Inhibiting proteasomal proteolysis sustains estrogen receptor-α activation

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72 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)2603-2615
Number of pages13
JournalMolecular Endocrinology
Volume18
Issue number11
DOIs
StatePublished - Nov 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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