Estrogen receptor interaction with estrogen response elements

The estrogen receptor (ER) is a ligand-activated enhancer protein that is a member of the steroid/ nuclear receptor superfamily. Two genes encode mamm alian ER: ER alpha and ER beta. ER binds to specific DNA sequences called e strogen response elements (EREs) with high affinity and transactivates gene expression in response to estradiol (E-2). The purpose of this review is t o summarize how natural and synthetic variations in the ERE sequence impact the affinity of ER-ERE binding and E-2-induced transcriptional activity. S urprisingly, although the consensus ERE sequence was delineated in 1989, th ere are only seven natural EREs for which both ER alpha binding affinity an d transcriptional activation have been examined. Even less information is a vailable regarding how variations in ERE sequence impact ERP binding and tr anscriptional activity. Review of data from our own laboratory and those in the literature indicate that ER alpha binding affinity does not relate lin early with E-2-induced transcriptional activation. We suggest that the reas ons for this discord include cellular amounts of coactivators and adaptor p roteins that play roles both in ER binding and transcriptional activation; phosphorylation of ER and other proteins involved in transcriptional activa tion; and sequence-specific and protein-induced alterations in chromatin ar chitecture.