Jiao Xuanmao, Katiyar Sanjay, Liu Manran, Mueller Susette C, Lisanti Michael P, Li Anping, Pestell Timothy G, Wu Kongming, Ju Xiaoming, Li Zhiping, Wagner Erwin F, Takeya Tatsuo, Wang Chenguang, Pestell Richard G
Department of Cancer Biology and Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Mol Biol Cell. 2008 Apr;19(4):1378-90. doi: 10.1091/mbc.e07-08-0753. Epub 2008 Jan 23.
The spread of metastatic tumors to different organs is associated with poor prognosis. The metastatic process requires migration and cellular invasion. The protooncogene c-jun encodes the founding member of the activator protein-1 family and is required for cellular proliferation and DNA synthesis in response to oncogenic signals and plays an essential role in chemical carcinogenesis. The role of c-Jun in cellular invasion remains to be defined. Genetic deletion of c-Jun in transgenic mice is embryonic lethal; therefore, transgenic mice encoding a c-Jun gene flanked by LoxP sites (c-jun(f/f)) were used. c-jun gene deletion reduced c-Src expression, hyperactivated ROCK II signaling, and reduced cellular polarity, migration, and invasiveness. c-Jun increased c-Src mRNA abundance and c-Src promoter activity involving an AP-1 site in the c-Src promoter. Transduction of c-jun(-/-) cells with either c-Jun or c-Src retroviral expression systems restored the defective cellular migration of c-jun(-/-) cells. As c-Src is a critical component of pathways regulating proliferation, survival, and metastasis, the induction of c-Src abundance, by c-Jun, provides a novel mechanism of cooperative signaling in cellular invasion.
转移性肿瘤向不同器官的扩散与预后不良相关。转移过程需要细胞迁移和侵袭。原癌基因c-jun编码激活蛋白-1家族的创始成员，是细胞响应致癌信号进行增殖和DNA合成所必需的，并且在化学致癌过程中起重要作用。c-Jun在细胞侵袭中的作用仍有待确定。转基因小鼠中c-Jun的基因缺失是胚胎致死性的；因此，使用了编码两侧带有LoxP位点的c-Jun基因的转基因小鼠（c-jun(f/f)）。c-jun基因缺失降低了c-Src表达，过度激活了ROCK II信号，并降低了细胞极性、迁移和侵袭能力。c-Jun增加了c-Src mRNA丰度和c-Src启动子活性，这涉及c-Src启动子中的一个AP-1位点。用c-Jun或c-Src逆转录病毒表达系统转导c-jun(-/-)细胞可恢复c-jun(-/-)细胞有缺陷的细胞迁移。由于c-Src是调节增殖、存活和转移的信号通路的关键组成部分，c-Jun对c-Src丰度的诱导为细胞侵袭中的协同信号传导提供了一种新机制。
