Direct Acetylation of the Estrogen Receptor α Hinge Region by p300 Regulates Transactivation and Hormone Sensitivity

Chenguang Wang, Maofu Fu, Ruth H. Angeletti, Linda Siconolfi-Baez, Anne T. Reutens, Chris Albanese, Michael P. Lisanti, Benita S. Katzenellenbogen, Shigeaki Kato, Torsten Hopp, Suzanne A.W. Fuqua, Gabriela N. Lopez, Peter J. Kushner, Richard G. Pestell

Research output: Contribution to journalArticlepeer-review

Abstract

Regulation of nuclear receptor gene expression involves dynamic and coordinated interactions with histone acetyl transferase (HAT) and deacetylase complexes. The estrogen receptor (ERα) contains two transactivation domains regulating ligand-independent and -dependent gene transcription (AF-1 and AF-2 (activation functions 1 and 2)). ERα-regulated gene expression involves interactions with cointegrators (e.g. p300/CBP, P/CAF) that have the capacity to modify core histone acetyl groups. Here we show that the ERα is acetylated in vivo. p300, but not P/CAF, selectively and directly acetylated the ERα at lysine residues within the ERα hinge/ligand binding domain. Substitution of these residues with charged or polar residues dramatically enhanced ERα hormone sensitivity without affecting induction by MAPK signaling, suggesting that direct ERα acetylation normally suppresses ligand sensitivity. These ERα lysine residues also regulated transcriptional activation by histone deacetylase inhibitors and p300. The conservation of the ERα acetylation motif in a phylogenetic subset of nuclear receptors suggests that direct acetylation of nuclear receptors may contribute to additional signaling pathways involved in metabolism and development.

Original languageEnglish (US)
Pages (from-to)18375-18383
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number21
DOIs
StatePublished - Jan 25 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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