Ligands Differentially Modify the Nuclear Mobility of Estrogen Receptors α and β

Abstract

Signaling of nuclear receptors depends on the structure of their ligands, with different ligands eliciting different responses. In this study using a comparative analysis, an array of ligands was examined for effects on estrogen receptor alpha (ERalpha) and ERbeta mobility. Our results indicated that these two receptors share similarities in response to some ligands but differ significantly in response to others. Our results suggest that for ERalpha, ligands can be classified into three distinct groups: 1) ligands that do not affect the mobility of the receptor, 2) ligands that cause a moderate effect, and 3) ligands that strongly impact mobility of ERalpha. Interestingly, we found that for ERbeta such a classification was not possible because ERbeta ligands caused a wider spectrum of responses. One of the main differences between the two receptors was the response toward the antiestrogens ICI and raloxifene, which was not attributable to differential subnuclear localization or different conformations of helix 12 in the C-terminal domain. We showed that both of these ligands caused a robust phenotype, leading to an almost total immobilization of ERalpha, whereas ERbeta retained its mobility; we provide evidence that the mobility of the two receptors depends upon the function of the proteasome machinery. This novel finding that ERbeta retains its mobility in the presence of antiestrogens could be important for its ability to regulate genes that do not contain classic estrogen response element sites and do not require DNA binding and could be used in the investigation of ligands that show ER subtype specificity.

New analogs of steroid estrogens

“…This fact provides a possibility to synthesize analog of VII from compound V under the R = CH 3 action of acids, for the probability of a rearrangement is large with the migration of the methyl group from C 13 into the position 17. The driving force of the rearrangement is the removal of the mentioned unfavorable sterical interactions.…”

“…It was established applying the NMR spectroscopy that 7α-methyl-3-methoxy-D-homo-6-oxa-8α,14β-estra-1,3,5(10)-trien-17a-one existed in solution in two conformations distinguished by the structure of the rings B, C, and D simultaneously. The reaction of 17-methylidene-3-methoxy-6-oxa-8α-estra-1,3,5(10)-triene with hydrobromic acid in acetic acid promotes a rearrangement with the migration of a methyl group into the position 17 resulting in the formation of 17,17-dimethyl-6-oxa-8α-gona-1,3,5(10),13(14)-tetraene derivatives.The study of the mechanism of the action of steroid estrogens mediated by their nuclear receptors made it possible to reveal numerous relations between the structure and the biologic properties of this hormone group [1][2][3][4][5], in particular, in the series of estrogens 8α-analogs [6-10]. The formation of an "active" complex between the estrogen α-receptor and the ligands of steroid character requires a precise orientation of the oxygen-containing substituents in the A and D rings with respect to the clusters Glu-353-Arg-394-water and His-524 respectively [11].…”

“…The study of the mechanism of the action of steroid estrogens mediated by their nuclear receptors made it possible to reveal numerous relations between the structure and the biologic properties of this hormone group [1][2][3][4][5], in particular, in the series of estrogens 8α-analogs [6][7][8][9][10]. The formation of an "active" complex between the estrogen α-receptor and the ligands of steroid character requires a precise orientation of the oxygen-containing substituents in the A and D rings with respect to the clusters Glu-353-Arg-394-water and His-524 respectively [11].…”

Genistein Selectively Inhibits Estrogen-Induced Cell Proliferation and Other Responses to Hormone Stimulation in the Prepubertal Rat Uterus

“…In addition to the classic ''cytosol-nuclear'' ERs 2 (now aERs [3][4][5], the existence of additional ERs has been proposed: eosinophil leukocyte ERs, 6-8 membrane ERs, 9,10 cytoplasmic and nuclear type II ERs, 11 and b-ERs. [3][4][5] The finding of different kinds of estrogen-binding proteins-presumably ERs-in the uterus opens the possibility of a dissociation of responses by agents displaying selective agonist or antagonist action on some but not all receptors.…”

“…[3][4][5] The finding of different kinds of estrogen-binding proteins-presumably ERs-in the uterus opens the possibility of a dissociation of responses by agents displaying selective agonist or antagonist action on some but not all receptors. This dissociation was reported under several experimental conditions in the rat uterus.…”