Peroxisome proliferator-activated receptor β (δ)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis
Peroxisome proliferator-activated receptor β (δ)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis
复制标题
DOI：
10.1074/jbc.m312063200
复制
发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Peters, JM
中科院分区：
文献类型：
--
作者：
Kim, DJ;Akiyama, TE;Peters, JM
研究了过氧化物酶体增殖物激活受体-β(PPARbeta)在皮肤癌变分子调控中的作用。野生型小鼠在12-O-十四烷基佛波醇-13-醋酸酯促瘤作用后，其皮肤caspase-3活性与细胞凋亡有关，而PPARβ缺失小鼠的这种作用减弱。与野生型小鼠相比，PPARβ基因缺失小鼠的肿瘤形成起始时间、肿瘤大小和通过两阶段致癌物生物测定(7，12-二甲基苯并[a]菲/12-O-十四酰佛波醇-13-醋酸酯)诱导的肿瘤多样性显著增加。为了开始描述这种依赖于PPARbeta的表型背后的分子变化，进行了微阵列分析，并鉴定了一些差异调控的基因产物，包括泛素C。随后的启动子分析、报告基因分析、定点突变和电泳迁移率改变分析提供了证据，证明PPARbeta调节泛素C的表达，并且蛋白质的泛素化受到PPARbeta的影响。这些结果有力地表明，激活依赖于PPARβ的靶基因为抑制肿瘤的促进和癌变提供了一种新的策略。
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 wildtype 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.