Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

Abstract

This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways. First, UPS performs the ubiquitination of ERs with a change in their functional activity. Second, UPS degrades ERs and their transcriptional regulators. Third, UPS affects the expression of ER genes. In addition, the opportunity of the regulation of proteasome functioning by ERs-in particular, the expression of immune proteasomes-is discussed. Understanding the complex mechanisms underlying the regulation of ERs and proteasomes has great prospects for the development of new therapeutic agents that can make a significant contribution to the treatment of diseases associated with the impaired function of these biomolecules.

Keywords: cancer; immune proteasomes; membrane estrogen receptors; nuclear estrogen receptors; ubiquitin proteasome system.

Figure 1

Scheme of estrogen receptor functioning. E—estrogen; ER—estrogen receptor; Gα, Gβ—G proteins; SRC—non-receptor tyrosine kinase; GPER—G protein-estrogen receptor; cAMP—cyclic adenosine monophosphate; PI3K—phosphoinositide 3-kinase; RAS—retrovirus-associated DNA sequence protein; PLC—phospholipase C; PKA—protein kinase A; Akt—protein kinase B; MAPK—mitogen-activated protein kinase; IP3—inositol triphosphate; TF—transcription factors.

Figure 2

The canonical pathway of protein ubiquitination for degradation in the 26S proteasome. 1: ATP-dependent activation of the ubiquitin (Ub) by ubiquitin-activating enzyme (Uba). 2: Transfer of the activated ubiquitin to ubiquitin-conjugating enzyme (Ubc). 3: Binding of ubiquitin–protein ligase (ubiquitin-recognizing factor, Ubr), containing the homologous to E6AP carboxyl terminus (HECT) domain, to the ubiquitin and target protein. 4: Covalent attachment of the ubiquitin molecule to the target protein. 5: Building of the ubiquitin chain with the formation of isopeptide bonds Lys48-Gly76. 6: Completion of the labeling of the target protein with a structure of four (or more) ubiquitin molecules recognized by the 26S proteasome.

Figure 3

Scheme of the mutual regulation of estrogen receptors and ubiquitin proteasome system. ER—estrogen receptor; P—phosphate group; Src, PKC, MAPK, ERK7—protein kinases; USP7—ubiquitin specific protease 7; E1—ubiquitin-activating enzyme; E2—ubiquitin-conjugating enzyme; E3—ubiquitin protein ligase; Ub—ubiquitin; ESR1—gene encoding ERα; SRCs—steroid receptor coactivators; MIR191—miRNA 191; SOX4, PU.1—transcription factors; LMP2—large multifunctional peptidase 2 (immune proteasome subunit); PSMB9—gene of proteasome subunit beta type 9 (LMP2).