Peroxisome proliferator-activated receptor β (δ)-dependent regulation of ubiquatin 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, Jeffrey M. Peters

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)23719-23727
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number22
DOIs
StatePublished - May 28 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, D. J., Akiyama, T. E., Harman, F. S., Burns, A. M., Shan, W., Ward, J. M., Kennett, M. J., Gonzalez, F. J., & Peters, J. M. (2004). Peroxisome proliferator-activated receptor β (δ)-dependent regulation of ubiquatin C expression contributes to attenuation of skin carcinogenesis. Journal of Biological Chemistry, 279(22), 23719-23727. https://doi.org/10.1074/jbc.M312063200