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Acetylation-mediated transcriptional activation of the ETS protein ER81 by p300, P/CAF, and HER2/Neu.

The regulated expression of the ETS transcription factor ER81 is a prerequisite for normal development, and its dysregulation contributes to neoplasia. Here, we demonstrate that ER81 is acetylated by two coactivators/acetyltransferases, p300 and p300- and CBP-associated factor (P/CAF) in vitro and in vivo. Whereas p300 acetylates two lysine residues (K33 and K116) within the ER81 N-terminal transactivation domain, P/CAF targets only K116. Acetylation of ER81 not only enhances its ability to transactivate but also increases its DNA binding activity and in vivo half-life. Furthermore, oncogenic HER2/Neu, which induces phosphorylation and thereby activation of ER81, was less able to activate acetylation-deficient ER81 mutants, indicating that both acetyltransferase and protein kinase-specific regulatory mechanisms control ER81 activity. Importantly, HER2/Neu overexpression stimulates the ability of p300 to acetylate ER81, likely by inducing phosphorylation of p300 through the Ras-->Raf-->mitogen-activated protein kinase pathway. This represents a novel mechanism by which oncogenic HER2/Neu, Ras, or Raf may promote tumor formation by enhancing acetylation not only of ER81 but also of other downstream effector transcription factors as well as histones.

Pubmed ID: 12917345

Authors

  • Goel A
  • Janknecht R

Journal

Molecular and cellular biology

Publication Data

September 14, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: CA085257

Mesh Terms

  • Acetylation
  • Acetyltransferases
  • Cell Cycle Proteins
  • Cells, Cultured
  • DNA
  • DNA-Binding Proteins
  • Histone Acetyltransferases
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • Humans
  • Lysine
  • Macromolecular Substances
  • Mutation
  • Nuclear Proteins
  • Phosphorylation
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Receptor, ErbB-2
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Trans-Activators
  • Transcription Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • p300-CBP Transcription Factors