A novel estrogen receptor-related protein γ splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors

A novel estrogen receptor-related protein (ERR) γ splice variant cDNA (ERRγ3) was found in human full-length cDNA libraries. ERRγ3 cDNA consists of 3362 base pairs and has an open reading frame of 1188 bp. The predicted peptide sequence of ERRγ3 differs from both ERRγ1 and ERRγ2 in missing 39 amino acid residues corresponding to the second zinc finger motif of the DNA binding domain (DBD). ERRγ3 gene consists of 8 exons including three unique 5′-terminal exons and lacks the exon encoding the second zinc finger motif. The expression of ERRγ3 was confined to adipocytes and prostate while that of ERRγ2 was fairly widespread. The ERRγ3 product was shown by transactivation assay to have no ability to activate ERE-controlled transcription. However, ERRγ3 has an ability to modulate the transcriptional activity of other nuclear hormone receptors. ERRγ3 augmented the ligand-dependent transcriptional activities of ER (estrogen receptor) α, ERβ, and thyroid receptor (TR) α by 1.3-, 4-, and 2.1-fold whereas it inhibited fully the activity of glucocorticoid receptor (GR). However, ERRγ3 had no effect on Vitamin D3 receptor, retinoic acid receptor α or peroxisome proliferator activated receptor α, β, and γ. These findings will help to elucidate the physiological role of the ERRγ subfamily.