Transactivation Function-1-Mediated Partial Agonist Activity of Selective Estrogen Receptor Modulator Requires Homo-Dimerization of the Estrogen Receptor α Ligand Binding Domain.

Yukitomo Arao,Kenneth S Korach

doi:10.3390/ijms20153718

Abstract

The isolation of estrogen receptor alpha (ERα) cDNA was successful around 30 years ago. The characteristics of ERα protein have been examined from various aspects, primarily through in vitro cell culture studies, but more recently using in vivo experimental models. There remains, however, some uncharacterized ERα functionalities. In particular, the mechanism of partial agonist activity of selective estrogen receptor modulators (SERMs) that involves control of the N-terminal transcription function of ERα, termed AF-1, is still an unsolved ERα functionality. We review the possible mechanism of SERM-dependent regulation of ERα AF-1-mediated transcriptional activity, which includes the role of helix 12 of ERα ligand binding domain (LBD) for SERM-dependent AF-1 regulation. In addition, we describe a specific portion of the LBD that associates with blocking AF-1 activity with an additional role of the F-domain in mediating SERM activity.

Highlights

Estrogen receptor alpha (ERα) is the first estrogen receptor protein that the cDNA was isolated from various species, including human, mouse, rat and chicken [1,2,3,4]
We describe a cooperative functionality of the ERα protein domains for eliciting a tissue selective gene response by controlling the N-terminal transcriptional activity
ERα possesses A through F domains and two transactivation functional regions, termed AF-1 and AF-2, which are localized in AB-domains and E-domain, respectively (Figure 1)

Summary

Introduction

Estrogen receptor alpha (ERα) is the first estrogen receptor protein that the cDNA was isolated from various species, including human, mouse, rat and chicken [1,2,3,4]. The molecular mechanism of partial agonist activity of selective estrogen receptor modulators (SERMs), controlling the N-terminal transcriptional activity of ERα is still unsolved. We describe a cooperative functionality of the ERα protein domains for eliciting a tissue selective gene response by controlling the N-terminal transcriptional activity. It is highly likely that the altered position of helix 12 with antagonists/SERMs prevents coactivator interaction, resulting in attenuation of ERα AF-2-mediated transcriptional activity.

Results

Conclusion