggest that this chemical may disrupt the interaction of ERR-1 with its coactivators. However, this compound is a man-made chemical and interacts with ERR-1 in the micromolar range. Several receptors that have ligands with micromolar Kds were reported recently (21)
. Although we have found that the ERR-1 activity can be significantly induced by GRIP1 coactivator without the addition of ligands, we cannot rule out completely the possibility that as yet unidentified natural ligands with high affinity are present in cells. On the basis of the finding for a lack of the ERR-1 transactivation activity in ROS 17/2.8 cells under stripped serum conditions, Vanacker et al. (22)
suggested that ligands for ERR-1 might be present in FCS.
We generated a computer model of the ligand binding domain of ERR-1 based on the X-ray structure of the ligand binding domain of ER (23)
.7
We have found that the "ligand-binding pocket" in the predicted ERR-1 structure contains several amino acid residues with bulky side chains that prevent the binding of estrogens. This may explain why estrogens are not ligands of ERR-1. Furthermore, toxaphene can only fit in the pocket in the model that was generated based on the X-ray structure of antagonist-ER complex. Whereas this is just a computer model, the finding does support our experimental results that toxaphene behaves like an antagonist of ERR-1.
Toxaphene and chlordane were widely used as insecticides until the mid 1980s. Despite a ban on their general use in United States, Canada, and Western Europe, these compounds are still being used in Central and South America, Africa, Eastern Europe, and Asia (24)
. These compounds belong to a class known as POPs: compounds that travel thousands of miles, accumulate in the food chain, and persist in the environment, taking up to centuries to fully degrade (25)
. It has been well documented that exposure to POPs can cause birth defects, various cancers, immune system dysfunction, and reproductive problems in wildlife. Toxaphene and chlordane are among the 12 POPs identified by the United Nations Environment Programme as requiring urgent attention. Chlordane binds readily to aquatic sediments and bioconcentrates in the fat of organisms. Mice that were fed diets containing chlordane were found to have reproductive defects. This compound is still used in termite control in some countries. Toxaphene is highly insoluble in water and its half-life in soil ranges up to 12 years. Toxaphene has been found to be highly toxic to some fish, causing effects such as reduction in weight and reduction in egg laying, hatching ability, and viability. Whereas the health effects of human exposure to these two compounds are not available, there is sufficient evidence in experimental animals that the IARC has classified these compounds as possible human carcinogens. Considering the fact that these compounds have long half-lives and bioconcentrate in the fat of organisms, and our findings that they behave as antagonists for ERR-1 that modulates the synthesis and action of estrogens as well as fat metabolism, it is not surprising that the experimental animals have reproductive defects and reduced body weights after exposure to these compounds.
The S1 element in the aromatase gene was previously demonstrated to be a negative regulatory element in several cell lines examined in our laboratory (9)
. ERR-1 has been shown to have a positive regulatory effect by interacting with S1 (7)
. Whereas it has been found that the negative regulatory effect of S1 can result from the binding of other orphan receptors8
or interaction of ERR-1 with corepressor proteins in cells, the positive action of ERR-1 can also be suppressed by antagonists, as shown here.
Many industrial and environmental chemicals mimic, antagonize, or indirectly alter the activity of hormones, particularly steroid hormones. These compounds, called endocrine disrupters, include chemicals isolated from plants (such as phytoestrogens) and man-made chemicals (such as toxaphene, chlordane, and so on). Endocrine disrupters are normally thought to bind to ER or androgen receptor and induce many components of estrogen or androgen action. However, the mechanisms of the action of endocrine disrupters are complicated. For example, methylsulfonyl polychlorinated biphenyls have been shown to be ligands of glucocorticoid receptor (26)
. Our laboratory has proposed and demonstrated that aromatase is an important target of the environmental chemicals. We propose that some of these compounds may act in an indirect fashion by inhibiting aromatase activity, resulting in a decrease in the level of estrogen or an increase in the level of androgen in cells. These compounds can also modify the expression of aromatase in various tissues, resulting in a change in the ratio between androgen to estrogen. The compounds that inhibit aromatase or suppress aromatase expression will behave as antiestrogens or androgen-like compounds in vivo. On the other hand, compounds that increase aromatase expression or enhance aromatase activity (or stability) may be categorized as antiandrogens or estrogen-like compounds. Our enzyme inhibition studies have found that endocrine disrupters such as flavones are inhibitors of aromatase (27)
. Recent experiments have revealed that chlordane is also an inhibitor of aromatase.5
Furthermore, research from our laboratory has revealed that ERR-1 has a positive regulatory effect on aromatase expression (7)
, and in this study, we demonstrate that toxaphene and chlordane behave as antagonists of ERR-1. Therefore, these compounds can modulate estrogen biosynthesis by at least two mechanisms: suppression of aromatase activity and aromatase expression.
