Transcriptional Activities of the Orphan Nuclear Receptor ERRα (Estrogen Receptor-Related Receptor-α)

Vanacker, Jean‐Marc; Bonnelye, Edith; Chopin-Delannoy, Sandrine; Delmarre, Cateline; Cavaillès, Vincent; Laudet, Vincent

doi:10.1210/mend.13.5.0281

Cited by 53 publications

(42 citation statements)

References 35 publications

(58 reference statements)

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“…In EMSA, ERR␣1 formed two complexes on either element, whereas ER␣ formed only one complex with SFRE. Homodimerization of ER␣ was well documented with EREs (18), and a recent report also showed homodimer binding with SFRE (44). Therefore, the single complex of ER␣-SFRE in EMSA (Fig.…”

Section: Discussionsupporting

confidence: 53%

“…These findings show a complicated picture of mechanisms of estrogen action and make the interpretation of estrogen response in different cell types difficult. In contrast to the synthetic SFRE, which required multiple copies to confer ERR␣1 response (38,44), a single copy of the lactoferrin SFRE is functioning in our current study (Fig. 2).…”

Section: Discussionmentioning

confidence: 59%

“…Despite the effort, we were unable to demonstrate the presence of heterodimerization between ERR␣1 and ER␣ in the current EMSA condition (data not shown). It is possible that the heterodimer of the receptors will occur in vivo and in the process of co-translation in the in vitro system (44). The two complexes produced by ERR␣1 binding implied that this receptor forms homodimer.…”

Section: (Lane 2) and D (Lane 1))mentioning

confidence: 99%

“…More extensive studies on the binding requirement of ERR␣1 showed that its binding is in fact permissive and can bind a wide variety of natural and synthetic estrogen response elements (38,39,44,45). Ligands for the ERR receptors are not clearly identified; however, the pesticides (46) and serum components have been suggested as the potential ligands for ERR␣1 (44). Contrary to the liganddependent receptors, ERR␣1 was shown as a potent transactivator when its C-terminal region was fused to the progesterone receptor DNA binding domain and tested with a progesterone receptor response element driven reporter in mammalian cells (47).…”

mentioning

confidence: 99%

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Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Zhang

Teng

2000

Journal of Biological Chemistry

130

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The human estrogen receptor-related receptor (ERR␣1, NR3B1a) was shown to bind a steroidogenic factor binding element (SFRE), TCAAGGTCATC, 26 base pairs upstream from the estrogen response element (ERE) of the human lactoferrin gene promoter. A mutation made at SFRE significantly reduced estrogen-dependent transcription from the lactoferrin ERE in human endometrial cells. In this study, we demonstrated that ERR␣1 binds both SFRE and ERE elements and constitutively transactivates the lactoferrin gene promoter. In DNase I footprinting protection analysis, both SFRE and ERE regions were protected by glutathione S-transferase-ERR␣1 fusion protein. The receptor formed two protein-DNA complexes with either SFRE or ERE in electrophoresis mobility shift assay. Homodimerization of ERR␣1 was confirmed with the mammalian two-hybrid system. ERR␣1 activates reporter constructs containing various types of estrogen response elements in endometrial and non-endometrial cells in transient transfection experiments. Overexpressing the coactivator, SRC1a or GRIP1, further enhances ERR␣1-induced transcriptional activity. We demonstrated that the AF2 domain of ERR␣1 is essential for the transactivation function and that deletion or mutation at this region abrogates the activation capability. Protein-protein interaction between the SRC1a and ERR␣1 C terminus was confirmed with a GST glutathione S-transferase "pull-down" assay. When comparing ERR␣1 and the estrogen receptor ␣ (ER␣) in many of the experiments, we found that ER␣ can also bind SFRE of the lactoferrin gene and transactivate the promoter activity in a ligand-dependent manner. The present study demonstrated that ERR␣1 binds similar DNA elements as ER␣ and confers its transactivation function constitutively. Therefore, ERR␣1 may actively modulate the estrogen response of lactoferrin gene as well as other estrogen-responsive genes.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 59%

Section: (Lane 2) and D (Lane 1))mentioning

confidence: 99%

mentioning

confidence: 99%

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Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Zhang

Teng

2000

Journal of Biological Chemistry

130

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“…Furthermore, whereas ERs are ligand-activated receptors, ERRs are constitutively active (13)(14)(15)(16), and a structural study confirmed that the ERR␥ LBD can adopt a transcriptionally active conformation and interact with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand (12). Together, these observations suggest that ERRs are ligand-independent activators of transcription whose activation potential may rather be determined by the presence of transcriptional coactivators (17)(18)(19)(20).…”

