title: ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.
abstract: The 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.
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Plotnik
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Budka
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA.
authors.forename: Mary W
authors.initials: MW
authors.lastname: Ferris
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA pchollen@indiana.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hollenhorst
mesh_terms: D001665:Binding Sites; D018938:Caco-2 Cells; D002277:Carcinoma / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015894:Genome, Human; D006801:Humans; D020935:MAP Kinase Signaling System; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism* / Q000502:physiology; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050784:Proto-Oncogene Protein c-ets-1; D050783:Proto-Oncogene Proteins c-ets; D018808:Transcription Factor AP-1; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)