Acetylation of estrogen receptor α by p300 at lysines 266 and 268 enhances the deoxyribonucleic acid binding and transactivation activities of the receptor

Young Kim Mi, Eileen M. Woo, Yee Ting Esther Chong, Daria R. Homenko, W. Lee Kraus

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Using a variety of biochemical and cell-based approaches, we show that estrogen receptor α (ERα) is acetylated by the p300 acetylase in a ligand- and steroid receptor coactivator-dependent manner. Using mutagenesis and mass spectrometry, we identified two conserved lysine residues in ERα (Lys266 and Lys268) that are the primary targets of p300-mediated acetylation. These residues are acetylated in cells, as determined by immunoprecipitation- Western blotting experiments using an antibody that specifically recognizes ERα acetylated at Lys266 and Lys268. The acetylation of ERα by p300 is reversed by native cellular deacetylases, including trichostatin A-sensitive enzymes (i.e. class I and II deacetylases) and nicotinamide adenine dinucleotide-dependent/nicotinamide-sensitive enzymes (i.e. class III deacetylases, such as sirtuin 1). Acetylation at Lys266 and Lys268, or substitution of the same residues with glutamine (i.e. K266/268Q), a residue that mimics acetylated lysine, enhances the DNA binding activity of ERα in EMSAs. Likewise, substitution of Lys266 and Lys268 with glutamine enhances the ligand-dependent activity of ERα in a cell-based reporter gene assay. Collectively, our results implicate acetylation as a modulator of the ligand-dependent gene regulatory activity of ERα. Such regulation is likely to play a role in estrogen-dependent signaling outcomes in a variety of estrogen target tissues in both normal and pathological states.

Original languageEnglish (US)
Pages (from-to)1479-1493
Number of pages15
JournalMolecular Endocrinology
Volume20
Issue number7
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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