Regulation of estrogen receptor beta activity and implications in health and disease

Abstract

Together with the estrogen receptor (ER) alpha, estrogen receptor beta (ER beta ) mediates many of the physiological effects of estrogens. As ER beta is crucially involved in a variety of important physiological processes, its activity should be tightly regulated. ER beta regulation is achieved by hormone binding as well as by posttranslational modifications of the receptor. Furthermore, ER beta expression levels are under circadian control and can be regulated by DNA methylation of the ER beta promoter region. There are also a number of factors that can interfere with ER beta activity, such as phytoestrogens, endocrine disruptive chemicals, and growth factors. In this article, we outline different mechanisms of ER beta regulation and how they are implicated in various diseases. We also discuss how these insights might help to specifically target ER beta in drug design.

Fig. 1

ERβ structure and signaling mechanisms. a Domain structure of full-length ERβ (ERβ1) and its isoforms ERβ2–5. b I “Classical” ER activity through direct binding to estrogen response elements (EREs); II activated ERs signal through protein–protein interactions with other transcription factors, such as AP-1 or Sp1; III non-genomic activity involves other signal transducers and causes rapid responses

Fig. 2

Posttranslational modifications of ERβ: the signaling cascades leading to the respective modification (green), and the effects of the modification on ERβ (blue). AF Activation function, DBD DNA binding domain, LBD ligand binding domain, Palm palmitoylation, PAT palmitoyltransferase, P phosphorylation, GlnNAc 2-amino-2-deoxyglucosylation, n.i. not investigated, ERK extracellular signal-regulated, EGF epidermal growth factor, IGF insulin-like growth factor

Fig. 3

Schematic model of circadian regulation of ERβ expression. a In wild-type mice and cells, CLOCK-BMAL1 heterodimers bind constantly to the E-box enhancer in the ERβ promoter and induces ERβ transcription. The negative circadian regulator PER-CRY works as the main driving force of the circadian expression of ERβ. Recruitment of PER-CRY causes an inhibition of ERβ expression, and the release of PER-CRY results in an upregulation of ERβ expression. b In BMAL1 KO mice, the negative regulator PER-CRY cannot be recruited to ERβ promoter. Instead, the expression of ERβ is induced by unknown activating transcription factors (X) and kept at high levels with no oscillation. Figure reproduced with permission from the American Society for Microbiology

Fig. 4

DNA methylation in the ERβ untranslated region. a Schematic drawing of the ERβ untranslated region and the splicing events leading to the two ERβ mRNAs (0K-1) and (0N-1). b Positioning of the CpG islands (light gray rectangles) in ERβ (0K-1) and ERβ (0N-1). The transcription initiation site is assigned as position +1