Wl. Kraus et al., LIGAND-DEPENDENT, TRANSCRIPTIONALLY PRODUCTIVE ASSOCIATION OF THE AMINO-TERMINAL AND CARBOXYL-TERMINAL REGIONS OF A STEROID-HORMONE NUCLEARRECEPTOR, Proceedings of the National Academy of Sciences of the United Statesof America, 92(26), 1995, pp. 12314-12318
The estrogen receptor (ER), a 66-kDa protein that mediates the actions
of estrogens in estrogen-responsive tissues, is a member of a large s
uperfamily of nuclear hormone receptors that function as ligand-activa
ted transcription factors, ER shares a conserved structural and functi
onal organization with other members of this superfamily, including tw
o transcriptional activation functions (AFs), one located in its amino
-terminal region (AF-1) and the second located in its carboxyl-termina
l, ligand-binding region (AF-2), In most promoter contexts, synergism
between AF-1 and AF-2 is required for full ER activity, In these studi
es, we demonstrate a functional interaction of the two AF-containing r
egions of ER, when expressed as separate polypeptides in mammalian cel
ls, in response to 17 beta-estradiol (E(2)) and antiestrogen binding,
The interaction was transcriptionally productive only in response to E
(2), and was eliminated by point or deletion mutations that destroy AF
-1 or AF-2 activity or E(2) binding, Our results suggest a definitive
mechanistic role for E(2) in the activity of ER-namely, to alter recep
tor conformation to promote an association of the amino- and carboxyl-
terminal regions, leading to transcriptional synergism between AF-1 an
d AF-2. The productive reassembly of two portions of ER expressed in c
ells as separate polypeptides demonstrates the evolutionarily conserve
d modular structural and functional organization of the nuclear hormon
e receptors, The ligand-dependent interaction of the two AF-containing
regions of ER allows for the assembly of a complete activation functi
on from two distinct regions within the same protein, providing a mech
anism for hormonally regulated transcription.