The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo.

Publisher: Biomed Central Country of Publication: England NLM ID: 101468937 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-8722 (Electronic) Linking ISSN: 17568722 NLM ISO Abbreviation: J Hematol Oncol Subsets: MEDLINE

Original Publication: [London] : Biomed Central, 2008-

Apoptosis/*drug effects ; Cell Proliferation/*drug effects ; DNA-Binding Proteins/*pharmacology ; Lymphopoiesis/*drug effects ; Transcription Factors/*pharmacology; Animals ; Cell Cycle ; Cell Line, Tumor ; Gene Expression Regulation ; Mice ; Precursor Cells, B-Lymphoid/drug effects ; Protein Isoforms ; T-Lymphocytes/drug effects

Background: ELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function.
Methods: We compared the function of ELF2 isoforms ELF2A and ELF2B with other ELF subfamily proteins ELF1 and ELF4 in primary and cancer cell lines using proliferation, colony-forming, cell cycle, and apoptosis assays. We further examined the role of ELF2 isoforms in haemopoietic development using a Rag1 ^-/- murine bone marrow reconstitution model.
Results: ELF2B overexpression significantly reduced cell proliferation and clonogenic capacity, minimally disrupted cell cycle kinetics, and induced apoptosis. In contrast, ELF2A overexpression only marginally reduced clonogenic capacity with little effect on proliferation, cell cycle progression, or apoptosis. Deletion of the N-terminal 19 amino acids unique to ELF2B abrogated the antiproliferative and proapoptotic functions of ELF2B thereby confirming its crucial role. Mice expressing Elf2a or Elf2b in haemopoietic cells variously displayed perturbations in the pre-B cell stage and multiple stages of T cell development. Mature B cells, T cells, and myeloid cells in steady state were unaffected, suggesting that the main role of ELF2 is restricted to the early development of B and T cells and that compensatory mechanisms exist. No differences in B and T cell development were observed between ELF2 isoforms.
Conclusions: We conclude that ELF2 isoforms are important regulators of cellular proliferation, cell cycle progression, and apoptosis. In respect to this, ELF2B acts in a dominant negative fashion compared to ELF2A and as a putative tumour suppressor gene. Given that these cellular processes are critical during haemopoiesis, we propose that the regulatory interplay between ELF2 isoforms contributes substantially to early B and T cell development.

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Keywords: Antiproliferative; Apoptosis; DNA binding; Dominant negative; ELF2; ELF2A; ELF2B; Ets domain; Isoform; Lymphoid development; Transcription factor; Tumour suppressor

0 (DNA-Binding Proteins)
0 (Elf2 protein, mouse)
0 (Protein Isoforms)
0 (Transcription Factors)

Date Created: 20170330 Date Completed: 20171201 Latest Revision: 20181113

20221213

PMC5371273

10.1186/s13045-017-0446-7

28351373