Abstract
The ETS-family transcription factors Ets1 and Ets2 are evolutionarily conserved effectors of the RAS/ERK signaling pathway, but their function in Ras cellular transformation and biology remains unclear. Taking advantage of Ets1 and Ets2 mouse models to generate Ets1/Ets2 double knockout mouse embryonic fibroblasts, we demonstrate that deletion of both Ets1 and Ets2 was necessary to inhibit HrasG12V induced transformation both in vitro and in vivo. HrasG12V expression in mouse embryonic fibroblasts increased ETS1 and ETS2 expression and binding to cis-regulatory elements on the c-Myc proximal promoter, and consequently induced a robust increase in MYC expression. The expression of the oncogenic microRNA 17-92 cluster was increased in HrasG12V transformed cells, but was significantly reduced when ETS1 and ETS2 were absent. MYC and ETS1 or ETS2 collaborated to increase expression of the oncogenic microRNA 17-92 cluster in HrasG12V transformed cells. Enforced expression of exogenous MYC or microRNA 17-92 rescued HrasG12V transformation in Ets1/Ets2-null cells, revealing a direct function for MYC and microRNA 17-92 in ETS1/ETS2-dependent HrasG12V transformation.
Highlights
Cancer cells exhibit unique transformation properties that include independence from mitogenic and growth signals, unresponsiveness to anti-growth signals, escape from apoptosis and senescence, changes in gene expression, and acquired invasion and metastastatic capabilities [1]
We hypothesized that both Ets1 and Ets2 might be required for efficient Ras transformation of MEFs
Western blot analysis demonstrated that ETS1 and ETS2 expression is very low in the immortalized MEFs, but expression of both ETS1 and ETS2 increased dramatically in response to HrasG12V introduction (Figure 1A)
Summary
Cancer cells exhibit unique transformation properties that include independence from mitogenic and growth signals, unresponsiveness to anti-growth signals, escape from apoptosis and senescence, changes in gene expression, and acquired invasion and metastastatic capabilities [1]. RAS gene family activating mutations are present in 30% of all human cancers, and cells harboring RAS mutations have self-sufficiency in growth signals [2]. RAS is a GTP-binding protein that activates cellular proliferation and survival among other biological functions in response to extracellular signals under normal conditions [3,4]. ETS1 and ETS2 are members of the ETS family of transcription factors and are downstream effectors of the RAS/ RAF/ERK pathway [6,7,8,9]. These factors regulate genes involved in cellular proliferation, differentiation, apoptosis and transformation [9]. For example specific deletion of Ets alone failed to inhibit Ras transformation in ES-cell derived fibroblasts [12]
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