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Molecular and Cellular Biology, May 2001, p. 3057-3070, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3057-3070.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibition of Cellular Proliferation through Ikappa B Kinase-Independent and Peroxisome Proliferator-Activated Receptor gamma -Dependent Repression of Cyclin D1

Chenguang Wang,1 Maofu Fu,1 Mark D'Amico,1 Chris Albanese,1 Jian-Nian Zhou,1 Michael Brownlee,1 Michael P. Lisanti,2 V. Krishna K. Chatterjee,3 Mitchell A. Lazar,4 and Richard G. Pestell1,*

Departments of Developmental and Molecular Biology and Medicine, The Albert Einstein Cancer Center,1 and Department of Pharmacology, Albert Einstein College of Medicine,2 Bronx, New York 10461; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom3; and Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191044

Received 6 September 2000/Returned for modification 9 October 2000/Accepted 13 February 2001

The nuclear receptor peroxisome proliferator-activated receptor gamma  (PPARgamma ) is a ligand-regulated nuclear receptor superfamily member. Liganded PPARgamma exerts diverse biological effects, promoting adipocyte differentiation, inhibiting tumor cellular proliferation, and regulating monocyte/macrophage and anti-inflammatory activities in vitro. In vivo studies with PPARgamma ligands showed enhancement of tumor growth, raising the possibility that reduced immune function and tumor surveillance may outweigh the direct inhibitory effects of PPARgamma ligands on cellular proliferation. Recent findings that PPARgamma ligands convey PPARgamma -independent activities through Ikappa B kinase (IKK) raises important questions about the specific mechanisms through which PPARgamma ligands inhibit cellular proliferation. We investigated the mechanisms regulating the antiproliferative effect of PPARgamma . Herein PPARgamma , liganded by either natural (15d-PGJ2 and PGD2) or synthetic ligands (BRL49653 and troglitazone), selectively inhibited expression of the cyclin D1 gene. The inhibition of S-phase entry and activity of the cyclin D1-dependent serine-threonine kinase (Cdk) by 15d-PGJ2 was not observed in PPARgamma -deficient cells. Cyclin D1 overexpression reversed the S-phase inhibition by 15d-PGJ2. Cyclin D1 repression was independent of IKK, as prostaglandins (PGs) which bound PPARgamma but lacked the IKK interactive cyclopentone ring carbonyl group repressed cyclin D1. Cyclin D1 repression by PPARgamma involved competition for limiting abundance of p300, directed through a c-Fos binding site of the cyclin D1 promoter. 15d-PGJ2 enhanced recruitment of p300 to PPARgamma but reduced binding to c-Fos. The identification of distinct pathways through which eicosanoids regulate anti-inflammatory and antiproliferative effects may improve the utility of COX2 inhibitors.

* Corresponding author. Mailing address: The Albert Einstein Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-8662. Fax: (718) 430-8674. E-mail: pestell{at}aecom.yu.edu.

Molecular and Cellular Biology, May 2001, p. 3057-3070, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3057-3070.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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