Plotnik, Joshua P.Budka, Justin A.Ferris, Mary W.Hollenhorst, Peter C.2015-09-152015-09-152014-10-29Plotnik, J. P., Budka, J. A., Ferris, M. W., & Hollenhorst, P. C. (2014). ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. Nucleic Acids Research, 42(19), 11928–11940. http://doi.org/10.1093/nar/gku929https://hdl.handle.net/1805/6918The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells. In vivo screening of candidate ETS proteins revealed that ETS1 is specifically required for migration of RAS/ERK activated cells. Furthermore, both migration and transcriptional activation through ETS/AP-1 required ERK phosphorylation of ETS1. Genome-wide mapping of multiple ETS proteins demonstrated that ETS1 binds specifically to enhancer ETS/AP-1 sequences. ETS1 occupancy, and its role in cell migration, was conserved in epithelial cells derived from multiple tissues, consistent with a chromatin organization common to epithelial cell lines. Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway. Consistently, ETS1 was required for robust RAS/ERK pathway activation. Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesBinding SitesCaco-2 CellsCarcinoma -- geneticsCell Line, TumorCell Movement -- geneticsCells, CulturedEpithelial Cells -- enzymologyEpithelial Cells -- metabolismEpithelial Cells -- physiologyExtracellular Signal-Regulated MAP Kinases -- metabolismGenome, HumanHumansMAP Kinase Signaling SystemProto-Oncogene Protein c-ets-1 -- metabolismProto-Oncogene Protein c-ets-1 -- physiologyProto-Oncogene Proteins c-ets -- metabolismProto-Oncogene Proteins c-ets -- physiologyProto-Oncogene Proteins p21(ras) -- metabolismRegulatory Elements, TranscriptionalTranscription Factor AP-1 -- metabolismTranscriptional ActivationArticle