NUCLEAR ORPHAN RECEPTOR AS A REPRESSOR OF GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL ACTIVITY

Nuclear orphan receptors belong to the superfamily of ligand activated transcription factors that show a close structural relationship and s equence homology. Ligands and functions of most of the orphan receptor s have not yet been identified. The first nuclear orphan receptors tha t 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 pote nt repressor of transcriptional activity mediated by the glucocorticoi d 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 a gonists was strongly suppressed by coexpression of ERR2. The orphan re ceptor displayed no promoter activity when expressed without GR. The i nhibitory activity of ERR2 is cell-specific and also receptor-specific because transactivation mediated by the progesterone receptor is unaf fected by ERR2. Our observations provide evidence that the nuclear orp han receptor ERR2 acts as an endogenous modulator of GR transcriptiona l activity.