Abstract
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.
MeSH terms
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Adenovirus E1A Proteins / genetics
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Alternative Splicing
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Amino Acid Sequence
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Binding Sites
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Carrier Proteins / metabolism*
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Cell Cycle Proteins
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Heterogeneous-Nuclear Ribonucleoproteins
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Humans
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Hyaluronan Receptors / genetics
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Leukemia, Myeloid / genetics*
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Molecular Sequence Data
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Neoplasm Proteins*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Precipitin Tests
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Protein Binding
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RNA Polymerase II / metabolism*
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RNA Splicing*
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RNA-Binding Protein FUS
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RNA-Binding Proteins*
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Recombinant Proteins / metabolism
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Repressor Proteins*
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism*
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Sequence Deletion
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Serine-Arginine Splicing Factors
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Two-Hybrid System Techniques
Substances
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Adenovirus E1A Proteins
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Carrier Proteins
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Cell Cycle Proteins
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Heterogeneous-Nuclear Ribonucleoproteins
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Hyaluronan Receptors
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Peptide Fragments
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RNA-Binding Protein FUS
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RNA-Binding Proteins
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Recombinant Proteins
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Repressor Proteins
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Ribonucleoproteins
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SRSF10 protein, human
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TLS-ERG fusion protein, human
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Serine-Arginine Splicing Factors
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RNA Polymerase II