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 occ urs via transcriptional repression exerted by the binding of the ER alpha-l igand complex to the 5' region of the coding region of the ER alpha gene. P lacement of the phenolic hydroxyl group on the various carbons of the aroma tic A-ring of estratrien-17 beta ol (carbons 1-3) produced ligands which di minished the steady state level of ER alpha mRNA in relation to their affin ity for receptor. 4-Hydoxyestratrien-17 beta ol, on the other hand, was ina ctive in the downregulation of ER alpha mRNA. Although this A-ring isomer b rought about apparent processing of the nuclear receptor, the ER alpha reap peared in the cytosol within 24 h. Unlike the stimulation of genes regulate d 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 el icited in the ER alpha molecule by various ligands create surfaces capable of interacting with other transcription factors in a manner which is differ ent when the receptor functions via a response element mechanism relative t o interactions during autologous negative regulation of the ER alpha gene. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.