Crawford E L, Blomquist T, Mullins D N, Yoon Y, Hernandez D R, Al-Bagdhadi M, Ruiz J, Hammersley J, Willey J C
Department of Medicine, The University of Toledo, Toledo, OH 43614, USA.
Carcinogenesis. 2007 Dec;28(12):2552-9. doi: 10.1093/carcin/bgm214. Epub 2007 Sep 24.
Marked inter-individual variation in lung cancer risk cannot be accounted for solely by cigarette smoke and other environmental exposures. Evidence suggests that variation in bronchial epithelial cell expression of key DNA repair genes plays a role. Variation in these genes correlates with variation in expression of CEBPG and E2F1 transcription factors. Here, we investigated the mechanistic basis for correlation of the DNA repair gene ERCC5 (previously known as XPG) with CEBPG and E2F1. CEBPG expression vector transfected into H23 or H460 cell lines up-regulated endogenous ERCC5 and also luciferase from a reporter construct containing 589 bp of ERCC5 5' regulatory region. A recognition site for CEBPG and a region containing sites for YY1 on the sense strand and E2F1 on the anti-sense strand participated in CEBPG up-regulation of ERCC5. CEBPG, E2F1 and YY1 binding to their respective sites were confirmed by electrophoretic mobility shift assay. Thus, we conclude that CEBPG regulates ERCC5 expression and this regulation is modified by E2F1/YY1 interactions. Several polymorphisms have been identified in these regions and, based on the data presented here, it is reasonable to hypothesize that they may contribute to risk for bronchogenic carcinoma.
肺癌风险在个体间存在显著差异，这不能仅由香烟烟雾和其他环境暴露来解释。有证据表明，关键DNA修复基因在支气管上皮细胞中的表达差异起了作用。这些基因的差异与CEBPG和E2F1转录因子的表达差异相关。在此，我们研究了DNA修复基因ERCC5（以前称为XPG）与CEBPG和E2F1相关性的机制基础。将CEBPG表达载体转染到H23或H460细胞系中，可上调内源性ERCC5以及来自含有589 bp ERCC5 5'调控区的报告构建体的荧光素酶。CEBPG的一个识别位点以及正义链上含有YY1位点和反义链上含有E2F1位点的区域参与了CEBPG对ERCC5的上调。通过电泳迁移率变动分析证实了CEBPG、E2F1和YY1与其各自位点的结合。因此，我们得出结论，CEBPG调节ERCC5的表达，并且这种调节受到E2F1/YY1相互作用的影响。在这些区域已鉴定出几种多态性，基于此处提供的数据，合理推测它们可能与支气管癌风险有关。
