Zhang Dongyun, Wang Yulei, Liang Yuguang, Zhang Min, Wei Jinlong, Zheng Xiao, Li Fei, Meng Yan, Zhu Nina Wu, Li Jingxia, Wu Xue-Ru, Huang Chuanshu
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
Departments of Urology and Pathology, New York University School of Medicine, and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, NY 10010, USA.
J Cell Sci. 2014 Jul 1;127(Pt 13):2920-33. doi: 10.1242/jcs.148130. Epub 2014 Apr 11.
Cell migration is a dynamic process that is central to a variety of physiological functions as well as disease pathogenesis. The modulation of cell migration by p27 (officially known as CDKN1B) has been reported, but the exact mechanism(s) whereby p27 interacts with downstream effectors that control cell migration have not been elucidated. By systematically comparing p27(+/+) mouse embryonic fibroblasts (MEFs) with genetically ablated p27(-/-) MEFs using wound-healing, transwell and time-lapse microscopic analyses, we provide direct evidence that p27 inhibits both directional and random cell migration. Identical results were obtained with normal and cancer epithelial cells using complementary knockdown and overexpression approaches. Additional studies revealed that overexpression of manganese superoxide dismutase (MnSOD, officially known as SOD2) and reduced intracellular oxidation played a key role in increased cell migration in p27-deficient cells. Furthermore, we identified signal transducer and activator of transcription 3 (STAT3) as the transcription factor responsible for p27-regulated MnSOD expression, which was further mediated by ERK- and ATF1-dependent transactivation of the cAMP response element (CRE) within the Stat3 promoter. Collectively, our data strongly indicate that p27 plays a crucial negative role in cell migration by inhibiting MnSOD expression in a STAT3-dependent manner.
细胞迁移是一个动态过程，对于多种生理功能以及疾病发病机制都至关重要。已有报道称p27（正式名称为CDKN1B）可调节细胞迁移，但p27与控制细胞迁移的下游效应器相互作用的确切机制尚未阐明。通过使用伤口愈合、Transwell和延时显微镜分析系统地比较p27(+/+)小鼠胚胎成纤维细胞（MEF）与基因敲除的p27(-/-) MEF，我们提供了直接证据表明p27抑制定向和随机细胞迁移。使用互补的敲低和过表达方法，在正常和癌细胞上皮细胞中也获得了相同的结果。进一步的研究表明，锰超氧化物歧化酶（MnSOD，正式名称为SOD2）的过表达和细胞内氧化的减少在p27缺陷细胞的细胞迁移增加中起关键作用。此外，我们确定信号转导和转录激活因子3（STAT3）是负责p27调节的MnSOD表达的转录因子，这进一步由Stat3启动子内cAMP反应元件（CRE）的ERK和ATF1依赖性反式激活介导。总体而言，我们的数据强烈表明p27通过以STAT3依赖性方式抑制MnSOD表达在细胞迁移中起关键的负向作用。
