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J. Biol. Chem., Vol. 281, Issue 37, 26802-26812, September 15, 2006

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Negative Regulation of the RelA/p65 Transactivation Function by the Product of the DEK Proto-oncogene^*

Morgan Sammons¹, Shan Shan Wan¹, Nancy L. Vogel, Edwin J. Mientjes^¶, Gerard Grosveld^¶, and Brian P. Ashburner²

From the Department of Biological Sciences and Undergraduate Honors Program, University of Toledo, Toledo, Ohio 43606 and ^¶Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

NF-B-mediated transcriptional activation is controlled at several levels including interaction with coregulatory proteins. To identify new proteins capable of modulating NF-B-mediated activation, a cytoplasmic two-hybrid screen was performed using the p65 C-terminal transactivation domain as bait and identified the product of the DEK proto-oncogene. DEK is a ubiquitous nuclear protein that has been implicated in several types of cancer and autoimmune diseases. DEK appears to function in several nuclear processes including transcriptional repression and modulation of chromatin structure. Our data indicate that DEK functions as a transcriptional corepressor to repress NF-B activity. DEK expression blocked p65-mediated activation of an NF-B-dependent reporter gene and also inhibited TNF-induced activation of the reporter gene. Chromatin Immunoprecipitation (ChIP) assays showed that DEK associates with the promoters of the NF-B-regulated cIAP2 and IL-8 genes in untreated cells and dissociates from these promoters upon NF-B binding in response to TNF treatment. Moreover, the expression levels of an NF-B-dependent reporter gene as well as the NF-B-regulated Mcp-1 and IB genes is increased in DEK^–/– cells compared with wild-type cells. ChIP assays on these promoters show enhanced and prolonged binding of p65 and increased recruitment of the P/CAF coactivator. Overall, these data provide further evidence that DEK functions to negatively regulate transcription.

Received for publication, January 30, 2006 , and in revised form, July 7, 2006.

^* This work was supported in part by grants from the Ohio Division of the American Cancer Society and from Grant 1 R15 GM071405-01 from the NIGMS, National Institutes of Health (to B. P. A.). 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biological Sciences, MS 601, 2801 W. Bancroft St., Toledo, OH 43606. Tel.: 419-530-1542; Fax: 419-530-7737; E-mail: brian.ashburner{at}utoledo.edu.

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