EWS.Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing.
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| Abstract |
Ewing's sarcoma displays a characteristic chromosomal translocation that results in fusion of the N-terminal domain of the Ewing's sarcoma protein (EWS) to the C-terminal DNA-binding domain of the ETS family transcription factor Fli-1 (Friend leukemia integration-1). EWS possesses structural motifs suggesting a role in transactivation as well as RNA binding. We demonstrate that wild-type EWS protein functions as an adapter molecule coupling transcription to RNA splicing by binding to hyperphosphorylated RNA polymerase II through the N-terminal domain of EWS and recruiting serine-arginine (SR) splicing factors through the C-terminal domain of EWS. The oncogenic EWS.Fli-1 fusion protein retains the ability to bind to hyperphosphorylated RNA polymerase II but lacks the ability to recruit SR proteins because of replacement of the C-terminal domain of EWS by Fli-1. In an in vivo splicing assay, the EWS.Fli-1 fusion protein inhibits SR protein-mediated E1A pre-mRNA splicing in a dominant-negative manner. These results indicate that EWS.Fli-1 interferes with the normal function of EWS and implicate uncoupling of gene transcription from RNA splicing in the pathogenesis of Ewing's sarcoma.
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| Authors | L Yang, H A Chansky, D D Hickstein |
| Journal | The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 48 Pg. 37612-8 (Dec 01 2000) ISSN: 0021-9258 [Print] United States |
| PMID | 10982800 (Publication Type: Journal Article) |
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