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J. Biol. Chem., Vol. 280, Issue 33, 29728-29742, August 19, 2005

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Cyclin D1 Represses p300 Transactivation through a Cyclin-dependent Kinase-independent Mechanism^*

Maofu Fu, Chenguang Wang, Mahadev Rao, Xiaofang Wu, Toula Bouras, Xueping Zhang, Zhiping Li, Xuanmao Jiao, Jianguo Yang, Anping Li, Neil D. Perkins, Bayar Thimmapaya¶, Andrew L. Kung||, Alberto Munoz**, Antonio Giordano, Michael P. Lisanti, and Richard G. Pestell¶¶

From the Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C. 20057, Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom, ^¶Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, ^||Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, ^**Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Cientificas-Universidad Autonoma de Madrid, Arturo Duperier 4, E-28029 Madrid, Spain, Department of Pathology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461

Cyclin D1 encodes a regulatory subunit, which with its cyclin-dependent kinase (Cdk)-binding partner forms a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. In addition to its Cdk binding-dependent functions, cyclin D1 regulates cellular differentiation in part by modifying several transcription factors and nuclear receptors. The molecular mechanism through which cyclin D1 regulates the function of transcription factors involved in cellular differentiation remains to be clarified. The histone acetyltransferase protein p300 is a co-integrator required for regulation of multiple transcription factors. Here we show that cyclin D1 physically interacts with p300 and represses p300 transactivation. We demonstrated further that the interaction of the two proteins occurs at the peroxisome proliferator-activated receptor -responsive element of the lipoprotein lipase promoter in the context of the local chromatin structure. We have mapped the domains in p300 and cyclin D1 involved in this interaction. The bromo domain and cysteine- and histidine-rich domains of p300 were required for repression by cyclin D1. Cyclin D1 repression of p300 was independent of the Cdk- and retinoblastoma protein-binding domains of cyclin D1. Cyclin D1 inhibits histone acetyltransferase activity of p300 in vitro. Microarray analysis identified a signature of genes repressed by cyclin D1 and induced by p300 that promotes cellular differentiation and induces cell cycle arrest. Together, our results suggest that cyclin D1 plays an important role in cellular proliferation and differentiation through regulation of p300.

Received for publication, March 23, 2005 , and in revised form, June 9, 2005.

^* This work was supported in part by Grants R01CA70896, R01CA75503, R01CA86072, R01CA93596, R01CA107382 from the National Institutes of Health (to R. G. P.) and NIDDK 1R21DK065220-02 from the National Institutes of Health (to M. F.). 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.

^¶¶ To whom correspondence should be addressed: Lombardi Comprehensive Cancer Center, Dept. of Oncology, Georgetown University, Research Bldg. Rm. E501, 3970 Reservoir Rd. NW, Box 571468, Washington, D. C. 20057-1468. Tel.: 202-687-2110; Fax: 202-687-6402; E-mail: pestell{at}georgetown.edu.

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