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Molecular and Cellular Biology, May 2000, p. 3345-3354, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

TLS-ERG Leukemia Fusion Protein Inhibits RNA Splicing Mediated by Serine-Arginine Proteins

Liu Yang,1,2 Lisa J. Embree,1,2 and Dennis D. Hickstein1,2,3,*

Medical Research Service, VA Puget Sound Health Care System, Seattle, Washington 98108,1 and Divisions of Oncology2 and Molecular Medicine,3 University of Washington School of Medicine, Seattle, Washington 98195

Received 25 October 1999/Returned for modification 1 December 1999/Accepted 16 February 2000

The translocation liposarcoma (TLS) gene is fused to the ETS-related gene (ERG) in human myeloid leukemia, resulting in the generation of a TLS-ERG protein. We demonstrate that both TLS and the TLS-ERG leukemia fusion protein bind to RNA polymerase II through the TLS N-terminal domain, which is retained in the fusion protein; however, TLS recruits members of the serine-arginine (SR) family of splicing factors through its C-terminal domain, whereas the TLS-ERG fusion protein lacks the ability to recruit SR proteins due to replacement of the C-terminal domain by the fusion partner ERG. In transient-transfection assays, the TLS-ERG fusion protein inhibits E1A pre-mRNA splicing mediated by these TLS-associated SR proteins (TASR), and stable expression of the TLS-ERG fusion protein in K562 cells alters the splicing profile of CD44 mRNA. These results suggest that TLS fusion proteins may lead to cellular abnormalities by interfering with the splicing of important cellular regulators.

* Corresponding author. Mailing address: Department of Medicine/Oncology, University of Washington School of Medicine, 1660 S. Columbian Way, GMR 151, Seattle, WA 98108. Phone: (206) 764-2705. Fax: (206) 764-2827. E-mail: dennishi{at}u.washington.edu.

Molecular and Cellular Biology, May 2000, p. 3345-3354, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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