Regulation of Estrogen Receptor alpha Ubiquitination and Proteasome-mediated Receptor Degradation
Year: 2008
Type: dissertation
Abstract: Cellular levels of estrogen receptor-alpha (ERα) protein are regulated primarily by the ubiquitin-proteasome pathway. Dynamic interactions between ERα and the protein degradation machinery facilitate the downregulation process by targeting receptor lysine residues for polyubiquitination. To date, the lysines that control receptor degradation have not been identified. Two receptor lysines, K302 and K303, located in the hingeregion of ERα, serve multiple regulatory functions, and we examined whether these might also regulate receptor polyubiquitination, turnover, and receptor-protein interactions. We utilized ERα-negative breast cancer C4-12 cells to generate cells stably expressing wild-type (wt) ERα or ERα with lysine-to-alanine substitutions at K302 and K303 (“ERα-AA”). In the unliganded state, ERα-AA displayed rapid polyubiquitination and enhanced basal turnover, as compared to wtERα, due to its elevated association with the ubiquitin ligase CHIP and the proteasome-associated cochaperone Bag1. Treatment of C4-12 cells with either 17β-estradiol (E2) or the pure anti-estrogen ICI 182,780 (ICI) induced rapid degradation of wtERα via the ubiquitin-proteasome pathway; however, in the presence of these ligands, ERα-AA was less efficiently degraded. Furthermore, ERαAA was resistant to ICI-induced polyubiquitination, suggesting that these lysines are polyubiquitinated in response to the antiestrogen and demonstrate a novel role for these two lysines in the mechanism of action of ICI-induced receptor downregulation. The reduced stability of ERα-AA in the unliganded state and the increased stability of ERα-
Author: Nicholas B Berry
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1603171105