Abstract
BackgroundRas 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.ResultsWe 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.ConclusionsTaken together, our results provide evidence of an Rb1-dependent Ets1-Zeb1 amplification loop in thymocyte differentiation and tumor invasion.Electronic supplementary materialThe online version of this article (doi:10.1186/s12867-015-0038-4) contains supplementary material, which is available to authorized users.
Highlights
Ras pathway mutation leads to induction and Erk phosphorylation and activation of the Ets1 transcription factor
We show that Zeb1 and Ets1 are expressed together at the invasive edge of K-Ras-initiated mouse lung adenocarcinomas, and there is a significant correlation between expression of Ets1 and Zeb1 in human lung adenocarcinoma
As we demonstrated previously [16], mutation of Rb1 family members led to induction of Zeb1 and this induction of Zeb1 was accompanied by repression of miR-200 (Figure 4C) and, as shown above, Ets1 (Figure 1)
Summary
Ras pathway mutation leads to induction and Erk phosphorylation and activation of the Ets transcription factor. Ets induces expression of the epithelial-mesenchymal transition (EMT) transcription factor Zeb, and thereby links Ras mutation to EMT, which is thought to drive tumor invasion. MiR-200 represses Zeb, but in a double negative loop Zeb binds the promoters of miR-200 family members and represses their expression [20,21] Such findings raised the possibility that Zeb might feedback to induce Ets via its repression of miR-200, and that Rb1 might influence Ets expression via its regulation of Zeb. Rb1 can interact with genes in a cell cycle-dependent fashion to regulate proliferation, it is found constitutively at other genes including pro-apoptotic factors and mutation or inactivate of Rb1 is required for induction of such genes [22]. We link the effect of Zeb to its regulation of miR-200, which in turn target Ets
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