Ligand structure influences autologous downregulation of estrogen receptor-alpha messenger RNA

A series of A- and D-ring substituted estrogen analogues have been examined for their effect on estrogen receptor-alpha (ER alpha) mRNA downregulation. Recently it has been proposed that ER alpha autologous downregulation occurs via transcriptional repression exerted by the binding of the ER alpha-ligand complex to the 5' region of the coding region of the ER alpha gene. Placement of the phenolic hydroxyl group on the various carbons of the aromatic A-ring of estratrien-17 beta ol (carbons 1-3) produced ligands which diminished the steady state level of ER alpha mRNA in relation to their affinity for receptor. 4-Hydoxyestratrien-17 beta ol, on the other hand, was inactive in the downregulation of ER alpha mRNA. Although this A-ring isomer brought about apparent processing of the nuclear receptor, the ER alpha reappeared in the cytosol within 24 h. Unlike the stimulation of genes regulated via estrogen response elements, maximum autologous negative regulation of the ER alpha gene required the presence of an hydroxyl group on carbon 17 of the D-ring. These results suggest that the conformational alterations elicited in the ER alpha molecule by various ligands create surfaces capable of interacting with other transcription factors in a manner which is different when the receptor functions via a response element mechanism relative to interactions during autologous negative regulation of the ER alpha gene. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.