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The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1

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Abstract

The Brn-3 family of POU (Pit-Oct-Unc) homeodomain transcription factors regulate differentiation of neuronal cell types. The transcriptional activator Brn-3a is expressed in Ewing's sarcomas, which also express characteristic chimaeric proteins as a consequence of fusion of the TET family gene EWS to one of several ETS genes. We have previously demonstrated a physical interaction between Brn-3a and EWS proteins, and show here that the C-terminal POU domain but not N-terminal activation domain of Brn-3a can interact in vitro with the RNA-binding domain of EWS. Likely due to POU domain homology, the related factor Brn-3b can also interact with EWS, but to a lesser extent than Brn-3a. Importantly, Brn-3a but not Brn-3b interacts in vitro with chimaeric EWS/Fli-1, EWS/ATF-1 and EWS/ERG proteins. Furthermore, overexpression of EWS/Fli-1 but not EWS or Fli-1 inhibits Brn-3a-associated growth arrest and neurite outgrowth in neuronal cells, and specifically inhibits Brn-3a-dependent activation of p21 and SNAP-25 transcription. In contrast, upregulation of Bcl-2 expression and inhibition of apoptosis by Brn-3a is antagonized more by EWS than by EWS/Fli-1. These data demonstrate that oncogenic rearrangement of EWS to produce EWS/Fli-1 may enhance the antiapoptotic effect of Brn-3a and inhibit its ability to promote neuronal differentiation.

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Acknowledgements

The funding for this study was provided by BBSRC and MRC. We are very grateful to C Denny (UCLA), O Delattre (Paris), T Okamoto (Nagoya), L Yang (Washington), K Lee (Hong Kong), W el-Deiry (Howard Hughes), and SJ Kim (Bethesda) for plasmids, and to Jo Buddle, ICH, for assistance with FACS analysis.

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  1. G Ruth Thomas

    Present address: Cancer Research Institute, UCSF, Box 0128, San Francisco, CA, 94143-0128, USA

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  1. Medical Molecular Biology Unit, Institute of Child Health, UCL, 30 Guilford Street, London, WC1N 1EH, UK

    Duncan M Gascoyne, G Ruth Thomas & David S Latchman

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  1. Duncan M Gascoyne
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  2. G Ruth Thomas
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Correspondence to Duncan M Gascoyne.

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Gascoyne, D., Thomas, G. & Latchman, D. The effects of Brn-3a on neuronal differentiation and apoptosis are differentially modulated by EWS and its oncogenic derivative EWS/Fli-1. Oncogene 23, 3830–3840 (2004). https://doi.org/10.1038/sj.onc.1207497

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