Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1 fusion protein

Ina Finkeltov, Scott Kuhn, Tova Glaser, Gila Idelman, John J. Wright, Charles Roberts, Haim Werner

    Research output: Contribution to journalArticle

    32 Scopus citations

    Abstract

    The EWS family of genes is involved in numerous chromosomal translocations that are characteristic of a variety of sarcomas. A recently described member of this group is desmoplastic small round cell tumor (DSRCT), which is characterized by a recurrent t(11;22)(p13;q12) translocation that fuses the 5′ exons of the EWS gene to the 3′ exons of the WT1 gene. The originally described chimera comprises exons 1-7 of EWS and exons 8-10 of WT1. We have previously reported that the WT1 protein represses the expression of the IGF-I receptor gene, whereas the EWS(1-7)-WT1(8-10) fusion protein activates IGF-I receptor gene expression. It has recently become apparent that EWS-WT1 chimeras produced in DSCRT are heterogeneous as a result of fusions of different regions of the EWS gene to the WT1 gene. We have recently characterized additional EWS-WT1 translocations that involve the juxtaposition of EWS exons 7 or 8 to WT1 exon 8, and an EWS-WT1 chimera that lacks EWS exon 6. The chimeric transcription factors encoded by these various translocations differ in their DNA-binding characteristics and their ability to transactivate the IGF-I receptor promoter. These data suggest that the molecular pathology of DSRCT is more complex than previously appreciated, and that this diversity may provide the foundation for predictive genotype-phenotype correlations in the future.

    Original languageEnglish (US)
    Pages (from-to)1890-1898
    Number of pages9
    JournalOncogene
    Volume21
    Issue number12
    DOIs
    StatePublished - Jan 1 2002

    Keywords

    • DSRCT
    • EWS
    • IGF-I receptor
    • Translocation
    • WT1

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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