EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene

Ewing sarcoma-specific chromosomal translocations fuse the EWS gene to a su bset of ets transcription factor family members, most commonly the FLII gen e and Less frequently ERG, ETV1, E1A-F, or FEV, These fusion proteins art t hought to act as aberrant transcription factors that bind DNA through their Ets DNA binding domain. Recently, we have shown (K-B. Hahm et al., Nat. Ge net., 23: 222-227, 1999) that the transforming growth factor beta (TGB-beta ) type II receptor (TGF-beta RII), a putative tumor suppressor gene, is a t arget of the EWS-FLI1 fusion protein. Here, me also examined effects of EWS -ETV1 and EWS-ERG on expression of the TGF-beta RII gene. We show that rela tive to the control, NIH-3T3 cell lines stably transfected with the EWS-FLI 1, EWS-ERG, or EWS-ETV1 gene fusion ex-press reduced levels of TGF-beta RII . mRNA and protein, and that these cell lines have reduced TGF-beta sensiti vity, Cotransfection of these fusion genes and the TGF-beta RII promoter su ppresses TGF-beta RII promoter activity and also FLI1-, ERG-, or ETV1-induc ed promoter activity. These results indicate that transcriptional repressio n of TGF-beta RII is an important target of the EWS-FLI1, EWS-ERG, or EWS-E TV1 oncogene, and that EWS-ets fusion proteins may function as dominant neg ative forms of ets transcription factors.