ORBi: Rajpert E. J. - Glucocorticoid receptors bound to the antagonist RU486 are not downregulated despite their capacity to interact in vitro with defined gene regions

Reference : Glucocorticoid receptors bound to the antagonist RU486 are not downregulated despite the...


	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biochemistry, biophysics & molecular biology
	To cite this reference:	http://hdl.handle.net/2268/23698

Title :	Glucocorticoid receptors bound to the antagonist RU486 are not downregulated despite their capacity to interact in vitro with defined gene regions
Language :	English
Author, co-author :	Rajpert, E. J. [> > > >]
	Lemaigre, F. P. [> > > >]
	Eliard, P. H. [> > > >]
	Place, M. [> > > >]
	Lafontaine, D. A. [ > > ]
	Economidis, I. V. [> > > >]
	Belayew, A. [> > > >]
	Martial, Joseph [Université de Liège - ULg > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire >]
	Rousseau, G. G. [> > > >]
Publication date :	1987
Journal title :	Journal of Steroid Biochemistry
Publisher :	Pergamon Press
Volume :	26
Issue/season :	5
Pages :	513-20
ISSN :	0022-4731
City :	Oxford
Country :	United Kingdom
Keywords :	[en] 5'-Nucleotidase ; DNA/metabolism ; Dexamethasone/pharmacology ; Estrenes/metabolism/pharmacology ; Gene Expression Regulation/drug effects ; Glucocorticoids/antagonists & inhibitors ; Half-Life ; Humans ; Lymphocytes/metabolism ; Mifepristone ; Nucleotidases/metabolism ; Receptors, Glucocorticoid/drug effects/genetics/metabolism
Abstract :	[en] Modulation of gene expression by glucocorticoids involves interaction of these hormones with an intracellular receptor followed by 'transformation' of the hormone-receptor complex into a nuclear binding form. The molecular basis for the antiglucocorticoid action of high-affinity steroid analogues such as RU486 remains controversial. The effects of dexamethasone and RU486 on in vitro and in vivo properties of the receptor were compared using human lymphoblastoid IM-9 cells. In these cells, RU486 fully antagonized the glucocorticoid-specific induction of 5'-nucleotidase activity by dexamethasone. In vitro, however, RU486-bound receptor could be transformed and shown to interact specifically with cloned DNA fragments containing glucocorticoid response elements. These fragments included one from the mouse mammary tumour virus and two from the human growth hormone gene. In vivo, RU486-bound receptor did not behave like dexamethasone-bound receptor. While receptor downregulation, a property of the transformed receptor, was achieved by dexamethasone, this did not occur with RU486. Likewise, RU486 did not affect receptor half-life under conditions when this was shortened by dexamethasone. These seemingly contradictory results can be reconciled by proposing that receptor transformation by agonists involves dissociation of the receptor oligomer to reveal a DNA-binding site that pre-exists on this protein. Although cell-free receptor dissociation and therefore DNA binding can occur even when the receptor is bound to RU486, this steroid maintains receptors in the untransformed state in the intact cell and therefore behaves a glucocorticoid antagonist in vivo.
Permalink :	http://hdl.handle.net/2268/23698
Mentions required by the publisher for OA :	1987/05/01

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