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

• Published in: The Journal of biological chemistry 2004-05, Vol.279 (22), p.23719
• Main Authors: Dae J. Kim, Taro E. Akiyama, Fred S. Harman, Amanda M. Burns, Weiwei Shan, Jerrold M. Ward, Mary J. Kennett, Frank J. Gonzalez, Jeffrey M. Peters
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M312063200

The role of peroxisome proliferator-activated receptor-β (PPARβ) 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 PPARβ-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 PPARβ-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARβ-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 PPARβ regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARβ. These results strongly suggest that activation of PPARβ-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.