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

Abstract
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.
AuthorsK B Hahm, K Cho, C Lee, Y H Im, J Chang, S G Choi, P H Sorensen, C J Thiele, S J Kim
JournalNature genetics (Nat Genet) Vol. 23 Issue 2 Pg. 222-7 (Oct 1999) ISSN: 1061-4036 [Print] United States
PMID10508522 (Publication Type: Journal Article)
Chemical References
  • DNA-Binding Proteins
  • EWS-FLI fusion protein
  • Fli1 protein, mouse
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA-Binding Protein EWS
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Luciferases
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
Topics
  • Animals
  • Cell Line
  • DNA-Binding Proteins (genetics)
  • Gene Expression Regulation (drug effects)
  • Humans
  • Immunohistochemistry
  • Luciferases (genetics, metabolism)
  • Mice
  • Mice, Nude
  • Neuroblastoma (genetics, metabolism, pathology)
  • Oncogene Proteins, Fusion (genetics, physiology)
  • Promoter Regions, Genetic (genetics)
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins
  • RNA, Messenger (genetics, metabolism)
  • RNA-Binding Protein EWS
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta (genetics)
  • Recombinant Fusion Proteins (genetics, metabolism)
  • Sarcoma, Ewing (genetics, metabolism, pathology)
  • Sequence Deletion
  • Trans-Activators (genetics)
  • Transcription Factors (genetics, physiology)
  • Transfection
  • Transforming Growth Factor beta (pharmacology)
  • Tumor Cells, Cultured (drug effects, metabolism)

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