title: The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Fiona H X
authors.initials: FH
authors.lastname: Guan
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Metierre
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Young
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Dadi
authors.initials: D
authors.lastname: Gao
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.|Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Teh Liane
authors.initials: TL
authors.lastname: Khoo
authors.affiliation: Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, NSW, 2050, Australia. j.rasko@centenary.org.au.|Sydney Medical School, University of Sydney, Camperdown, NSW, 2006, Australia. j.rasko@centenary.org.au.|Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia. j.rasko@centenary.org.au.
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005786:Gene Expression Regulation; D038041:Lymphopoiesis / Q000187:drug effects*; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects; D020033:Protein Isoforms; D013601:T-Lymphocytes / Q000187:drug effects; D014157:Transcription Factors / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; C103652:Elf2 protein, mouse; D020033:Protein Isoforms; D014157:Transcription Factors
keywords: Antiproliferative; Apoptosis; DNA binding; Dominant negative; ELF2; ELF2A; ELF2B; Ets domain; Isoform; Lymphoid development; Transcription factor; Tumour suppressor