title: Transcriptional regulation of IGF-I receptor gene expression by novel isoforms of the EWS-WT1 fusion protein.
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.
authors.affiliation: Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel.
authors.forename: Ina
authors.initials: I
authors.lastname: Finkeltov
authors.forename: Scott
authors.initials: S
authors.lastname: Kuhn
authors.forename: Tova
authors.initials: T
authors.lastname: Glaser
authors.forename: Gila
authors.initials: G
authors.lastname: Idelman
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Charles T
authors.initials: CT
authors.lastname: Roberts
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
mesh_terms: D024202:Electrophoretic Mobility Shift Assay; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured / Q000502:physiology*
chemical_list: C106032:EWS1-WT1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D008156:Luciferases; D017526:Receptor, IGF Type 1