Casalino Laura, Bakiri Latifa, Talotta Francesco, Weitzman Jonathan B, Fusco Alfredo, Yaniv Moshe, Verde Pasquale
A Buzzati Traverso Institute of Genetics and Biophysics, CNR, Naples, Italy.
EMBO J. 2007 Apr 4;26(7):1878-90. doi: 10.1038/sj.emboj.7601617. Epub 2007 Mar 8.
Fra-1 is frequently overexpressed in epithelial cancers and implicated in invasiveness. We previously showed that Fra-1 plays crucial roles in RAS transformation in rat thyroid cells and mouse fibroblasts. Here, we report a novel role for Fra-1 as a regulator of mitotic progression in RAS-transformed thyroid cells. Fra-1 expression and phosphorylation are regulated during the cell cycle, peaking at G2/M. Knockdown of Fra-1 caused a proliferative block and apoptosis. Although most Fra-1-knockdown cells accumulated in G2, a fraction of cells entering M-phase underwent abortive cell division and exhibited hallmarks of genomic instability (micronuclei, lagging chromosomes and anaphase bridges). Furthermore, we established a link between Fra-1 and the cell-cycle machinery by identifying cyclin A as a novel transcriptional target of Fra-1. During the cell cycle, Fra-1 was recruited to the cyclin A gene (ccna2) promoter, binding to previously unidentified AP-1 sites and the CRE. Fra-1 also induced the expression of JunB, which in turn interacts with the cyclin A promoter. Hence, Fra-1 induction is important in thyroid tumorigenesis, critically regulating cyclin expression and cell-cycle progression.
Fra-1在上皮癌中经常过度表达，并与侵袭性有关。我们之前表明Fra-1在大鼠甲状腺细胞和小鼠成纤维细胞的RAS转化中起关键作用。在此，我们报告Fra-1作为RAS转化的甲状腺细胞有丝分裂进程调节因子的新作用。Fra-1的表达和磷酸化在细胞周期中受到调控，在G2/M期达到峰值。敲低Fra-1会导致增殖阻滞和细胞凋亡。虽然大多数敲低Fra-1的细胞积累在G2期，但一小部分进入M期的细胞经历了失败的细胞分裂，并表现出基因组不稳定的特征（微核、落后染色体和后期桥）。此外，我们通过鉴定细胞周期蛋白A作为Fra-1的新转录靶点，建立了Fra-1与细胞周期机制之间的联系。在细胞周期中，Fra-1被招募到细胞周期蛋白A基因（ccna2）启动子上，与先前未鉴定的AP-1位点和CRE结合。Fra-1还诱导JunB的表达，而JunB又与细胞周期蛋白A启动子相互作用。因此，Fra-1的诱导在甲状腺肿瘤发生中很重要，它严格调节细胞周期蛋白的表达和细胞周期进程。
