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Inhibiting Proteasomal Proteolysis Sustains Estrogen Receptor- Activation

Medical Sciences (M.F., K.P.N.), Indiana University School of Medicine, Bloomington, Indiana 47405; Department of Surgery (H.N.), Department of Biochemistry and Molecular Biology, Walther Oncology Center; Indiana University Cancer Center (H.N., K.P.N.); and Department of Cellular and Integrative Physiology (K.P.N.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to:Kenneth P. Nephew, Ph.D., Medical Sciences, Indiana University School of Medicine, 302 Jordan Hall, 1001 East 3rd Street, Bloomington, Indiana 47405-4401. E-mail: knephew{at}indiana.edu.

Estrogen receptor- (ER) is a ligand-dependent transcription factor that mediates physiological responses to 17ß-estradiol (E2). Ligand binding rapidly down-regulates ER 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-mediated transcriptional responses. In HeLa cells transfected with ER, 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 resulted in prolonged stimulation of ER-responsive gene transcription. In breast cancer MCF7 cells containing endogenous ER, 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 steroid receptor coactivator 1, 4-hydroxytamoxifen displayed full agonist activity and stimulated ER-mediated transcription without inducing receptor degradation. Collectively, these results demonstrate that proteasomal degradation is not essential for ER 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 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 transcription activity than a gene like PR, which contains a complex promoter requiring cooperation between ER and other transcription factors.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Coregulators:   SRC-1

Ligands:   17β-Estradiol  |  4-Hydroxytamoxifen

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