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J. Biol. Chem., Vol. 280, Issue 31, 28507-28518, August 5, 2005

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Functional Characterization of JMJD2A, a Histone Deacetylase- and Retinoblastoma-binding Protein^*

From the ^aLaboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital Laboratories, Cambridge, Massachusetts 02139, the ^bReceptor Biology Laboratory, Hagedorn Research Institute, Novo Nordisk, Niels Steensens Vej, Gentofte DK-2820, Denmark, the ^cLaboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, the ^dThoracic Oncology Research Group, Departments of Oncology and Clinical Medicine, Institute of Molecular Medicine, Trinity Sciences Health Center, St. James's Hospital, Dublin 8, Ireland, the ^fLaboratory of Molecular Biology, School of Medicine, La Sabana University, Bogota, Colombia, the ^gDepartment of Physiology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan, ^hGene Regulation Research, Eli Lilly Co., Indianapolis, Indiana 46285, the ⁱMolecular Medicine Laboratory and Macromolecular Crystallography Unit, Division of Experimental Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115

To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G₂/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis.

Received for publication, December 6, 2004 , and in revised form, May 26, 2005.

^* This work was supported in part by a grant from the Van Andel Research Institute (to B. T. T.) and National Institutes of Health Grant CA80084 (to F. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1 and data.

^e These authors contributed equally to this work.

^j To whom correspondence should be addressed: Laboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital Laboratories, 3rd floor, 65 Landsdowne St., Cambridge, MA 02139. Tel.: 617-768-8597; Fax: 617-768-8595; E-mail: fdangond{at}rics.bwh.harvard.edu.

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