Nuclear orphan receptors belong to the superfamily of ligand-activated transcription factors that show a close structural relationship and sequence homology. Ligands and functions of most of the orphan receptors have not yet been identified. The first nuclear orphan receptors that were cloned displayed a high degree of amino acid identity with the human estrogen receptor and were termed estrogen receptor-related (ERR) 1 and 2. In the present study, we show that ERR2 functions as a potent repressor of transcriptional activity mediated by the glucocorticoid receptor (GR). Transient transfection of different cell lines with a steroid-responsive reporter plasmid and receptor expression plasmids revealed that transcriptional activity mediated by GR in response to agonists was strongly suppressed by coexpression of ERR2. The orphan receptor displayed no promoter activity when expressed without GR. The inhibitory activity of ERR2 is cell-specific and also receptor-specific because transactivation mediated by the progesterone receptor is unaffected by ERR2. Our observations provide evidence that the nuclear orphan receptor ERR2 acts as an endogenous modulator of GR transcriptional activity.

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