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Thyroid Hormone Is an Inhibitor of Estrogen-Induced Degradation of Estrogen Receptor- Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary

Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706

Address all correspondence and requests for reprints to: Elaine T. Alarid, Ph.D., Department of Physiology, University of Wisconsin Madison, 120 Service Memorial Institute, 1300 University Avenue, Madison, Wisconsin 53706. E-mail: alarid{at}physiology.wisc.edu.

Proteolysis by the 26S proteasome is an important regulatory mechanism that governs the protein stability of several steroid/nuclear receptors and that has been implicated in the control of receptor transcriptional activation function. Herein, we report that thyroid hormone can prevent estrogen-induced proteolysis of estrogen receptor- (ER) protein in lactotrope cells of the pituitary. The stabilization of ER protein by thyroid hormone represents a selective blockade against estradiol-stimulated degradation, because thyroid hormone (but not glucocorticoid) can protect estrogen-activated ER. Moreover, thyroid hormone treatment does not interfere with signal-induced proteolysis of a separate proteasome target, IB or ER proteolysis induced by ICI182780. Using thyroid hormone as a tool to inhibit ER proteolysis, we examined the effect of loss of this regulatory function on estrogen-induced transcriptional responses. Consistent with earlier reports, estrogen activation of an idealized estrogen response element reporter gene was inhibited. However, thyroid hormone did not prevent induction of prolactin gene expression or the ability of ER to stimulate proliferation. These results demonstrate that estrogen-induced proteolysis of ER is not a general requirement for receptor transcriptional activation function, and they demonstrate that proteolytic regulation is a means by which other endocrine factors can indirectly modulate ER activity.

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