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J. Biol. Chem., Vol. 280, Issue 17, 16934-16941, April 29, 2005

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Cyclin D1 Inhibits Peroxisome Proliferator-activated Receptor -mediated Adipogenesis through Histone Deacetylase Recruitment^*

Maofu Fu, Mahadev Rao, Toula Bouras, Chenguang Wang, Kongming Wu, Xueping Zhang, Zhiping Li, Tso-Pang Yao, and Richard G. Pestell¶

From the Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C. 20057 and the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710

The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo. We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor (PPAR)-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism. In this study, we determined the molecular mechanism by which cyclin D1 regulated PPAR function. Herein, murine embryonic fibroblast (MEF) differentiation by PPAR ligand was associated with a reduction in histone deacetylase (HDAC1) activity. Cyclin D1^–/– MEFs showed an increased propensity to undergo differentiation into adipocytes. Genetic deletion of cyclin D1 reduced HDAC1 activity. Reconstitution of cyclin D1 into the cyclin D1^–/– MEFs increased HDAC1 activity and blocked PPAR-mediated adipogenesis. PPAR activity was enhanced in cyclin D1^–/– cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPAR activity and enhanced HDAC repression of PPAR activity. Cyclin D1 bound HDAC in vivo and preferentially physically associated with HDAC1, HDAC2, HDAC3, and HDAC5. Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of HDAC1 and HDAC3 and histone methyltransferase SUV39H1 to the PPAR response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9. Collectively, these studies suggest an important role of cyclin D1 in regulation of PPAR-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPAR function.

Received for publication, January 12, 2005 , and in revised form, February 14, 2005.

^* This work was supported in part by awards from the Susan G. Komen Breast Cancer Foundation, R01CA70896, R01CA75503, R01CA86072, R01CA93596, and R01CA107382 (to R. G. P.) and NIDDK, National Institutes of Health Grant 1 R21DK065220-02 (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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