mentioning

confidence: 92%

Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity

Greschik

Flaig

Renaud

et al. 2004

Journal of Biological Chemistry

120

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The estrogen-related receptor (ERR) ␥ behaves as a constitutive activator of transcription. Although no natural ligand is known, ERR␥ is deactivated by the estrogen receptor (ER) agonist diethylstilbestrol and the selective ER modulator 4-hydroxytamoxifen but does not significantly respond to estradiol or raloxifene. Here we report the crystal structures of the ERR␥ ligand binding domain (LBD) complexed with diethylstilbestrol or 4-hydroxytamoxifen. Antagonist binding to ERR␥ results in a rotation of the side chain of Phe-435 that partially fills the cavity of the apoLBD. The new rotamer of Phe-435 displaces the "activation helix" (helix 12) from the agonist position observed in the absence of ligand. In contrast to the complexes of the ER␣ LBD with 4-hydroxytamoxifen or raloxifene, helix 12 of antagonist-bound ERR␥ does not occupy the coactivator groove but appears to be completely dissociated from the LBD body. Comparison of the ligand-bound LBDs of ERR␥ and ER␣ reveals small but significant differences in the architecture of the ligand binding pockets that result in a slightly shifted binding position of diethylstilbestrol and a small rotation of 4-hydroxytamoxifen in the cavity of ERR␥ relative to ER␣. Our results provide detailed molecular insight into the conformational changes occurring upon binding of synthetic antagonists to the constitutive orphan receptor ERR␥ and reveal structural differences with ERs that explain why ERR␥ does not bind estradiol or raloxifene and will help to design new selective antagonists.The estrogen-related receptors ERR␣, 1 ERR␤, and ERR␥ (NR3B1, -2, and -3) (1) form a subfamily of orphan nuclear receptors that share significant amino acid homology with the estrogen receptors ER␣ and ER␤ (NR3A1 and -2) (2, 3). Because of the high conservation in the DNA binding domain, ERRs and ERs have overlapping DNA binding selectivity (4 -6) and, accordingly, may co-regulate target genes in tissues in which they are co-expressed. ERR subfamily members have for example been shown to modulate the expression of ER target genes in bone (7,8) or breast tissue (9, 10). Importantly, overexpression of ERR␣ and ERR␥ in samples from breast cancer patients correlates with unfavorable and favorable biomarkers, respectively (11). Therefore, these receptors might serve as prognostic markers themselves or even be targets for endocrine therapy in human breast cancer.Despite their significant homology with ERs in the ligand binding domain (LBD), ERRs do not (or only very weakly) respond to estradiol (E2) (2, 12). Furthermore, whereas ERs are ligand-activated receptors, ERRs are constitutively active (13-16), and a structural study confirmed that the ERR␥ LBD can adopt a transcriptionally active conformation and interact with the steroid receptor coactivator 1 (SRC-1) in the absence of any ligand (12). Together, these observations suggest that ERRs are ligand-independent activators of transcription whose activation potential may rather be determined by the presence of transcriptional coactivators (17)(18)(1...

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Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

et al. 2005

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A subfamily of orphan receptors, estrogen receptor-related receptors (ERRs), has been demonstrated to modulate the transcription of some estrogen responsive genes via variant estrogen response elements (EREs). This study was conducted to determine whether human ERRalpha, ERRbeta, and ERRgamma might be involved in the tumorigenesis of ovarian cancer. RT-PCR was performed to analyze the expression of hERRalpha, hERRbeta, hERRbeta-2, and hERRgamma mRNA in five ovarian cancer cell lines as well as 33 samples of ovarian cancer and 12 samples of normal ovary. Serum CA-125 levels were also analyzed in all samples by ELISA. Progression-free survival and overall survival of patients with different expression of ERRs were analyzed by the Kaplan-Meier method. To analyze the subcellular localization of ERRalpha, a green fluorescent protein (GFP)-reporter plasmid of hERRalpha was constructed and transfected into the ovarian cancer cell line OVCAR-3. Expression of hERRalpha-GFP fusion protein was observed in the nucleus of OVCAR-3 ovarian cancer cell lines. We observed increased expression of hERRalpha mRNA (P = 0.020) and hERRgamma mRNA (P = 0.045) in ovarian cancers compared to normal ovaries. In contrast, hERRbeta was only observed in 9.1% of ovarian cancers. We found a positive correlation between the serum CA-125 levels and hERRalpha expression (P = 0.012), but not hERRbeta and hERRgamma expression. Survival analysis showed that the hERRalpha-positive group has a reduced overall survival (P = 0.015), and the ERRgamma-positive group has a longer progression-free survival (P = 0.020). In multivariate analysis, expression of hERRalpha was an independent prognostic factor for poor survival (relative risk, 3.032; 95% CI, 1.27-6.06). Based on our results, ERRs may play an important role in ovarian cancer. hERRalpha may represent a biomarker of poor prognosis, and hERRgamma may be a new therapeutic target in ovarian cancer.

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Transcriptional Activities of the Orphan Nuclear Receptor ERRα (Estrogen Receptor-Related Receptor-α)

Cited by 53 publications

References 35 publications

Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Estrogen Receptor-related Receptor α1 Interacts with Coactivator and Constitutively Activates the Estrogen Response Elements of the Human Lactoferrin Gene

Structural Basis for the Deactivation of the Estrogen-related Receptor γ by Diethylstilbestrol or 4-Hydroxytamoxifen and Determinants of Selectivity

Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells

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