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Originally published In Press as doi:10.1074/jbc.M400036200 on January 27, 2004

J. Biol. Chem., Vol. 279, Issue 15, 14909-14916, April 9, 2004
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Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu*

Apollina Goel and Ralf Janknecht{ddagger}

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

Activator of thyroid and retinoic acid receptor (ACTR) is overexpressed in ~60% of primary human breast tumors and belongs to the p160 steroid receptor coactivator family. In this study, we identified a novel interaction partner of ACTR, the ETS transcription factor ER81 that is also heavily implicated in mammary tumor formation. ACTR and related p160 family members (steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein-1 (GRIP-1)) augment ER81-mediated transcription. Although ACTR and GRIP-1 can acetylate ER81, this posttranslational modification of ER81 is not required for its stimulation by ACTR or GRIP-1. In addition, ACTR collaborates with the p300 coactivator, a joint interaction partner of ACTR and ER81, to stimulate ER81 function and the ability of p300 to acetylate ER81 is indispensable for this collaboration. Furthermore, the receptor tyrosine kinase HER2/Neu, an oncoprotein particularly found overexpressed in breast tumors, cooperates with both ACTR and p300 to stimulate ER81-mediated transcription. Thus, oncogenic HER2/Neu and ACTR may synergize to orchestrate mammary tumorigenesis through the dysregulation of the transcription factor ER81 and its target genes.

Received for publication, January 5, 2004

* This work was supported by the Mayo Foundation, Grant CA085257 from the National Cancer Institute, and a grant from the Fraternal Order of Eagles' Cancer Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Mayo Clinic, Guggenheim Bldg. 1501A, 200 First St., S. W., Rochester, MN 55905. Tel.: 507-266-4393; Fax: 507-284-1767; E-mail: janknecht.ralf{at}mayo.edu.


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