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.
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
Mol. Cell. Biol.
Date: Sep. 01, 2003
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