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J. Biol. Chem., Vol. 283, Issue 9, 5728-5737, February 29, 2008

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Nucleophosmin/B23 Negatively Regulates GCN5-dependent Histone Acetylation and Transactivation^*

Yonglong Zou¹, Jun Wu, Richard J. Giannone, Lorrie Boucher², Hansen Du^¶3, Ying Huang, Dabney K. Johnson, Yie Liu^¶3, and Yisong Wang⁴

From the Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada, and the ^¶Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224-6825

Nucleophosmin/B23 is a multifunctional phosphoprotein that is overexpressed in cancer cells and has been shown to be involved in both positive and negative regulation of transcription. In this study, we first identified GCN5 acetyltransferase as a B23-interacting protein by mass spectrometry, which was then confirmed by in vivo co-immunoprecipitation. An in vitro assay demonstrated that B23 bound the PCAF-N domain of GCN5 and inhibited GCN5-mediated acetylation of both free and mononucleosomal histones, probably through interfering with GCN5 and masking histones from being acetylated. Mitotic B23 exhibited higher inhibitory activity on GCN5-mediated histone acetylation than interphase B23. Immunodepletion experiments of mitotic extracts revealed that phosphorylation of B23 at Thr¹⁹⁹ enhanced the inhibition of GCN5-mediated histone acetylation. Moreover, luciferase reporter and microarray analyses suggested that B23 attenuated GCN5-mediated transactivation in vivo. Taken together, our studies suggest a molecular mechanism of B23 in the mitotic inhibition of GCN5-mediated histone acetylation and transactivation.

Received for publication, December 5, 2007 , and in revised form, December 27, 2007.

^* This work was supported by the Laboratory Directed Research and Development Program (LDRD) of Oak Ridge National Laboratory, and the Office of Biological and Environmental Research, U.S. Department of Energy, under Contract DE-AC05-00OR22725 with UT-Battelle, LLC, and Battelle Memorial Institute under Contract NFE-06-00308. The initial phase of this study was supported in part by a grant from the Canadian Institutes of Health Research to Dr. Mike Tyers, whose generosity is greatly acknowledged. 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 supplemental Table S1 and Figs. S1-S4.

¹ Present address: Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8807.

² Supported by a studentship of National Cancer Institute of Canada.

³ Supported by the Intramural Research Program of the NIA, National Institutes of Health.

⁴ To whom correspondence should be addressed: Biosciences Division, Oak Ridge National Laboratory, Bethel Valley Rd., Oak Ridge, Tennessee 37831. Tel.: 865-574-5396; Fax: 865-574-5345; E-mail: ywa{at}ornl.gov.

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