Non-classical regulation of estrogen receptor-α by ICI182,780

Abstract

Estrogen receptor-α (ERα) regulates transcription through a number of molecular mechanisms. Two mechanisms by which ERα acts directly in the nucleus have emerged: (1) in classical ERα action, estrogen-bound receptor binds estrogen response elements (ERE) and regulates promoters by recruiting coactivators or corepressors to DNA; (2) non-classical action is not dependent on ERα binding to EREs; its mechanism is not as clearly defined as classical action. In many instances, non-classical action is mediated by tethering of ERα to other DNA-binding proteins, facilitating recruitment of coregulators to transcription regulatory sequences. In some cell types, non-classical stimulation can be enhanced by antagonists and repressed by agonists of ERα. Here, we show that non-classical action of ERα in 293 cells occurs in a wide range of enhancers and enhancer binding proteins. ERα stimulates AP-1 elements, cyclic AMP response elements (CRE), and serum response elements (SRE) in the presence of the antiestrogen ICI182,780. Further, in the presence of ICI182,780, ERα stimulates activation domains of Jun, ATF-2, Elk, and CRE-binding protein (CREB). Non-classical ERα regulation described here does not appear to be sensitive to point mutations which affect classical and tethered ERα action; moreover, in our experiments, non-classical action is uniquely sensitive to nuclear transport inhibition by leptomycin B. Because ICI182,780 appears to affect multiple and diverse transcriptional systems, our results are likely explained by ERα-dependent modulation of common components of the transcriptional machinery and may not be completely explained by tethering of ERα to specific transcription factors.