An Rb1-dependent amplification loop between Ets1 and Zeb1 is evident in thymocyte differentiation and invasive lung adenocarcinoma

BMC Molecular Biology

Yongqing Liu⁴  Xiaoqin Lu³  Yao Chen¹  Li Huang²  Kevin C Dean³ 

[1] The Second Affiliated Hospital, Central South University Xiangya School of Medicine, Changsha 410011, Hunan Province, China;College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, Zhejiang Province, China;Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville 40202, KY, USA;Birth Defects Center, University of Louisville Health Sciences Center, Louisville 40202, KY, USA

关键词: Lung adenocarcinoma;    Thymocyte differentiation;    miR-200;    Zeb1;    Ets1;   

Others  :  1139092
DOI  :  10.1186/s12867-015-0038-4

 received in 2014-08-01, accepted in 2015-02-26,  发布年份 2015

【 摘 要 】

Background

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.

Results

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.

Conclusions

Taken together, our results provide evidence of an Rb1-dependent Ets1-Zeb1 amplification loop in thymocyte differentiation and tumor invasion.

【 授权许可】

   
2015 Dean et al.; licensee BioMed Central.

【 图 表 】

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