title: The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1.
abstract: EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-1 has been shown to be a potent transforming gene, suggesting that it plays an important role in the genesis of these human tumors. We now demonstrate that EWS/FLI-1 has the characteristics of an aberrant transcription factor. Subcellular fractionation experiments localized the EWS/FLI-1 protein to the nucleus of primitive neuroectodermal tumor cells. EWS/FLI-1 specifically bound in vitro an ets-2 consensus sequence similarly to normal FLI-1. When coupled to a GAL4 DNA-binding domain, the amino-terminal EWS/FLI-1 region was a much more potent transcriptional activator than the corresponding amino-terminal domain of FLI-1. Finally, EWS/FLI-1 efficiently transformed NIH 3T3 cells, but FLI-1 did not. These data suggest that EWS/FLI-1, functioning as a transcription factor, leads to a phenotype dramatically different from that of cells expressing FLI-1. EWS/FLI-1 could disrupt normal growth and differentiation either by more efficiently activating FLI-1 target genes or by inappropriately modulating genes normally not responsive to FLI-1.
authors.affiliation: Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles.
authors.forename: W A
authors.initials: WA
authors.lastname: May
authors.forename: S L
authors.initials: SL
authors.lastname: Lessnick
authors.forename: B S
authors.initials: BS
authors.lastname: Braun
authors.forename: M
authors.initials: M
authors.lastname: Klemsz
authors.forename: B C
authors.initials: BC
authors.lastname: Lewis
authors.forename: L B
authors.initials: LB
authors.lastname: Lunsford
authors.forename: R
authors.initials: R
authors.lastname: Hromas
authors.forename: C T
authors.initials: CT
authors.lastname: Denny
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002880:Chromosomes, Human, Pair 11; D002892:Chromosomes, Human, Pair 22; D003001:Cloning, Molecular; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009857:Oncogenes; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators