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Gene Review

ESRRA  -  estrogen-related receptor alpha

Homo sapiens

Synonyms: ERR-alpha, ERR1, ERRa, ERRalpha, ESRL1, ...
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Disease relevance of ESRRA

  • Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer [1].
  • We observed increased expression of hERRalpha mRNA (P = 0.020) and hERRgamma mRNA (P = 0.045) in ovarian cancers compared to normal ovaries [2].
  • Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERRalpha gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells [3].
  • Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism [4].
  • This effect is cell-specific since ERR-1 activates transcription in the rat osteosarcoma cell line ROS 17.2/8 as well as in HeLa, NB-E, and FREJ4 cells but not in COS1 and HepG2 cells [5].
  • ERRalpha immunoreactivity was detected in the nuclei of aldosterone producing adenoma (APA), cortisol producing adenoma (CPA) and adrenocortical carcinoma (ACC), and higher average mRNA levels of ERRα were detected in ACC when compared to APA, CPA and normal adrenal cortex [6].

High impact information on ESRRA

  • Partial amino acid sequence data obtained from the approximately 55-kD component of IBP-s indicate that it is hERR1, an orphan member of the steroid-thyroid hormone receptor superfamily [7].
  • In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells [8].
  • Starting from this apparent contradiction, we have evaluated the potentials of two related receptors ERRalpha and ERRbeta to intervene in estrogen signaling [9].
  • Our findings demonstrate that ERRalpha is a key regulator of mitochondrial biogenesis and oxidative metabolism, and essential for adaptive thermogenesis [10].
  • Rather, we show that ERRalpha is needed for the high levels of mitochondrial biogenesis and oxidative capacity characteristic of brown adipose tissue (BAT), and thus for providing the energy necessary for thermogenesis [10].
  • In normal adrenal cortex tissues, ERRalpha expression is possibly related to adrenal development, playing a role in fetal adrenal function, in DHEAS production in adrenarche, and also in steroid production of post-adrenarche/adult life [6].

Chemical compound and disease context of ESRRA


Biological context of ESRRA

  • Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage [14].
  • All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance [15].
  • Using fluorescence in situ hybridization, we have mapped the human ESRRA gene to chromosome 11q12-q13 and the human ESRRB gene to chromosome 14q24 [16].
  • ERR alpha was initially isolated based on its sequence homology to the estrogen receptor but is not activated by classic estrogens [17].
  • We show that the major isoform of the human ERRalpha gene, ERRalpha1, can sequence-specifically bind a consensus palindromic estrogen response element (ERE) and directly compete with estrogen receptor alpha (ERalpha) for binding [18].

Anatomical context of ESRRA

  • However, no association was observed between ESRRA and QUS heel bone measures [15].
  • The crystal structure of the ligand binding domain (LBD) of the estrogen-related receptor alpha (ERRalpha, NR3B1) complexed with a coactivator peptide from peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) reveals a transcriptionally active conformation in the absence of a ligand [19].
  • RT-PCR showed that ERRalpha and ERRgamma transcripts were detected in most cell lines and xenografts, whereas ERRbeta was detected in normal epithelial cells and few immortalized cell lines but not in most cancer lines [20].
  • 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 [2].
  • In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha [14].
  • ERRalpha has been detected in fetal, post-birth, and adult human adrenocortex; in the fetal adrenal, a higher labeling index (LI) was detected in the neocortex (NC) ( 71.2 ± 4.99%), when compared to the fetal zone (FZ) (24.9 ± 5.17%) (P = 0.0017) [6].

Associations of ESRRA with chemical compounds

  • The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene [17].
  • Consequently, ERRalpha may potentiate constitutive transcription of estrogen response element-containing genes independently of ERalpha and antiestrogens in ErbB2-positive tumors [1].
  • In addition, we show that a PGC-1alpha peptide containing this nuclear box motif from the L3 site binds ERRalpha LBD with a higher affinity than a peptide containing a steroid receptor coactivator-1 motif and that the affinity is further enhanced when all three leucine-rich regions of PGC-1alpha are present [19].
  • Herein we test the hypothesis that ERRalpha regulates transcription of the genes encoding the enzymes involved in adrenal steroid production [21].
  • The human estrogen-related receptor alpha 1 (hERR alpha 1) is an orphan member of the steroid/thyroid hormone receptor superfamily [22].

