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Molecular and Cellular Biology, September 2003, p. 6243-6254, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6243-6254.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Acetylation-Mediated Transcriptional Activation of the ETS Protein ER81 by p300, P/CAF, and HER2/Neu

Apollina Goel and Ralf Janknecht*

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905

Received 10 December 2002/ Returned for modification 3 March 2003/ Accepted 10 June 2003

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.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Mayo Clinic, Guggenheim Building 1501A, 200 First St. SW, Rochester, MN 55905. Phone: (507) 266-4393. Fax: (507) 284-1767. E-mail: janknecht.ralf{at}mayo.edu.

Molecular and Cellular Biology, September 2003, p. 6243-6254, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6243-6254.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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