ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells

Joshua P. Plotnik, Justin A. Budka, Mary W. Ferris, Peter C. Hollenhorst

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11928-11940
Number of pages13
JournalNucleic acids research
Volume42
Issue number19
DOIs
StatePublished - Oct 29 2014

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MAP Kinase Signaling System
Transcription Factor AP-1
Cell Movement
Epithelial Cells
Genome
Genes
Trans-Activators
Chromosome Mapping
Transcriptional Activation
Chromatin
Carcinogenesis
Proteins
Binding Sites
Phosphorylation
Carcinoma
Cell Line

ASJC Scopus subject areas

  • Genetics

Cite this

ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. / Plotnik, Joshua P.; Budka, Justin A.; Ferris, Mary W.; Hollenhorst, Peter C.

In: Nucleic acids research, Vol. 42, No. 19, 29.10.2014, p. 11928-11940.

Research output: Contribution to journalArticle

Plotnik, Joshua P. ; Budka, Justin A. ; Ferris, Mary W. ; Hollenhorst, Peter C. / ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. In: Nucleic acids research. 2014 ; Vol. 42, No. 19. pp. 11928-11940.
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