Chansky H A, Hu M, Hickstein D D, Yang L
Department of Orthopedics, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Cancer Res. 2001 May 1;61(9):3586-90.
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.
易位性脂肪肉瘤蛋白TLS最近被证明作为一种衔接分子，将基因转录与RNA剪接偶联起来。在此，我们证明了YB-1（一种已知在转录和翻译中发挥重要作用的蛋白质）与TLS的羧基末端结构域以及结构相关的尤文肉瘤蛋白EWS相互作用。通过这种相互作用，YB-1被招募到RNA聚合酶II，并促进E1A前体mRNA剪接为13S异构体。YB-1的这种剪接功能受到外源性TLS/ERG或EWS/Fli-1融合蛋白的抑制，这些融合蛋白与RNA聚合酶II结合，但无法招募YB-1蛋白。在表达内源性EWS/Fli-1的尤文肉瘤细胞中，发现YB-1与RNA聚合酶II通过EWS（或TLS）的这种联系存在缺陷。总之，这些结果表明，TLS和EWS融合蛋白可能通过破坏由TLS和EWS结合蛋白（如YB-1）介导的RNA剪接而导致恶性转化。
