Disease relevance of ESRRG

• Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer [1].
• To identify activation function-1 (AF-1)-dependent cofactors involved in the transcriptional function of ERRgamma, we screened for human cDNAs coding for proteins that bind to the bacterial expressed AF-1 by biopanning of a phage display library [2].

High impact information on ESRRG

• These results provide structural and functional evidence for ligand-independent transcriptional activation by ERR3 [3].
• 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma [4].
• The observed agonist-bound state contains the ERRgamma LBD, a ligand (GSK4716), and the RIP140 peptide and reveals an unexpected rearrangement of the phenol-binding residues [5].
• Two structures were obtained describing the inverse agonist-bound state, the ERRgamma LBD with 4-hydroxytamoxifen (4-OHT), and the ERRgamma LBD with 4-OHT and a peptide representing a portion of the silencing mediator of retinoid and thyroid hormone action protein (SMRT) [5].
• ERR3 bound specifically to an estrogen response element and activated reporter genes controlled by estrogen response elements, both in yeast and in mammalian cells, in the absence of any added ligand [6].

Biological context of ESRRG

• Surprisingly, not only PNRC2 but also the corepressor TLE1 functioned as ERRgamma coactivator in a reporter gene analysis [2].
• Dimerization modulates the activity of the orphan nuclear receptor ERRgamma [7].
• ERRgamma transactivates constitutively reporter genes driven by ERR response elements (ERREs) or estrogen response elements (EREs) [8].

Anatomical context of ESRRG

• Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor highly expressed in heart, skeletal muscle, kidney, and brain [2].
• ERRgamma-mediated transactivation is further enhanced by peroxisome proliferator-activated receptor coactivator-1 [8].
• When examined in the reporter gene assay for ERRgamma using HeLa cells, BPA completely preserved ERRgamma's high constitutive activity [9].

Associations of ESRRG with chemical compounds

• However, 4-hydroxytamoxifen and diethylstilbestrol were recently shown to bind to and inhibit ERRgamma activity [7].
• A conserved AF-2 activation domain located in the hormone-binding domain of ERR3 was primarily responsible for transcriptional activation [6].
• Similarly, in the orphan nuclear receptor called estrogen-related receptor 3 (ERR3), the replacement of Asp-273 (the corresponding amino acid to Asp-351 in ERalpha) with lysine abolished constitutive transcriptional activity of ERR3 without affecting DNA-binding activity and impaired the ability of the receptor to interact with p160 coactivators [10].
• In contrast, ERRgamma activates transcription at AP-1 sites in the presence of 4OHT and 4OHtor [8].
• Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor gamma (ERRgamma) with high constitutive activity [9].

Regulatory relationships of ESRRG

• In contrast, heterodimerization with the related receptor ERRalpha inhibits the activities of both ERRgamma and ERRalpha [7].

Other interactions of ESRRG

• Simulation of the different biological activities of diethylstilbestrol (DES) on estrogen receptor alpha and estrogen-related receptor gamma [11].

Analytical, diagnostic and therapeutic context of ESRRG

• In the present work, RT-PCR analysis with gene-specific primers also identified a transcript fragment of human estrogen-related receptor gamma [12].

References