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J. Biol. Chem., Vol. 279, Issue 24, 25241-25250, June 11, 2004

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Positive and Negative Modulation of the Transcriptional Activity of the ETS Factor ESE-1 through Interaction with p300, CREB-binding Protein, and Ku 70/86^*

Hong Wang¶, Ruihua Fang||, Je-Yoel Cho, Towia A. Libermann, and Peter Oettgen**

From the Cardiology Division and the New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center and Harvard Medical School and the ^||Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Epithelium-specific ETS (ESE)-1 is a prototypic member of a novel subset of the ETS transcription factor family that is predominantly expressed in cells of epithelial origin but can also be induced in other cell types including vascular endothelial and smooth muscle cells in response to inflammatory stimuli. To further define the molecular mechanisms by which the transcriptional activity of ESE-1 is regulated, we have focused our attention on identifying proteins that interact with ESE-1. We have determined that Ku70, Ku86, p300, and CREB-binding protein (CBP) are ESE-1 interacting proteins. The Ku proteins have previously been shown to bind to breaks in DNA where they function to recruit additional proteins that promote DNA repair. Interestingly, Ku70 and Ku 86 negatively regulate the transcriptional activity of ESE-1. Using a series of deletion constructs, we have determined that the Ku proteins bind to the DNA-binding domain of ESE-1. The Ku proteins inhibit the ability of ESE-1 to bind to oligonucleotide probes in gel mobility shift assays. The finding that Ku proteins can interact with other transcription factors and block their function has not been previously demonstrated. In contrast, co-transfection of p300 and CBP with ESE-1 enhances the transcriptional activity of ESE-1. Moreover, the induction of ESE-1 in response to inflammatory cytokine interleukin-1 is associated with a parallel increase of the expression of p300 in vascular endothelial cells, suggesting that in the setting of inflammation, the transcriptional activity of ESE-1 is positively modulated by interaction with the transcriptional co-activator p300. In summary, our results demonstrated that the activity of ESE-1 is positively and negatively modulated by other interacting proteins including Ku70, Ku86, p300, and CBP.

Received for publication, February 6, 2004 , and in revised form, April 8, 2004.

^* This work was supported by National Institutes of Health Grant HL-67219 (to P. O.). 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.

^¶ Recipient of Fellowship T32 HL07374-24 from the National Institutes of Health Cardiovascular Training Program.

^** To whom correspondence should be addressed: Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-667-3390; Fax: 617-975-5299; E-mail: joettgen{at}bidmc.harvard.edu.

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