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

Hahm, KB; Cho, K; Lee, C; Im, YH; Chang, J; Choi, SG; Sorensen, PH; Thiele, CJ; Kim, SJ
Nature genetics, 23(2):222-227, 1999
Journal Title
Nature genetics
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.
MeSH terms
AnimalsCell LineDNA-Binding Proteins/geneticsGene Expression Regulation/drug effectsHumansImmunohistochemistryLuciferases/geneticsLuciferases/metabolismMiceMice, NudeNeuroblastoma/geneticsNeuroblastoma/metabolismNeuroblastoma/pathologyOncogene Proteins, Fusion/geneticsOncogene Proteins, Fusion/physiology*Promoter Regions, Genetic/geneticsProtein-Serine-Threonine KinasesProto-Oncogene Protein c-fli-1Proto-Oncogene Proteins*RNA, Messenger/geneticsRNA, Messenger/metabolismReceptors, Transforming Growth Factor beta/genetics*Recombinant Fusion Proteins/geneticsRecombinant Fusion Proteins/metabolismSarcoma, Ewing's/geneticsSarcoma, Ewing's/metabolismSarcoma, Ewing's/pathologySequence DeletionTrans-Activators/geneticsTranscription Factors/geneticsTranscription Factors/physiology*TransfectionTransforming Growth Factor beta/pharmacologyTumor Cells, Cultured/drug effectsTumor Cells, Cultured/metabolism
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Journal Papers > School of Medicine / Graduate School of Medicine > Gastroenterology
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함, 기백
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