17β-Estradiol-induced cell proliferation requires estrogen receptor (ER) α monoubiquitination

Protein monoubiquitination (monoUbq) (i.e., the attachment of one single ubiquitin to the substrate) is a non-proteolytic reversible modification that controls protein functions. Among other proteins, the estrogen receptor alpha (ER alpha), which mediates the pleiotropic effects of the cognate hormone 17 beta-estradiol (E2), is a monoubiquitinated protein. Although it has been demonstrated that E2 rapidly reduces ER alpha monoUbq in breast cancer cells, the impact of monoUbq in the regulation of the ER alpha activities is poorly appreciated. Here, we show that mutation of the ER alpha monoUbq sites prevents the E2-induced ER alpha phosphorylation in the serine residue 118 (S118), reduces ER alpha transcriptional activity, and precludes the ER alpha-mediated extranuclear activation of signaling pathways (i.e., AKT activation) thus impeding the E2-induced cyclin D1 promoter activation and consequently cell proliferation. In addition, the interference with ER alpha monoUbq deregulates E2-induced association of ER alpha to the insulin like growth factor receptor (IGF-1-R). Altogether these data demonstrate an inherent role for monoUbq in ER alpha signaling and point to the physiological function of ER alpha monoUbq in the regulation of E2-induced cell proliferation. (C) 2011 Elsevier Inc. All rights reserved.