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

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Abstract
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 pro- tein by thyroid hormone represents a selective blockade against estradiol-stimulated degradation, because thyroid hormone (but not glucocorticoid) can protect estrogen-acti- vated ER. Moreover, thyroid hormone treatment does not interfere with signal-induced proteolysis of a separate pro- teasome 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, thy- roid 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 transcrip- tional activation function, and they demonstrate that proteo- lytic regulation is a means by which other endocrine factors can indirectly modulate ER activity. (Endocrinology 144: 3469 -3476, 2003)

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