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This version published online on July 29, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0164
A more recent version of this article appeared on November 1, 2004
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Submitted on April 19, 2004
Accepted on July 21, 2004

Inhibiting Proteasomal Proteolysis Sustains Estrogen Receptor-{alpha} Activation

Meiyun Fan, Harikrishna Nakshatri, and Kenneth P. Nephew*

Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405; Department of Surgery, Department of Biochemistry and Molecular Biology, Walther Oncology Center; Indiana University Cancer Center; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202

* To whom correspondence should be addressed. E-mail: knephew{at}indiana.edu.

Estrogen receptor-alpha (ER{alpha}) is a ligand-dependent transcription factor that mediates physiological responses to 17{beta}-estradiol (E2). Ligand binding rapidly down-regulates ER{alpha} levels through proteasomal proteolysis, but the functional impact of receptor degradation on cellular responses to E2 has not been fully established. In this study, we investigated the effect of blocking the ubiquitin-proteasome pathway on ER{alpha}-mediated transcriptional responses. In HeLa cells transfected with ER{alpha}, blocking either ubiquitination or proteasomal degradation markedly increased E2-induced expression of an ER-responsive reporter. Time course studies further demonstrated that blocking ligand-induced degradation of ER{alpha} resulted in prolonged stimulation of ER-responsive gene transcription. In breast cancer MCF7 cells containing endogenous ER{alpha}, proteasome inhibition enhanced E2-induced expression of endogenous pS2 and cathepsin D. However, inhibiting the proteasome decreased expression of progesterone receptor (PR), presumably due to the heterogeneity of the PR promoter, which contains multiple regulatory elements. In addition, in endometrial cancer Ishikawa cells overexpressing coactivator SRC-1, 4-hydroxytamoxifen displayed full agonist activity and stimulated ER{alpha}-mediated transcription without inducing receptor degradation. Collectively, these results demonstrate that proteasomal degradation is not essential for ER{alpha} transcriptional activity and functions to limit E2-induced transcriptional output. The results further indicate that promoter context must be considered when evaluating the relationship between ER{alpha} transcription and proteasome inhibition. We suggest that the transcription of a gene driven predominantly by an estrogen responsive element, such as pS2, is a more reliable indicator of ER{alpha} transcription activity than a gene like PR, which contains a complex promoter requiring cooperation between ER{alpha} and other transcription factors.
Key words: estrogen receptor • proteasome • transactivation • degradation

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR
Coregulators:   SRC-1
Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen



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