In the DNA complex of coactivator-bound estrogen receptor alpha (ERα), the N-terminal domain (NTD) and C-terminal ligand-binding domain (LBD) interact specifically. ERα-NTD and LBD constitute activation function 1 (AF-1) and activation function 2 (AF-2), respectively. We recently revealed that, despite the complete inactivity of ERα-NTD(AF-1), desNTD(AF-1)-ERα exhibited approximately 65% of the activity of the natural estrogen 17β-estradiol (E2) for wild-type full-length ERα. It remains unclear how a deficiency of NTD(AF-1) influences the activity of desNTD(AF-1)-ERα especially with respect to other estrogens and xenoestrogens. The major objective of this study is to evaluate the ligand specificity of desNTD(AF-1)-ERα for a series of xenoestrogens, including bisphenol A (BPA), BPAF, and BPC, together with E2, and the antagonists 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (ICI). The receptors were transiently expressed in HeLa cells, and receptor activation activity was evaluated by luciferase reporter gene assay. Antagonist activity was examined for ERα and desNTD(AF-1)-ERα using E2 as a reference agonist. E2 exhibited full agonist activity for both ERα and desNTD(AF-1)-ERα, whereas 4-OHT and ICI were completely inactive and exhibited antagonist activity for E2 in both ERα and desNTD(AF-1)-ERα. All bisphenols were active for full-length ERα. Surprisingly, however, BPAF and BPC were almost completely inactive for desNTD(AF-1)-ERα, whereas BPA was fully active. BPAF and BPC exhibited distinct antagonist activity for E2 in desNTD(AF-1)-ERα, with pA 2 values of 7.62 and 7.86, respectively. The present results revealed that the presence of the N-terminal NTD(AF-1) domain substantiates the agonist activity of halogen-containing BPAF and BPC in wild-type full-length ERα. ERα-NTD(AF-1) plays an essential role in determining the agonist/antagonist activity of BPAF and BPC for estrogen receptor ERα.
Liu et al. (Mon,) studied this question.