Dean Kevin C, Huang Li, Chen Yao, Lu Xiaoqin, Liu Yongqing
Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA.
College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China.
BMC Mol Biol. 2015 Mar 19;16:8. doi: 10.1186/s12867-015-0038-4.
Ras pathway mutation leads to induction and Erk phosphorylation and activation of the Ets1 transcription factor. Ets1 in turn induces cyclin E and cyclin dependent kinase (cdk) 2 to drive cell cycle progression. Ets1 also induces expression of the epithelial-mesenchymal transition (EMT) transcription factor Zeb1, and thereby links Ras mutation to EMT, which is thought to drive tumor invasion. Ras pathway mutations are detected by the Rb1 tumor suppression pathway, and mutation or inactivation of the Rb1 pathway is required for EMT.
We examined linkage between Rb1, Ets1 and Zeb1. We found that an Rb1-E2F complex binds the Ets1 promoter and constitutively limits Ets1 expression. But, Rb1 repression of Zeb1 provides the major impact of Rb1 on Ets1 expression. We link Rb1 repression of Zeb1 to induction of miR-200 family members, which in turn target Ets1 mRNA. These findings suggest that Ets1 and Zeb1 comprise an amplification loop that is dependent upon miR-200 and regulated by Rb1. Thus, induction of Ets1 when the Rb1 pathway is lost may contribute to deregulated cell cycle progression through Ets1 induction of cyclin E and cdk2. Consistent with such an amplification loop, we correlate expression of Ets1 and Zeb1 in mouse and human lung adenocarcinoma. In addition we demonstrate that Ets1 expression in thymocytes is also dependent upon Zeb1.
Taken together, our results provide evidence of an Rb1-dependent Ets1-Zeb1 amplification loop in thymocyte differentiation and tumor invasion.
Ras信号通路突变导致Ets1转录因子的诱导及Erk磷酸化和激活。Ets1继而诱导细胞周期蛋白E和细胞周期蛋白依赖性激酶（cdk）2以驱动细胞周期进程。Ets1还诱导上皮-间质转化（EMT）转录因子Zeb1的表达，从而将Ras突变与EMT联系起来，而EMT被认为可驱动肿瘤侵袭。Ras信号通路突变由Rb1肿瘤抑制通路检测到，并且EMT需要Rb1通路的突变或失活。
我们研究了Rb1、Ets1和Zeb1之间的联系。我们发现Rb1-E2F复合物结合Ets1启动子并组成性地限制Ets1表达。但是，Rb1对Zeb1的抑制对Ets1表达产生主要影响。我们将Rb1对Zeb1的抑制与miR-200家族成员的诱导联系起来，而miR-200家族成员又靶向Ets1 mRNA。这些发现表明Ets1和Zeb1构成了一个依赖于miR-200并受Rb1调节的扩增环。因此，当Rb1通路缺失时Ets1的诱导可能通过Ets1诱导细胞周期蛋白E和cdk2导致细胞周期进程失调。与这样一个扩增环一致,我们将Ets1和Zeb1的表达与小鼠和人肺腺癌相关联。此外，我们证明胸腺细胞中Ets1的表达也依赖于Zeb1。
综上所述，我们的结果提供了在胸腺细胞分化和肿瘤侵袭中存在Rb1依赖性Ets1-Zeb1扩增环的证据。