Because ERR-1 binds to several functional EREs (8)
, it has been proposed that ERR-1 can modify the ER function by competing with ER for the binding to ERE or by forming ER-ERR-1 heterodimer. Using far-Western analysis (2)
and glutathione S-transferase pull-down assays (8
, 28)
, direct interaction of ERR-1 with ER has been demonstrated. However, the functional impact of ER-ERR-1 interaction is not yet known. Considering the fact that the binding analyses by Yang et al. (2)
and Johnston et al. (8)
were performed without the addition of estradiol, it is thought that the heterodimer formation does not require ligand. Therefore, toxaphene and chlordane may not interfere with the ER-ERR-1 interaction. Mammalian transfection experiments and yeast two-hybrid assays are being performed in our laboratory to functionally characterize the ER-ERR-1 interaction and to determine the effect of toxaphene and chlordane on the modulating activity of ERR-1 on ER. Results obtained thus far indicate that, in the absence of ligand (estradiol or toxaphene), ER-ERR-1 heterodimer has a slightly higher transactivation activity than ER homodimer. In addition, estradiol or toxaphene does not modify the activity of ER-ERR-1 heterodimer.9
In summary, we have found that toxaphene and chlordane behave as antagonists of an orphan receptor ERR-1 using molecular biology techniques. This is the first time that antagonists of ERR-1 have been identified. The identified ligands are endocrine disrupters, and the antagonistic action against ERR-1 may be one of the endocrine disrupting effects of these organochlorine pesticides. Finally, the expression of aromatase can be suppressed by these compounds through an ERR-1-mediated mechanism. Considering the ability of ERR-1 to interact with ER and to modulate aromatase expression/estrogen biosynthesis, exposure to these organochlorine pesticides could have a critical effect on normal endocrine function involving estrogen and may play an important role in the pathogenesis of breast cancer.
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FOOTNOTES |
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1 This research was supported by NIH Grants ES08258 and CA44735. S. C. is a member of the City of Hope Breast Cancer Program (supported by NIH Grant CA 65767). 
2 Predoctoral student of the Third Military Medical University, Chongquing, China.
3 To whom requests for reprints should be addressed. Phone: (626) 359-8111 ext. 2601; Fax: (626) 301-8186; E-mail: schen{at}coh.org
4 The abbreviations used are: ERR, estrogen-related receptor; ER, estrogen receptor; hERR, human ERR; CAT, chloramphenicol acetyltransferase; POP, persistent organic pollutant; ERE, estrogen response element.
5 Y-C. Kao and S. Chan, unpublished results.
6 B. Yu, C. Yang, and S. Chen, unpublished results.
7 M. Sherman and S. Chen, unpublished results.
8 C. Yang, B. Yu, and S. Chen, unpublished results.
Received 6/ 8/99. Accepted 7/30/99.
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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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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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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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 W. J. Hendry III, D. M. Sheehan, S. A. Khan, and J. V. May Developing a Laboratory Animal Model for Perinatal Endocrine Disruption: The Hamster Chronicles Exp Biol Med, October 1, 2002; 227(9): 709 - 723. [Abstract] [Full Text] [PDF]
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E. Bonnelye, V. Kung, C. Laplace, D. L. Galson, and J. E. Aubin Estrogen Receptor-Related Receptor {alpha} Impinges on the Estrogen Axis in Bone: Potential Function in Osteoporosis Endocrinology, September 1, 2002; 143(9): 3658 - 3670. [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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 C. Campagna, M.-A. Sirard, P. Ayotte, and J. L. Bailey Impaired Maturation, Fertilization, and Embryonic Development of Porcine Oocytes Following Exposure to an Environmentally Relevant Organochlorine Mixture Biol Reprod, August 1, 2001; 65(2): 554 - 560. [Abstract] [Full Text] [PDF]
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 E. Bonnelye, L. Merdad, V. Kung, and J.E. Aubin The Orphan Nuclear Estrogen Receptor-Related Receptor {alpha} (Err{alpha}) Is Expressed Throughout Osteoblast Differentiation and Regulates Bone Formation in Vitro J. Cell Biol., May 28, 2001; 153(5): 971 - 984. [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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D. J. Heard, P. L. Norby, J. Holloway, and H. Vissing Human ERR{gamma}, a Third Member of the Estrogen Receptor-Related Receptor (ERR) Subfamily of Orphan Nuclear Receptors: Tissue-Specific Isoforms Are Expressed during Development and in the Adult Mol. Endocrinol., March 1, 2000; 14(3): 382 - 392. [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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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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