10508522

pubmed:Citation

2

Chromosomal translocations resulting in the expression of chimaeric transcription factors are frequently observed in tumour cells, and have been suggested to be a common mechanism in human carcinogenesis. Ewing sarcoma and related peripheral primitive neuroectodermal tumours share recurrent translocations that fuse the gene EWSR1 (formerly EWS) from 22q-12 to FLI1 and genes encoding other ETS transcription factors (which bind DNA through the conserved ETS domain). It has been shown that transduction of the gene EWSR1-FLI1 (encoding EWS-FLI1 protein) can transform NIH3T3 cells, and that mutants containing a deletion in either the EWS domain or the DNA-binding domain in FLI1 lose this ability. This indicates that the EWS-FLI1 fusion protein may act as an aberrant transcription factor, but the exact mechanism of oncogenesis remains unknown. Because ETS transcription factors regulate expression of TGFBR2 (encoding the TGF-beta type II receptor, TGF-beta RII; Refs 9,14), a putative tumour suppressor gene, we hypothesized that TGFBR2 may be a target of the EWS-FLI1 fusion protein. We show here that Ewing sarcoma [corrected] (ES) cell lines with the EWSR1-FLI1 fusion have reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumours both express low or undetectable levels of TGFBR2 mRNA and protein product. Co-transfection of FLI1 and the TGFBR2 promoter induces promoter activity, whereas EWSR1-FLI1 leads to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppresses TGF-beta RII expression, whereas antisense to EWSR1-FLI1 in ES cell lines positive for this gene fusion restores TGF-beta RII expression. Furthermore, introduction of normal TGF-beta RII into ES cell lines restores TGF-beta sensitivity and blocks tumorigenicity. Our results implicate TGF-beta RII as a direct target of EWS-FLI1.

eng

IM

MEDLINE

1061-4036

Print

NLM

222-7

pubmed-meshheading:10508522-Animals, pubmed-meshheading:10508522-Cell Line, pubmed-meshheading:10508522-DNA-Binding Proteins, pubmed-meshheading:10508522-Gene Expression Regulation, pubmed-meshheading:10508522-Humans, pubmed-meshheading:10508522-Immunohistochemistry, pubmed-meshheading:10508522-Luciferases, pubmed-meshheading:10508522-Mice, pubmed-meshheading:10508522-Mice, Nude, pubmed-meshheading:10508522-Neuroblastoma, pubmed-meshheading:10508522-Oncogene Proteins, Fusion, pubmed-meshheading:10508522-Promoter Regions, Genetic, pubmed-meshheading:10508522-Protein-Serine-Threonine Kinases, pubmed-meshheading:10508522-Proto-Oncogene Protein c-fli-1, pubmed-meshheading:10508522-Proto-Oncogene Proteins, pubmed-meshheading:10508522-RNA, Messenger, pubmed-meshheading:10508522-RNA-Binding Protein EWS, pubmed-meshheading:10508522-Receptors, Transforming Growth Factor beta, pubmed-meshheading:10508522-Recombinant Fusion Proteins, pubmed-meshheading:10508522-Sarcoma, Ewing, pubmed-meshheading:10508522-Sequence Deletion, pubmed-meshheading:10508522-Trans-Activators, pubmed-meshheading:10508522-Transcription Factors, pubmed-meshheading:10508522-Transfection, pubmed-meshheading:10508522-Transforming Growth Factor beta, pubmed-meshheading:10508522-Tumor Cells, Cultured

Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein.

Journal Article