Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein.
The translocation liposarcoma protein TLS has recently been shown to function as an adapter molecule coupling gene transcription to RNA splicing. Here we demonstrate that YB-1, a protein known to play important roles in transcription and translation, interacts with the COOH-terminal domains of TLS and the structurally related Ewing's sarcoma protein EWS. Through this interaction, YB-1 is recruited to RNA polymerase II and promotes splicing of E1A pre-mRNA to the 13S isoform. This splicing function of YB-1 is inhibited by exogenous TLS/ERG or EWS/Fli-1 fusion proteins, which bind to RNA polymerase II but fail to recruit the YB-1 protein. In Ewing's sarcoma cells that express endogenous EWS/Fli-1, this linkage between YB-1 and RNA Pol II via EWS (or TLS) was found to be defective. Together, these results suggest that TLS and EWS fusion proteins may contribute to malignant transformation through disruption of RNA splicing mediated by TLS- and EWS-binding proteins such as YB-1.
Chansky
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HA
Department of Orthopedics, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Hu
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M
Hickstein
D D
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Yang
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L
D016475:3T3 Cells; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D019556:COS Cells; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D051379:Mice; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051789:Proto-Oncogene Protein c-fli-1; D012319:RNA Polymerase II / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D012261:Ribonucleoproteins / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology*; D051840:Y-Box-Binding Protein 1
D017500:Adenovirus E1A Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C106031:EWS-FLI fusion protein; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D012261:Ribonucleoproteins; C107302:TLS-ERG fusion protein, human; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D012319:RNA Polymerase II