DIFFERENT REGIONS IN ACTIVATION FUNCTION-1 OF THE HUMAN ESTROGEN-RECEPTOR REQUIRED FOR ANTIESTROGEN-DEPENDENT AND ESTRADIOL-DEPENDENT TRANSCRIPTION ACTIVATION
Em. Mcinerney et Bs. Katzenellenbogen, DIFFERENT REGIONS IN ACTIVATION FUNCTION-1 OF THE HUMAN ESTROGEN-RECEPTOR REQUIRED FOR ANTIESTROGEN-DEPENDENT AND ESTRADIOL-DEPENDENT TRANSCRIPTION ACTIVATION, The Journal of biological chemistry, 271(39), 1996, pp. 24172-24178
The human estrogen receptor (ER) is a ligand-inducible transcription f
actor that contains two transcriptional activation functions, one loca
ted in the NH2-terminal region of the protein (AF-1) and the second in
the COOH-terminal region (AF-2). Antiestrogens, such as trans-hydroxy
tamoxifen (TOT), have partial agonistic activity in certain cell types
, and studies have implied that this agonism is AF-1-dependent. We hav
e made progressive NH2-terminal and other segment deletions and ligati
ons in the A/B domain, and studied the transcriptional activity of the
se mutant ERs in ER-negative MDA-MB-231 human breast cancer and HEC-1
human endometrial cancer cells. Using several estrogens and several pa
rtial agonist/antagonist antiestrogens, we find that estrogens and ant
iestrogens require different regions of AF-1 for transcriptional activ
ation. Deletion of the first 40 amino acids has no effect on receptor
activity. Antiestrogen agonism is lost upon deletion to amino acid 87,
while estrogen agonism is not lost until deletions progress to amino
acid 109. Antiestrogen agonism has been further defined to require ami
no acids 41-64, as deletion of only these amino acids results in an ER
that exhibits 100% activity with E(2), but no longer shows an agonist
response to TOT. With A/B-modified receptors in which antiestrogens l
ose their agonistic activity, the antiestrogens then function as pure
estrogen antagonists. Our studies show that in these cellular contexts
, hormone-dependent transcription utilizes a range of the amino acid s
equence within the A/B domain. Furthermore, the agonist/antagonist bal
ance and activity of antiestrogens such as TOT are determined by speci
fic sequences within the A/B domain and thus may be influenced by diff
erences in levels of specific factors that interact with these regions
of the ER.