title: Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis.
abstract: The role of peroxisome proliferator-activated receptor-beta (PPARbeta) 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 PPARbeta-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 PPARbeta-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARbeta-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 PPARbeta regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARbeta. These results strongly suggest that activation of PPARbeta-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.
authors.affiliation: Department of Veterinary Science and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park 16802, USA.
authors.forename: Dae J
authors.initials: DJ
authors.lastname: Kim
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.forename: Fred S
authors.initials: FS
authors.lastname: Harman
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Burns
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025822:Ubiquitin C / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D025822:Ubiquitin C