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J. Biol. Chem., Vol. 280, Issue 36, 31760-31767, September 9, 2005

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p300/CBP-associated Factor Drives DEK into Interchromatin Granule Clusters^*

From the ^aDepartment of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109-0640, the ^dProgram in Cellular and Molecular Biology, ^fProgram in Immunology, ^hDepartments of Obstetrics and Gynecology and Biological Chemistry, and the ^kDepartment of Pharmacology and Molecular Sciences, The Johns Hopkins University, Baltimore, Maryland 21205, and the ^lFaculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland

DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.

Received for publication, January 24, 2005 , and in revised form, June 9, 2005.

^* This work was supported in part by grants (to D. M. M.) from the National Institutes of Health (NIH), the American Cancer Society, and the Arthritis Foundation, and a Clinical Scientist Award in Translational Research from the Burroughs Wellcome 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.

^b Both authors contributed equally to this work.

^c Supported in part by NIH Training Grant T32 CA88784-03 through the University of Michigan Tumor Immunology Training Program.

^e Supported in part by NIH Training Grant T32-GM07863 through the University of Michigan Medical Scientist Training Program.

^g Additionally supported by a graduate research fellowship from the National Science Foundation.

ⁱ Supported by Michigan Diabetes Research and Training Center Grant NIH5P-60-DK20572.

^j Supported by a grant from the Arthritis Foundation.

^m Supported by NIH Grant GM62437.

ⁿ To whom correspondence should be addressed: Dept. of Internal Medicine, 5220 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0640. Tel.: 734-647-1786; Fax: 734-764-0101; E-mail: dmarkov{at}umich.edu.

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