FEV acts as a transcriptional repressor through its DNA-binding ETS domain and alanine-rich domain

• Published in: Oncogene Vol. 22; no. 21; pp. 3319 - 3329
• Main Authors: MAURER, Philippe, T'SAS, France, COUTTE, Laurent, CALLENS, Nathalie, BRENNER, Carmen, VAN LINT, Carine, DE LAUNOIT, Yvan, BAERT, Jean-Luc
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 22.05.2003; Nature Publishing Group
• Subjects: Alanine; Alanine - analysis; Animals; Binding sites; Biological and medical sciences; Cell Line; Cell lines; Cell Nucleus - chemistry; Cloning; COS Cells; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Fundamental and applied biological sciences. Psychology; Gene Silencing; Genes; Histone deacetylase; Humans; Intercellular adhesion molecule 1; Molecular and cellular biology; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Prostate; Protein Structure, Tertiary; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ets; Rabbits; Repressor Proteins - chemistry; Repressor Proteins - physiology; Response Elements; Transcription factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Trichostatin A; Tumor Cells, Cultured; Belgium; France; transcription factor; Genetics; repression; Ets
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206572

Although most Ets transcription factors have been characterized as transcriptional activators, some of them display repressor activity. Here we characterize an Ets-family member, the very specifically expressed human Fifth Ewing Variant (FEV), as a transcriptional repressor. We show that among a broad range of human cell lines, only Dami megakaryocytic cells express FEV. This nuclear protein binds to Ets-binding sites, such as that of the human ICAM-1 promoter. We used this promoter to demonstrate that FEV can repress both basal transcription and, even more strongly, ectopically Ets-activated transcription. We identified two domains responsible for FEV-mediated repression: the ETS domain, responsible for passive repression, and the carboxy-terminal alanine-rich domain, involved in active repression. In the Ets-independent LEXA system also, FEV acts as a transcriptional repressor via its alanine-rich carboxy-terminal domain. The mechanism by which FEV actively represses transcription is currently unknown, since FEV-triggered repression is not reversed by the histone deacetylase inhibitor trichostatin A. We also showed that long-term overexpression of FEV proteins containing the alanine-rich domain prevents cell clones from growing, whereas clones expressing a truncated FEV protein lacking this domain develop like control cells. This confirms the importance of this domain in FEV-triggered repression.