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Steroid-Independent Activation of ER by GnRH in Gonadotrope Pituitary Cells

Université de Rennes I, Interactions Cellulaires et Moléculaires, Centre National de la Recherche Scientifique, UMR 6026, Campus de Beaulieu, 35042 Rennes, France

Address all correspondence and requests for reprints to: Dr. M.-L. Thieulant, Equipe d’Information et Programmation Cellulaire, UMR 6026, Batiment 13, Campus de Beaulieu, 35042 Rennes Cedex, France. E-mail: marie-lise.thieulant{at}univ-rennes1.fr

In the rat pituitary gland the mechanism responsible for ER regulation has not been fully elucidated. Using transient transfection assays in T3–1 cells, a cell line of gonadotrope origin, we show that GnRH stimulates estrogen response element-containing promoters in an estrogen-independent manner. This effect was strictly ER and GnRH receptor dependent, as no activation of the reporter gene was observed in presence of the anti-estrogen ICI 182,780 or a GnRH antagonist. These data suggest that the GnRH-triggered signaling pathway results in 17ß-estradiol-independent trans-activation of the ER in T3–1 cells. Furthermore, an additive activation was achieved when cells were treated with both GnRH and 17ß-estradiol. In primary pituitary cells, GnRH alone (100 nM) did not cause a significant stimulation of reporter gene activity, presumingly due to the low amount of gonadotropes. Interestingly, the combination of 17ß-estradiol and GnRH resulted in a significant increase in ER trans-activation compared with that in cells treated with 17ß-estradiol alone. This enhancement was prevented by ICI 182,780, showing an ER requirement. Moreover, we show that the effects of GnRH on ER transcriptional activity in gonadotrope cell lines are mediated by the PKC/MAPK pathway. In conclusion, our data demonstrate that GnRH is an important signal in the regulation of ER trans-activation in gonadotrope cells.