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Endocrinology Vol. 142, No. 8 3361-3368
Copyright © 2001 by The Endocrine Society

ARTICLES

Ligand-Independent Activation of Pituitary ER: Dependence on PKA-Stimulated Pathways

Derek A. Schreihofer, Eileen M. Resnick, Vicky Y. Lin and Margaret A. Shupnik

Department of Internal Medicine, Division of Endocrinology and Metabolism (D.A.S., M.A.S.), and Department of Pharmacology (E.M.R., V.Y.L.), University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Margaret A. Shupnik, Ph.D., Box 800578, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: mas3x{at}virginia.edu

In pituitary and other target tissues, estrogen acts through ERs, which are ligand-activated nuclear transcription factors. ERs can also be activated by intracellular signaling pathways in a ligand-independent manner in some cells. Because the pituitary is the target of several cAMP-activating factors, we examined the ability of cAMP to activate ERs in the {alpha}T3 gonadotrope cell line. Forskolin, 8-bromo-cAMP, and pituitary adenylate cyclase-activating polypeptide all enhanced ER-dependent promoter activity, which was inhibited by antiestrogen or a pituitary-specific inhibitory ER variant. Activation was PKA dependent and was blocked by the PKA inhibitor H89 or cotransfection of the inhibitor PKI. Although cAMP activated MAPK in {alpha}T3 cells, inhibition of MAPK with the MEK inhibitor PD98059 did not prevent forskolin-induced ER activation. Similarly, epidermal growth factor did not stimulate ER activity, although it increased MAPK activation. Forskolin-induced activation of ER was enhanced by cotransfection of steroid receptor coactivator-1 and was inhibited by the repressor of ER action, suggesting that cAMP does not alter the normal interactions between ER and cofactors. In contrast to results with estrogen, cAMP treatment did not decrease ER protein levels. These results demonstrate that in the pituitary, cAMP activates ER in a ligand-independent manner exclusively through PKA.




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