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Molecular and Cellular Biology, December 2004, p. 10954-10964, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10954-10964.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Ras/Mitogen-Activated Protein Kinase Signaling Activates Ets-1 and Ets-2 by CBP/p300 Recruitment{dagger}

Charles E. Foulds, Mary L. Nelson, Adam G. Blaszczak, and Barbara J. Graves*

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah

Received 17 June 2004/ Returned for modification 15 July 2004/ Accepted 17 September 2004

Cell signaling affects gene expression by regulating the activity of transcription factors. Here, we report that mitogen-activated protein kinase (MAPK) phosphorylation of Ets-1 and Ets-2, at a conserved site N terminal to their Pointed (PNT) domains, resulted in enhanced transactivation by preferential recruitment of the coactivators CREB binding protein (CBP) and p300. We discovered this phosphorylation-augmented interaction in an unbiased affinity chromatography screen of HeLa nuclear extracts by using either mock-treated or ERK2-phosphorylated ETS proteins as ligands. Binding between purified proteins demonstrated a direct interaction. Both the phosphoacceptor site, which lies in an unstructured region, and the PNT domain were required for the interaction. Minimal regions that were competent for induced CBP/p300 binding in vitro also supported MAPK-enhanced transcription in vivo. CBP coexpression potentiated MEK1-stimulated Ets-2 transactivation of promoters with Ras-responsive elements. Furthermore, CBP and Ets-2 interacted in a phosphorylation-enhanced manner in vivo. This study describes a distinctive interface for a transcription factor-coactivator complex and demonstrates a functional role for inducible CBP/p300 binding. In addition, our findings decipher the mechanistic link between Ras/MAPK signaling and two specific transcription factors that are relevant to both normal development and tumorigenesis.

* Corresponding author. Mailing address: Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550. Phone: (801) 581-7308. Fax: (801) 585-1980. E-mail: barbara.graves{at}hci.utah.edu.

{dagger} This study is dedicated by C.E.F. to the memory of his father, Jon M. Foulds.

Molecular and Cellular Biology, December 2004, p. 10954-10964, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10954-10964.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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