Homotypic and heterotypic interactions of EWS, FLI1 and their oncogenic fusion protein View Full Text


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Article Info

DATE

2003-10-09

AUTHORS

Laura Spahn, Christine Siligan, Radostina Bachmaier, Johannes A Schmid, Dave N T Aryee, Heinrich Kovar

ABSTRACT

In Ewing's sarcoma family tumors, the ets transcription factor gene FLI1 is rearranged with one EWS allele resulting in coexpression of germline EWS and chimeric EWS-FLI1 proteins. Here, we investigated the potential of germline EWS, FLI1 and EWS-FLI1 to oligomerize. In two functional in vivo tests, fluorescence resonance energy transfer (FRET) and the mammalian two-hybrid (MTH) assay, self-association of EWS and EWS-FLI1, but not of FLI1 was detected. In addition, interaction of EWS-FLI1 with EWS and FLI1 was observed. GST pull-down assays and immunoprecipitation experiments largely confirmed these results. The EWS N-terminal domain present in both EWS and EWS-FLI1 was found to contribute to homotypic and heterotypic interactions of these proteins. However, in the context of germline EWS, the presence of the whole or part of the C-terminal RNA-binding domain greatly supported the self-association potential of the protein. Involvement of an RNA component in EWS oligomerization was confirmed by sensitivity of the corresponding GST pull-down assay to RNaseA treatment. In contrast, EWS-FLI1 was able to self-associate and also bind to FLI1 via its C-terminal domain, which comprises the FLI1 DNA-binding motif. Accordingly, the EWS-FLI1 interaction was not disrupted by RNaseA treatment. Despite its potential to oligomerize, EWS-FLI1 bound to a tandem ets-binding site of the TGFβ type II receptor promoter as a monomer. Therefore, the functional consequences of homo- and hetero-oligomerization of EWS and EWS-FLI1 proteins remain to be elucidated. More... »

PAGES

6819-6829

References to SciGraph publications

  • 2003-01-09. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma in ONCOGENE
  • 1998-08-06. Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II in ONCOGENE
  • 2001-02-01. PDGF-C is an EWS/FLI induced transforming growth factor in Ewing family tumors in ONCOGENE
  • 2001-03-20. Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G1regulatory genes in BRITISH JOURNAL OF CANCER
  • 2001-07-12. A repetitive element containing a critical tyrosine residue is required for transcriptional activation by the EWS/ATF1 oncogene in ONCOGENE
  • 2001-05-31. Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2 and c-Myc expression in ONCOGENE
  • 1997-01. Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides in JOURNAL OF NEURO-ONCOLOGY
  • 2000-12-18. Regulation of Ets function by protein–protein interactions in ONCOGENE
  • 1997-12. EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic in NATURE GENETICS
  • 1998-06-25. Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains in ONCOGENE
  • 1999-09-30. Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity in ONCOGENE
  • 1994-02. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS–family transcription factor, ERG in NATURE GENETICS
  • 2000-12-18. Proteins of the ETS family with transcriptional repressor activity in ONCOGENE
  • 1998-10-21. EWS/FLI1 up regulates mE2-C, a cyclin-selective ubiquitin conjugating enzyme involved in cyclin B destruction in ONCOGENE
  • 1992-09. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours in NATURE
  • 2001-03-29. Phosphorylation of the EWS IQ domain regulates transcriptional activity of the EWS/ATF1 and EWS/FLI1 fusion proteins in ONCOGENE
  • 1999-10. Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein in NATURE GENETICS
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/sj.onc.1206810

    DOI

    http://dx.doi.org/10.1038/sj.onc.1206810

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1008836489

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/14534527


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    41 schema:description In Ewing's sarcoma family tumors, the ets transcription factor gene FLI1 is rearranged with one EWS allele resulting in coexpression of germline EWS and chimeric EWS-FLI1 proteins. Here, we investigated the potential of germline EWS, FLI1 and EWS-FLI1 to oligomerize. In two functional in vivo tests, fluorescence resonance energy transfer (FRET) and the mammalian two-hybrid (MTH) assay, self-association of EWS and EWS-FLI1, but not of FLI1 was detected. In addition, interaction of EWS-FLI1 with EWS and FLI1 was observed. GST pull-down assays and immunoprecipitation experiments largely confirmed these results. The EWS N-terminal domain present in both EWS and EWS-FLI1 was found to contribute to homotypic and heterotypic interactions of these proteins. However, in the context of germline EWS, the presence of the whole or part of the C-terminal RNA-binding domain greatly supported the self-association potential of the protein. Involvement of an RNA component in EWS oligomerization was confirmed by sensitivity of the corresponding GST pull-down assay to RNaseA treatment. In contrast, EWS-FLI1 was able to self-associate and also bind to FLI1 via its C-terminal domain, which comprises the FLI1 DNA-binding motif. Accordingly, the EWS-FLI1 interaction was not disrupted by RNaseA treatment. Despite its potential to oligomerize, EWS-FLI1 bound to a tandem ets-binding site of the TGFβ type II receptor promoter as a monomer. Therefore, the functional consequences of homo- and hetero-oligomerization of EWS and EWS-FLI1 proteins remain to be elucidated.
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