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 functi on as an adapter molecule coupling gene transcription to RNA splicing. Here we demonstrate that YB-1, a protein known to play important roles in trans cription and translation, interacts with the COOH-terminal domains of TLS a nd the structurally related Ewing's sarcoma protein EWS. Through this inter action, 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 b y exogenous TLS/ERG or EWS/ Fli-1 fusion proteins, which bind to RNA polyme rase 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 th at TLS and EWS fusion proteins may contribute to malignant transformation t hrough disruption of RNA splicing mediated by TLS- and EWS-binding proteins such as YB-1.