Type II antagonists impair the DNA binding of steroid hormone receptors without affecting dimerization.
Two types of steroid antagonists exert their activity by different mechanisms when bound to the cognate receptor. Type I anti-progestins, such as RU486, induce DNA binding of the human progesterone receptor (hPR), while no hPR/DNA complexes were seen in gel shift assays in the presence of the type II anti-progestin ZK98,299 or RU50,331. ZK98,299-liganded hPR exerted significantly less tight nuclear binding than receptor complexes formed with RU486. Also a type II anti-glucocorticoid (RU43,044) was detected which completely abrogated DNA binding of its cognate receptor in vivo. In keeping with the existence of two different classes of anti-progestins, agonist- or RU486-induced hyperphosphorylation of the two hPR isoforms present in the T47D breast cancer cells was not induced by ZK98,299. This lack of hyperphosphorylation was, however, not the cause but most likely the consequence, of the reduced ability of the hPR/ZK98,299 complex to interact with DNA. No "mixed-ligand" heterodimers were formed in vitro between hPR isoform A bound to ZK98,299 and R5020-liganded isoform B, but nuclear co-translocation studies indicated that ZK98,299 efficiently induced hPR dimerization in vivo.
Bocquel
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MT
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique de l'INSERM, Faculté de Médecine, Strasbourg, France.
Ji
J
J
Ylikomi
T
T
Benhamou
B
B
Vergezac
A
A
Chambon
P
P
Gronemeyer
H
H
D000818:Animals; D001667:Binding, Competitive; D004247:DNA / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology*; D015870:Gene Expression; D006067:Gonanes / Q000378:metabolism / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010766:Phosphorylation; D011374:Progesterone / Q000037:antagonists & inhibitors*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
D005663:Furans; D006067:Gonanes; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; C081460:RU 50331; D015735:Mifepristone; D011374:Progesterone; D004247:DNA; C053238:onapristone