Physical interactions of ESRRA


Enzymatic interactions of ESRRA

  • Here, we investigated growth factor regulation of ERRalpha function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding [13].

Regulatory relationships of ESRRA


Other interactions of ESRRA


Analytical, diagnostic and therapeutic context of ESRRA


  1. Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Ariazi, E.A., Clark, G.M., Mertz, J.E. Cancer Res. (2002) [Pubmed]
  2. Expression of estrogen receptor-related receptors, a subfamily of orphan nuclear receptors, as new tumor biomarkers in ovarian cancer cells. Sun, P., Sehouli, J., Denkert, C., Mustea, A., Könsgen, D., Koch, I., Wei, L., Lichtenegger, W. J. Mol. Med. (2005) [Pubmed]
  3. Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element. Liu, D., Zhang, Z., Teng, C.T. J. Mol. Endocrinol. (2005) [Pubmed]
  4. Estrogen-related Receptors Stimulate Pyruvate Dehydrogenase Kinase Isoform 4 Gene Expression. Zhang, Y., Ma, K., Sadana, P., Chowdhury, F., Gaillard, S., Wang, F., McDonnell, D.P., Unterman, T.G., Elam, M.B., Park, E.A. J. Biol. Chem. (2006) [Pubmed]
  5. The ERR-1 orphan receptor is a transcriptional activator expressed during bone development. Bonnelye, E., Vanacker, J.M., Dittmar, T., Begue, A., Desbiens, X., Denhardt, D.T., Aubin, J.E., Laudet, V., Fournier, B. Mol. Endocrinol. (1997) [Pubmed]
  6. Estrogen-related receptor α in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis. Felizola, S.J., Nakamura, Y., Hui, X.G., Satoh, F., Morimoto, R., M McNamara, K., Midorikawa, S., Suzuki, S., Rainey, W.E., Sasano, H. Mol. Cell. Endocrinol. (2013) [Pubmed]
  7. SV40 early-to-late switch involves titration of cellular transcriptional repressors. Wiley, S.R., Kraus, R.J., Zuo, F., Murray, E.E., Loritz, K., Mertz, J.E. Genes Dev. (1993) [Pubmed]
  8. Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs. Gaillard, S., Grasfeder, L.L., Haeffele, C.L., Lobenhofer, E.K., Chu, T.M., Wolfinger, R., Kazmin, D., Koves, T.R., Muoio, D.M., Chang, C.Y., McDonnell, D.P. Mol. Cell (2006) [Pubmed]
  9. Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta. Vanacker, J.M., Pettersson, K., Gustafsson, J.A., Laudet, V. EMBO J. (1999) [Pubmed]
  10. Orphan nuclear receptor estrogen-related receptor {alpha} is essential for adaptive thermogenesis. Villena, J.A., Hock, M.B., Chang, W.Y., Barcas, J.E., Giguère, V., Kralli, A. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  11. Transcriptional regulation of the estrogen-inducible pS2 breast cancer marker gene by the ERR family of orphan nuclear receptors. Lu, D., Kiriyama, Y., Lee, K.Y., Giguère, V. Cancer Res. (2001) [Pubmed]
  12. Function of estrogen-related receptor alpha in human endometrial cancer. Watanabe, A., Kinoshita, Y., Hosokawa, K., Mori, T., Yamaguchi, T., Honjo, H. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  13. Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha. Barry, J.B., Giguère, V. Cancer Res. (2005) [Pubmed]
  14. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression. Laganière, J., Tremblay, G.B., Dufour, C.R., Giroux, S., Rousseau, F., Giguère, V. J. Biol. Chem. (2004) [Pubmed]
  15. A frequent regulatory variant of the estrogen-related receptor alpha gene associated with BMD in French-Canadian premenopausal women. Laflamme, N., Giroux, S., Loredo-Osti, J.C., Elfassihi, L., Dodin, S., Blanchet, C., Morgan, K., Giguère, V., Rousseau, F. J. Bone Miner. Res. (2005) [Pubmed]
