Estrogen-related receptor gamma explained

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.^{[1] [2] [3]} 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.^[4] 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).,^[5] 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.^[6]

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.^[7]

Further reading

• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 6 . 355–64 . Dec 1998 . 10048485 . 10.1093/dnares/5.6.355 . free .
• Hong H, Yang L, Stallcup MR . Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3 . The Journal of Biological Chemistry . 274 . 32 . 22618–26 . Aug 1999 . 10428842 . 10.1074/jbc.274.32.22618 . free .
• Heard DJ, Norby PL, Holloway J, Vissing H . 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 . Mar 2000 . 10.1210/mend.14.3.0431 . 10707956 . free .
• Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP . Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3 . Molecular Cell . 9 . 2 . 303–13 . Feb 2002 . 11864604 . 10.1016/S1097-2765(02)00444-6 . free .
• Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K . 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 . Jun 2002 . 12107410 .
• Hentschke M, Süsens U, Borgmeyer U . Domains of ERRgamma that mediate homodimerization and interaction with factors stimulating DNA binding . European Journal of Biochemistry . 269 . 16 . 4086–97 . Aug 2002 . 12180985 . 10.1046/j.1432-1033.2002.03102.x .
• Hentschke M, Süsens U, Borgmeyer U . PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma . Biochemical and Biophysical Research Communications . 299 . 5 . 872–9 . Dec 2002 . 12470660 . 10.1016/S0006-291X(02)02753-5 .
• Hentschke M, Schulze C, Süsens U, Borgmeyer U . Characterization of calmodulin binding to the orphan nuclear receptor Errgamma . Biological Chemistry . 384 . 3 . 473–82 . Mar 2003 . 12715898 . 10.1515/BC.2003.053 . 41163978 .
• Hentschke M, Borgmeyer U . 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 . Dec 2003 . 14651967 . 10.1016/j.bbrc.2003.11.025 .
• Cheung CP, Yu S, Wong KB, Chan LW, Lai FM, Wang X, Suetsugi M, Chen S, Chan FL . 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 . Mar 2005 . 15598686 . 10.1210/jc.2004-1421 . free .
• Liu D, Zhang Z, Teng CT . 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 . Apr 2005 . 15821111 . 10.1677/jme.1.01586 . free .
• Gao M, Sun P, Wang J, Zhao D, Wei L . Expression of estrogen receptor-related receptor isoforms and clinical significance in endometrial adenocarcinoma . International Journal of Gynecological Cancer . 16 . 2 . 827–33 . 2006 . 16681769 . 10.1111/j.1525-1438.2006.00527.x . 37213476 .
• Wang L, Zuercher WJ, Consler TG, Lambert MH, Miller AB, Orband-Miller LA, McKee DD, Willson TM, Nolte RT . 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 . Dec 2006 . 16990259 . 10.1074/jbc.M608410200 . free .
• Babu S, Vellore NA, Kasibotla AV, Dwayne HJ, Stubblefield MA, Uppu RM . 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 . Sep 2012 . 22935422 . 10.1016/j.bbrc.2012.08.065 .

Notes and References

1. Web site: Entrez Gene: ESRRG estrogen-related receptor gamma.
2. Eudy JD, Yao S, Weston MD, Ma-Edmonds M, Talmadge CB, Cheng JJ, Kimberling WJ, Sumegi J . Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41 . Genomics . 50 . 3 . 382–4 . Jun 1998 . 9676434 . 10.1006/geno.1998.5345 .
3. Chen F, Zhang Q, McDonald T, Davidoff MJ, Bailey W, Bai C, Liu Q, Caskey CT . Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR . Gene . 228 . 1–2 . 101–9 . Mar 1999 . 10072763 . 10.1016/S0378-1119(98)00619-2 .
4. Huppunen J, Aarnisalo P . Dimerization modulates the activity of the orphan nuclear receptor ERRgamma . Biochemical and Biophysical Research Communications . 314 . 4 . 964–70 . Feb 2004 . 14751226 . 10.1016/j.bbrc.2003.12.194 .
5. Babu S, Vellore NA, Kasibotla AV, Dwayne HJ, Stubblefield MA, Uppu RM . 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 . Sep 2012 . 22935422 . 10.1016/j.bbrc.2012.08.065 .
6. Matsushima A, Kakuta Y, Teramoto T, Koshiba T, Liu X, Okada H, Tokunaga T, Kawabata S, Kimura M, Shimohigashi Y . Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma . Journal of Biochemistry . 142 . 4 . 517–24 . Oct 2007 . 17761695 . 10.1093/jb/mvm158 .
7. Takeda Y, Liu X, Sumiyoshi M, Matsushima A, Shimohigashi M, Shimohigashi Y . Placenta expressing the greatest quantity of bisphenol A receptor ERR among the human reproductive tissues: Predominant expression of type-1 ERRgamma isoform . Journal of Biochemistry . 146 . 1 . 113–22 . Jul 2009 . 19304792 . 10.1093/jb/mvp049 .