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J. Biol. Chem., Vol. 279, Issue 22, 23719-23727, May 28, 2004

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Peroxisome Proliferator-activated Receptor ()-dependent Regulation of Ubiquitin C Expression Contributes to Attenuation of Skin Carcinogenesis^*

Dae J. Kim, Taro E. Akiyama¶||, Fred S. Harman**, Amanda M. Burns, Weiwei Shan, Jerrold M. Ward, Mary J. Kennett, Frank J. Gonzalez¶, and Jeffrey M. Peters**¶¶

From the Department of Veterinary Science and The Center for Molecular Toxicology and Carcinogenesis, the ^**Graduate Program in Biochemistry, Microbiology, Molecular Biology, Graduate Program in Genetics, Graduate Program in Molecular Toxicology, The Huck Institute for Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, the ^¶Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the Veterinary and Tumor Pathology Section, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702

The role of peroxisome proliferator-activated receptor- (PPAR) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPAR-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPAR-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPAR-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPAR regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPAR. These results strongly suggest that activation of PPAR-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.

Received for publication, November 4, 2003 , and in revised form, February 27, 2004.

^* This work supported by NCI, National Institutes of Health Grant R01 CA89607 (to J. M. P.). 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.

^|| Current address: Merck Research Laboratories, Rahway, NJ 07065.

^¶¶ To whom correspondence should be addressed: Dept. of Veterinary Science and Center for Molecular Toxicology and Carcinogenesis, 226 Fenske Laboratory, The Pennsylvania State University, University Park, PA 16802. Tel.: 814-863-1387; Fax: 814-863-1696; E-mail: jmp21{at}psu.edu.

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