Pesiri V, Totta P, Segatto M, Bianchi F, Pallottini V, Marino M, Acconcia F

17?-Estradiol (E2)-dependent cell proliferation requires both estrogen receptor ? (ER?)-based integrated control of gene transcription and kinase pathways activation. Such coordination of intracellular E2:ER?-dependent signaling mechanisms is finely tuned by receptor association with specific partner proteins. Recently, we identified the leucine (L) 429 and alanine (A) 430 within the ER? ...

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ligand binding domain as important residues for receptor non-covalent interaction to ubiquitinated species [i.e., ER? ubiquitin-binding surface (ER? UBS)] and for E2-induced ER? activation. To date, if these two ER? amino acids are involved in the control of E2-dependent pathways required for cell proliferation is unknown. Here, by using stably expressing ER? mutated in L429 and A430 (i.e., L429A,A430G-LAAG) cell lines, we show that L429 and A430 are critical for E2-induced cell proliferation, PI3K/AKT pathway activation, and ER?-mediated transcriptional changes. Moreover, we demonstrate that these two receptor structural determinants direct the E2-induced PI3K/AKT/CREB1 pathway activation and CREB1-mediated transcriptional activity that in turn control the hormone-induced cell proliferation. As a whole, our data demonstrate for the first time that the ER? UBS contributes to the modulation of E2-induced ER?-mediated cell proliferation and provide a novel connection between the receptor structure and the functional molecular mechanisms by which E2:ER? complex can regulate cell processes.

Date: Dec. 01, 2015

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