Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors α and β by coactivators and corepressors

Carolyn M. Klinge, S. C. Jernigan, K. A. Mattingly, K. E. Risinger, J. Zhang

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

One mechanism by which ligand-activated estrogen receptors α and β (ERα and ERβ) stimulate gene transcription is through direct ER interaction with specific DNA sequences, estrogen response elements (EREs). ERE-bound ER recruits coactivators that stimulate gene transcription. Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity, conformation, and transcriptional activity, indicating that the ERE sequence is an allosteric effector of ER action. Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors. CHO-K1 cells transfected with ERα or ERβ show ERE sequence-dependent differences in the functional interaction of ERα and ERβ with coactivators steroid receptor coativator 1 (SRC-1), SRC-2 (glucocorticoid receptor interacting protein 1 (GRIP1)), SRC-3 amplified in breast cancer 1 (AIB1) and ACTR, cyclic AMP binding protein (CBP), and steroid receptor RNA activator (SRA), corepressors nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone recpetors (SMRT), and secondary coactivators coactivator associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferase 1 (PRMT1). We note both ligand-independent as well estradiol- and 4-hydroxytamoxifen-dependent differences in ER-coregulator activity. In vitro ER-ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell-based results, substantiating the importance of the full-length proteins in regulating ER activity. These data demonstrated that the ERE sequence impacts estradiol- and 4-hydroxytamoxifen-occupied ERα and ERβ interaction with coregulators as measured by transcriptional activity in mammalian cells.

Original languageEnglish (US)
Pages (from-to)387-410
Number of pages24
JournalJournal of Molecular Endocrinology
Volume33
Issue number2
DOIs
StatePublished - Oct 1 2004

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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