Estrogen-related receptor gamma (ERR-gamma), also known as NR3B3 (nuclear receptor subfamily 3, group B, member 3), is a nuclear receptor that in humans is encoded by the ESRRG (EStrogen Related Receptor Gamma) gene. It behaves as a constitutive activator of transcription.
This protein is a member of nuclear hormone receptor family of steroid hormone receptors. No physiological activating ligand is known for this orphan receptor, but 4-hydroxytamoxifen and diethylstilbestrol act as inverse agonists and deactivate ESRRG. It also seems to be the target of bisphenol A (see below).
Bisphenol A binding
There is evidence that bisphenol A functions as a xenoestrogen by binding strongly to ERR-γ. BPA as well as its nitrated and chlorinated metabolites seems to binds strongly to ERR-γ (dissociation constant = 5.5 nM), but not to the estrogen receptor (ER)., BPA binding to ERR-γ preserves its basal constitutive activity. It can also protect it from deactivation from the selective estrogen receptor modulator 4-hydroxytamoxifen.
Different expression of ERR-γ in different parts of the body may account for variations in bisphenol A effects. For instance, ERR-γ has been found in high concentration in the placenta, explaining reports of high bisphenol A accumulation there.
References
Further reading
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- Hong H, Yang L, Stallcup MR (Aug 1999). "Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3". The Journal of Biological Chemistry. 274 (32): 22618–26. doi:10.1074/jbc.274.32.22618. PMID 10428842.
- Heard DJ, Norby PL, Holloway J, Vissing H (Mar 2000). "Human ERRgamma, 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". Molecular Endocrinology. 14 (3): 382–92. doi:10.1210/mend.14.3.0431. PMID 10707956.
- Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP (Feb 2002). "Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3". Molecular Cell. 9 (2): 303–13. doi:10.1016/S1097-2765(02)00444-6. PMID 11864604.
- Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (Jun 2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants". Molecular Vision. 8: 205–20. PMID 12107410.
- Hentschke M, Süsens U, Borgmeyer U (Aug 2002). "Domains of ERRgamma that mediate homodimerization and interaction with factors stimulating DNA binding". European Journal of Biochemistry. 269 (16): 4086–97. doi:10.1046/j.1432-1033.2002.03102.x. PMID 12180985.
- Hentschke M, Süsens U, Borgmeyer U (Dec 2002). "PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma". Biochemical and Biophysical Research Communications. 299 (5): 872–9. doi:10.1016/S0006-291X(02)02753-5. PMID 12470660.
- Hentschke M, Schulze C, Süsens U, Borgmeyer U (Mar 2003). "Characterization of calmodulin binding to the orphan nuclear receptor Errgamma". Biological Chemistry. 384 (3): 473–82. doi:10.1515/BC.2003.053. PMID 12715898. S2CID 41163978.
- Hentschke M, Borgmeyer U (Dec 2003). "Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma". Biochemical and Biophysical Research Communications. 312 (4): 975–82. doi:10.1016/j.bbrc.2003.11.025. PMID 14651967.
- Cheung CP, Yu S, Wong KB, Chan LW, Lai FM, Wang X, Suetsugi M, Chen S, Chan FL (Mar 2005). "Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues". The Journal of Clinical Endocrinology and Metabolism. 90 (3): 1830–44. doi:10.1210/jc.2004-1421. PMID 15598686.
- Liu D, Zhang Z, Teng CT (Apr 2005). "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". Journal of Molecular Endocrinology. 34 (2): 473–87. doi:10.1677/jme.1.01586. PMID 15821111.
- Gao M, Sun P, Wang J, Zhao D, Wei L (2006). "Expression of estrogen receptor-related receptor isoforms and clinical significance in endometrial adenocarcinoma". International Journal of Gynecological Cancer. 16 (2): 827–33. doi:10.1111/j.1525-1438.2006.00527.x. PMID 16681769. S2CID 37213476.
- Wang L, Zuercher WJ, Consler TG, Lambert MH, Miller AB, Orband-Miller LA, McKee DD, Willson TM, Nolte RT (Dec 2006). "X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation". The Journal of Biological Chemistry. 281 (49): 37773–81. doi:10.1074/jbc.M608410200. PMID 16990259.
- Babu S, Vellore NA, Kasibotla AV, Dwayne HJ, Stubblefield MA, Uppu RM (Sep 2012). "Molecular docking of bisphenol A and its nitrated and chlorinated metabolites onto human estrogen-related receptor-gamma". Biochemical and Biophysical Research Communications. 426 (2): 215–20. doi:10.1016/j.bbrc.2012.08.065. PMID 22935422.