Modulation of ERα transcriptional activity by the orphan nuclear receptor ERRβ 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 ERRβ (ERRβS [short], ERRβL [long]) expressed in human endometrium, where they are coexpressed with the oestrogen receptor alpha (ERα). Over-expression of ERRβL enhanced ERα-dependent ligand-induced activation of an ERE-luciferase reporter construct, altered the induction of c-myc mRNA and increased proliferation of Ishikawa cells whereas ERRβS was found to reduce these endpoints.Fluorescent recovery after photobleaching (FRAP) revealed that intra-nuclear mobility of YFP-ERRβS was more rapid than YFP-ERRβL. Fluorescence resonance energy transfer (FRET) assays revealed a close association between ERRβL and ERα following addition of ligand. We speculate that ERRβL may alter ERα-dependent gene activation by enhancing the recruitment of co-activators. In conclusion, variant isoforms of ERRβ have differential effects on ERα-dependent gene expression and this has implications for human endometrial cell function.