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Am J Physiol Endocrinol Metab (December 18, 2001). doi:10.1152/ajpendo.00353.2001
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Articles in PresS, published online ahead of print December 18, 2001
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00353.2001
Submitted on August 3, 2001
Accepted on December 14, 2001

Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor {alpha}

Mara T Preisler-Mashek1, Natalia Solodin1, Bethany L Stark1, Michael K Tyriver1, and Elaine T Alarid1*

1 Department of Physiology, University of Wisconsin-Madison, Madison, WI, USA

* To whom correspondence should be addressed. E-mail: alarid{at}physiology.wisc.edu.

Proteasome-mediated proteolysis modulates the cellular concentration of estrogen receptor {alpha}(ER{alpha}) and is induced by treatment of cells with 17ß-estradiol. Herein, we show that multiple receptor agonists including 17{alpha}-estradiol and estriol, as well as the antagonist ICI 182,780 stimulate proteasome-dependent proteolysis of ER{alpha} in a process that requires ligand binding to the receptor. Proteolysis of receptor depends on ligand concentration and there exists a direct correlation between ligand-binding affinity and the half-maximal dose of ligand required to stimulate receptor degradation. Furthermore, introduction of a point mutation into the receptor ligand-binding pocket yields a stable receptor resistant to proteolysis. Interestingly, though all ligands stimulate receptor degradation, the extent to which overall ER{alpha} levels are affected varies with each ligand and is not related to ligand-binding affinity or activation of transcription. These results demonstrate ligand-specific regulation of ER{alpha} proteolysis and they introduce the concept that cellular receptor concentration is governed not only at the level of induction of proteolysis but also by the efficiency with which receptor is degraded.




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