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The ETS transcription factors ELK1 and GABPA regulate different gene networks to control MCF10A breast epithelial cell migration.

ABSTRACT: Members of the ETS transcription factor family often target the same binding regions and hence have the potential to regulate the same genes and downstream biological processes. However, individual family members also preferentially bind to other genomic regions, thus providing the potential for controlling distinct transcriptional programmes and generating specific biological effects. The ETS transcription factor ELK1 controls cell migration in breast epithelial cells through targeting a cohort of genes, independently from another family member GABPA, and therefore achieves biological specificity. Here, we demonstrate that GABPA also controls cell migration in breast epithelial cells. However, GABPA controls the expression of a different network of target genes to ELK1. Both direct and indirect target genes for GABPA are identified and amongst the direct targets we confirm the importance of RAC1 and KIF20A for cell migration. Therefore, although ELK1 and GABPA ultimately control the same biological process, they do so by regulating different cohorts of target genes associated with cytoskeletal functions and cell migration control.

SUBMITTER: Odrowaz Z

PROVIDER: S-EPMC3527487 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The ETS transcription factors ELK1 and GABPA regulate different gene networks to control MCF10A breast epithelial cell migration.

Odrowaz Zaneta Z Sharrocks Andrew D AD

PloS one 20121220 12

Members of the ETS transcription factor family often target the same binding regions and hence have the potential to regulate the same genes and downstream biological processes. However, individual family members also preferentially bind to other genomic regions, thus providing the potential for controlling distinct transcriptional programmes and generating specific biological effects. The ETS transcription factor ELK1 controls cell migration in breast epithelial cells through targeting a cohort ...[more]

PMID: 23284628

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Project description:BackgroundAngiopoietin-1 (Ang-1) is the main ligand of Tie-2 receptors. It promotes endothelial cell (EC) survival, migration, and differentiation. Little is known about the transcription factors (TFs) in ECs that are downstream from Tie-2 receptors.ObjectiveThe main objective of this study is to identify the roles of the ETS family of TFs in Ang-1 signaling and the angiogenic response.MethodsIn silico enrichment analyses that were designed to predict TF binding sites of the promotors of eighty-six Ang-1-upregulated genes showed significant enrichment of ETS1, ELK1, and ETV4 binding sites in ECs. Human umbilical vein endothelial cells (HUVECs) were exposed for different time periods to recombinant Ang-1 protein and mRNA levels of ETS1, ELK1, and ETV4 were measured with qPCR and intracellular localization of these transcription factors was assessed with immunofluorescence. Electrophoretic mobility shift assays and reporter assays were used to assess activation of ETS1, ELK1, and ETV4 in response to Ang-1 exposure. The functional roles of these TFs in Ang-1-induced endothelial cell survival, migration, differentiation, and gene regulation were evaluated by using a loss-of-function approach (transfection with siRNA oligos).ResultsAng-1 exposure increased ETS1 mRNA levels but had no effect on ELK1 or ETV4 levels. Immunostaining revealed that in control ECs, ETS1 has nuclear localization whereas ELK1 and ETV4 are localized to the nucleus and the cytosol. Ang-1 exposure increased nuclear intensity of ETS1 protein and enhanced nuclear mobilization of ELK1 and ETV4. Selective siRNA knockdown of ETS1, ELK1, and ETV4 showed that these TFs are required for Ang-1-induced EC survival and differentiation of cells, while ETS1 and ETV4 are required for Ang-1-induced EC migration. Moreover, ETS1, ELK1, and ETV4 knockdown inhibited Ang-1-induced upregulation of thirteen, eight, and nine pro-angiogenesis genes, respectively.ConclusionWe conclude that ETS1, ELK1, and ETV4 transcription factors play significant angiogenic roles in Ang-1 signaling in ECs.

Dataset Information

The ETS transcription factors ELK1 and GABPA regulate different gene networks to control MCF10A breast epithelial cell migration.

Publications

The ETS transcription factors ELK1 and GABPA regulate different gene networks to control MCF10A breast epithelial cell migration.

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