title: An Rb1-dependent amplification loop between Ets1 and Zeb1 is evident in thymocyte differentiation and invasive lung adenocarcinoma.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA. kcdean2442@gmail.com.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dean
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA. lihuang@zju.edu.cn.|College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang Province, 310058, China. lihuang@zju.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA. sandytur22@gmail.com.|The Second Affiliated Hospital, Central South University Xiangya School of Medicine, Changsha, Hunan Province, 410011, China. sandytur22@gmail.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA. xiaoqin.lu@louisville.edu.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, 301 E. Muhammad Ali Blvd., Louisville, KY, 40202, USA. y0liu016@louisville.edu.|James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY, 40202, USA. y0liu016@louisville.edu.|Birth Defects Center, University of Louisville Health Sciences Center, Louisville, KY, 40202, USA. y0liu016@louisville.edu.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D015398:Signal Transduction; D060168:Thymocytes / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1