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J. Biol. Chem., Vol. 279, Issue 17, 16927-16938, April 23, 2004

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Peroxisome Proliferator-activated Receptor Activation Modulates Cyclin D1 Transcription via -Catenin-independent and cAMP-response Element-binding Protein-dependent Pathways in Mouse Hepatocytes^*

Chandan Sharma, Anamika Pradeep, Richard G. Pestell, and Basabi Rana¶

From the Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504 and the Lombardi Cancer Center, Georgetown University Medical Center, Washington, D. C. 20007

Activation of peroxisome proliferator-activated receptor (PPAR) following exposure to PPAR-specific ligands resulted in growth inhibition in various carcinoma cell lines. Our aim was to elucidate the pathway of PPAR2 activation-mediated modulation of cyclin D1 transcription in mouse hepatocytes. To address this we utilized stable control and PPAR hepatocyte cell lines created via retroviral overexpression utilizing AML-12 hepatocytes. Addition of PPAR ligand troglitazone (TZD) activated PPAR2 in proliferating hepatocytes and resulted in growth arrest accompanied by a down-regulation of proliferating cell nuclear antigen, cyclin D1, and -catenin expression. Furthermore activation of PPAR2 attenuated cyclin D1 promoter activity indicating a transcriptional regulation of cyclin D1. Since -catenin plays a pivotal role in regulating cyclin D1 transcription, we studied whether PPAR2-mediated inhibition of cyclin D1 transcription involved -catenin. Interestingly overexpression of either wild-type or S37A mutant -catenin was unable to rescue PPAR2-mediated suppression of cyclin D1 transcription, whereas overexpression of cAMP-response element-binding protein (CREB) was capable of antagonizing this inhibitory effect of PPAR2. Additionally pretreatment with okadaic acid antagonized PPAR2-mediated inhibition of cyclin D1 transcription without any effect on -catenin expression. These studies also showed a TZD-mediated inhibition of total and phospho-CREB^Ser133 levels, CREB promoter activity, and cAMP-response element-mediated transcription in PPAR hepatocytes. Pretreatment of PPAR hepatocytes with okadaic acid, however, maintained higher total and phospho-CREB^Ser133 levels in the presence of TZD. These results indicated that PPAR2 activation inhibited cyclin D1 transcription in hepatocytes via CREB-dependent and -catenin-independent pathways.

Received for publication, August 15, 2003 , and in revised form, February 4, 2004.

^* This work was supported by Texas A&M Institutional Start Up funds (to B. R.) and by National Institutes of Health Grants R01CA70896, RO1CA75503, RO1CA86072, and RO1CA86071 (to R. G. P.). Work conducted at the Lombardi Cancer Center was supported by the National Institutes of Health Cancer Center Core grant. 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: Cardiovascular Research Inst., Division of Molecular Cardiology, Texas A&M University System Health Science Center, 1901 South First St., Bldg. 205, Temple, TX 76504. Tel.: 254-778-4811 (ext. 1222); Fax: 254-899-6165; E-mail: brana{at}medicine.tamu.edu.

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