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J. Biol. Chem., Vol. 279, Issue 34, 35583-35594, August 20, 2004

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Peroxisome Proliferator-activated Receptor Activation Can Regulate -Catenin Levels via a Proteasome-mediated and Adenomatous Polyposis Coli-independent Pathway^*

Chandan Sharma, Anamika Pradeep, Lucas Wong, Ajay Rana, and Basabi Rana¶

From the Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine and the Division of Hematology/Oncology, Scott & White Hospital, Temple, Texas 76504

The transcription factor peroxisome proliferator-activated receptor (PPAR) belongs to the family of nuclear hormone receptors and consists of two isotypes, PPAR1 and PPAR2. Our earlier studies have shown that troglitazone (TZD)-mediated activation of PPAR2 in hepatocytes inhibits growth and attenuates cyclin D1 transcription via modulating CREB levels. Because this process of growth inhibition was also associated with an inhibition of -catenin expression at a post-translational level, our aim was to elucidate the mechanism involved. -Catenin is a multifunctional protein, which can regulate cell-cell adhesion by interacting with E-cadherin and other cellular processes via regulating target gene transcription in association with TCF/LEF transcription factors. Two adenomatous polyposis coli (APC)-dependent proteasomal degradation pathways, one involving glycogen synthase kinase 3 (GSK3) and the other involving p53-Siah-1, degrade excess -catenin in normal cells. Our immunofluorescence and Western blot studies indicated a TZD-dependent decrease in cytoplasmic and membrane-bound -catenin, indicating no increase in its membrane translocation. This was associated with a reduction in E-cadherin expression. PPAR2 activation inhibited GSK3 kinase activity, and pharmacological inhibition of GSK3 activity was unable to restore -catenin expression following PPAR2 activation. Additionally, this -catenin degradation pathway was operative in cells, with inactivating mutations of both APC and p53. Inhibition of the proteasomal pathway inhibited PPAR2-mediated degradation of -catenin, and incubation with TZD increased ubiquitination of -catenin. We conclude that PPAR2-mediated suppression of -catenin levels involves a novel APC/GSK3/p53-independent ubiquitination-mediated proteasomal degradation pathway.

Received for publication, March 22, 2004 , and in revised form, May 5, 2004.

^* These studies were supported by the Texas A&M Institutional Start Up funds and Scott & White Grant 7843 (to B. R.) and National Institutes of Health Grant RO1GM055835 (to A. R.). 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 Institute, 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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