Modulation of ER alpha transcriptional activity by the orphan nuclear receptor ERR beta and evidence for differential effects of long- and short-form splice variants.

Oestrogen receptor related proteins (ERRs) affect target gene expression without binding oestradiol. We investigated the functional activity of two splice variant isoforms of ERR beta (ERR beta S [short], ERR beta L [long]) expressed in human endometrium, where they are coexpressed with the oestrogen receptor alpha (ER alpha). Over-expression of ERRbetaL enhanced ER alpha-dependent ligand-induced activation of an ERE-luciferase reporter construct, altered the induction of c-myc mRNA and increased proliferation of Ishikawa cells whereas ERR beta S was found to reduce these endpoints. Fluorescent recovery after photobleaching (FRAP) revealed that intra-nuclear mobility of YFP-ERR beta S was more rapid than YFP-ERR beta L. Fluorescence resonance energy transfer (FRET) assays revealed a close association between ERR beta L and ER alpha following addition of ligand. We speculate that ERR beta L may alter ER alpha-dependent gene activation by enhancing the recruitment of co-activators. In conclusion, variant isoforms of ERR beta have differential effects on ER alpha-dependent gene expression and this has implications for human endometrial cell function.