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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 Expression and Transactivation

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 (PPAR) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR induces hepatic steatosis, and liganded PPAR promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR function, transactivation, expression, and promoter activity. PPAR 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 ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR-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 ligands of PPAR and PPAR-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 in vivo. The inhibition of PPAR function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR ligands and mitogenic signals that induce cyclin D1.

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