Dynamics of Estrogen Receptor-mediated Transcriptional Activation of Responsive Genes In Vivo: Apprehending Transcription in Four Dimensions

摘要

Estrogens, such as 17P-estradiol (E_2), are commonly recognized as pivotal hormones controlling female reproductive physiology (1), but they also exhibit pleiotropic actions in male reproductive development and physiology, bone and lipid metabolisms, and the maintenance of the cardiovascular and neuronal systems (2-4). These effects of E_2 are mainly transduced through specific receptors, the estrogen receptors (ERa and ERP), although another protein, G protein-coupled receptor (GPR30) has been recently suggested to transduce some of the estrogenic responses (5). Further studies are awaited to identify the exact respective contribution of both pathways to E_2 signaling. ERs are dimeric, intranuclear, ligand-dependent transcription factors belonging to the superfamily of nuclear receptors (NRs) (6). ERs classically recognize defined palindromic target DNA sequences located within the promoter regions of estrogen responsive target genes (7, 8). Upon binding its ligand, ER undergoes drastic conformational changes (8) that generate surfaces that associate with transcriptional cofactors that in turn allow the recruitment to the target promoter and activation of the RNA polymerase II complex (Pol II) (9).