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Molecular and Cellular Biology, September 2003, p. 6159-6173, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6159-6173.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor {gamma} Expression and Transactivation

Chenguang Wang,1 Nagarajan Pattabiraman,1 Jian Nian Zhou,2 Maofu Fu,1 Toshiyuki Sakamaki,1 Chris Albanese,1 Zhiping Li,1 Kongming Wu,1 James Hulit,2 Peter Neumeister,2 Phyllis M. Novikoff,3 Michael Brownlee,3 Philipp E. Scherer,4 Joan G. Jones,5 Kathleen D. Whitney,5 Lawrence A. Donehower,6 Emily L. Harris,7 Thomas Rohan,8 David C. Johns,9 and Richard G. Pestell1*

Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007,1 Departments of Developmental and Molecular Biology,2 Medicine,3 Epidemiology and Population Health,8 Pathology,5 Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461,4 Division of Molecular Virology, Baylor College of Medicine, Houston. Texas 77030,6 Center for Health Research, Kaiser Permanente, Portland, Oregon 97227,7 Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore, Maryland 212319

Received 21 November 2002/ Returned for modification 10 January 2003/ Accepted 9 May 2003

The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR{gamma} induces hepatic steatosis, and liganded PPAR{gamma} promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR{gamma} function, transactivation, expression, and promoter activity. PPAR{gamma} transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR{gamma} ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR{gamma}-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1-/- fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR{gamma} ligands of PPAR{gamma} and PPAR{gamma}-responsive genes, and cyclin D1-/- mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR{gamma} in vivo. The inhibition of PPAR{gamma} function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR{gamma} ligands and mitogenic signals that induce cyclin D1.

* Corresponding author. Mailing address: Department of Oncology, Lombardi Cancer Center, Research Building, Room E501, 3970 Reservoir Rd. NW, Box 571468, Georgetown University, Washington, DC 20007. Phone: (202) 687-2110. Fax: (202) 687-6402. E-mail: pestell{at}georgetown.edu.

Molecular and Cellular Biology, September 2003, p. 6159-6173, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6159-6173.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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