  16. Chromosomal mapping of the human and murine orphan receptors ERRalpha (ESRRA) and ERRbeta (ESRRB) and identification of a novel human ERRalpha-related pseudogene. Sladek, R., Beatty, B., Squire, J., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Giguère, V. Genomics (1997) [Pubmed]
  17. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Sladek, R., Bader, J.A., Giguère, V. Mol. Cell. Biol. (1997) [Pubmed]
  18. Estrogen-related receptor alpha 1 actively antagonizes estrogen receptor-regulated transcription in MCF-7 mammary cells. Kraus, R.J., Ariazi, E.A., Farrell, M.L., Mertz, J.E. J. Biol. Chem. (2002) [Pubmed]
  19. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha. Kallen, J., Schlaeppi, J.M., Bitsch, F., Filipuzzi, I., Schilb, A., Riou, V., Graham, A., Strauss, A., Geiser, M., Fournier, B. J. Biol. Chem. (2004) [Pubmed]
  20. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. Cheung, C.P., Yu, S., Wong, K.B., Chan, L.W., Lai, F.M., Wang, X., Suetsugi, M., Chen, S., Chan, F.L. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  21. Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha. Seely, J., Amigh, K.S., Suzuki, T., Mayhew, B., Sasano, H., Giguere, V., Laganière, J., Carr, B.R., Rainey, W.E. Endocrinology (2005) [Pubmed]
  22. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Johnston, S.D., Liu, X., Zuo, F., Eisenbraun, T.L., Wiley, S.R., Kraus, R.J., Mertz, J.E. Mol. Endocrinol. (1997) [Pubmed]
  23. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha). Schreiber, S.N., Knutti, D., Brogli, K., Uhlmann, T., Kralli, A. J. Biol. Chem. (2003) [Pubmed]
  24. Estrogen-related receptor, hERR1, modulates estrogen receptor-mediated response of human lactoferrin gene promoter. Yang, N., Shigeta, H., Shi, H., Teng, C.T. J. Biol. Chem. (1996) [Pubmed]
  25. Sequence-specific interaction of the Ets1 protein with the long terminal repeat of the human T-lymphotropic virus type I. Gitlin, S.D., Bosselut, R., Gégonne, A., Ghysdael, J., Brady, J.N. J. Virol. (1991) [Pubmed]
  26. A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters. Barry, J.B., Laganière, J., Giguère, V. Mol. Endocrinol. (2006) [Pubmed]
  27. Sp1 is involved in a protein kinase C-independent activation of human T cell leukemia virus type I long terminal repeat by 12-O-tetradecanoylphorbol-13-acetate. Torgeman, A., Mor-Vaknin, N., Aboud, M. Virology (1999) [Pubmed]
  28. Estrogen-related receptors-stimulated monoamine oxidase B promoter activity is down-regulated by estrogen receptors. Zhang, Z., Chen, K., Shih, J.C., Teng, C.T. Mol. Endocrinol. (2006) [Pubmed]
  29. Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes. Castet, A., Herledan, A., Bonnet, S., Jalaguier, S., Vanacker, J.M., Cavaillès, V. Mol. Endocrinol. (2006) [Pubmed]
  30. Dimerization modulates the activity of the orphan nuclear receptor ERRgamma. Huppunen, J., Aarnisalo, P. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  31. Human estrogen receptor-like 1 (ESRL1) gene: genomic organization, chromosomal localization, and promoter characterization. Shi, H., Shigeta, H., Yang, N., Fu, K., O'Brian, G., Teng, C.T. Genomics (1997) [Pubmed]
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