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.
Bombail
Vincent
V
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom.
Collins
Frances
F
Brown
Pamela
P
Saunders
Philippa T K
PT
D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004717:Endometrium / Q000166:cytology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; C107914:estrogen receptor-related receptor beta