Em. Mcinerney et al., TRANSCRIPTION ACTIVATION BY THE HUMAN ESTROGEN-RECEPTOR SUBTYPE BETA (ER-BETA) STUDIED WITH ER-BETA AND ER-ALPHA RECEPTOR CHIMERAS, Endocrinology, 139(11), 1998, pp. 4513-4522
We have studied the two estrogen receptor (ER) subtypes, ER alpha and
ER beta, and chimeric constructs with ER alpha and ER beta to examine
the bioactivities of these receptors and their responses to estrogen a
nd antiestrogen ligands. Transcriptional activity of ER beta is highly
dependent on cell/promoter context and on the nature of the ligand. E
R beta activated significant levels of transcription in response to es
trogens in certain cell types, but showed only moderate activity compa
red with ER alpha in others. Antiestrogens such as tamoxifen and 2-phe
nylbenzofuran, which show some agonistic activity with ER alpha, exhib
it no agonistic activity with ER alpha. Alteration of the amino-termin
al A/B receptor domain can result in a dramatic change in cell type- a
nd ligand-specific transcriptional activity of ER beta. Upon replacing
the A/B domain of ER beta with the A/B domain of ER alpha, this recep
tor chimera not only exhibits an improved transcriptional response to
estrogens, but also is now able to activate transcription upon treatme
nt with these antiestrogens. As antiestrogen agonism was lacking in ER
beta and the ER beta/alpha chimera containing the amino-terminal A/B
domain of ER beta fused to domains C through F of ER alpha, but was re
stored in an ER alpha/beta chimera containing the AIB domain of ER alp
ha, antiestrogen agonism was shown to depend on the A/B domain (activa
tion function-l-containing region) of ER alpha. Together, these result
s indicate that the differences in the amino-terminal regions of ER al
pha and ER beta contribute to the cell and promoter-specific differenc
es in transcriptional activity of these receptors, and their ability t
o respond to different ligands, thus providing a mechanism for differe
ntially regulated transcription by these two ERs.