Aberrant TGF-beta function has been implicated in the pathogenesis of many diseases, and it has also suggested that diminished responsiveness to TGF-beta may contribute to the process of malignant transformation. This decreased responsiveness to TGF-beta could be caused by defects not only in TGF-beta expression of activation, but also by defects in the regulation of TGF-beta receptors. Ewing sarcoma (ES) specific chromosomal translocations fuse the EWS gene to a subset of the ets transcription factor family, the FLI1, ERG, or ETV1 gene. EWS-FLI1, EWS-EGR, and EWS-ETV1 are thought to act as aberrant transcription factors that bind DNA through their ETS DNA binding domains. Since ets transcription factors regulate expression of the TGF-beta type II receptor (TGF-beta RII), a putative tumor suppressor gene, we hypothesized that TGF-beta RII may be a target of these fusion proteins. We show that ES cell lines with the EWS-FLI1 gene fusion have reduced TGF-beta sensitivity, and that fusion positive ES cells and primary tumors both express low to undetectable levels of TGF-beta RII mRNA and protein. Co-transfection of the FLI1 gene and the TGF-b RII promoter induces promoter activity, while the EWS-FLI1 gene leads to suppression of TGF-beta RII promoter activity and also FLI1-induced promoter activity. Introduction of EWS-FLI1, EWS-ERG, or EWS-ETV1 in cells without the EWS-FLI1 gene fusion suppresses TGF-beta RII expression, whereas antisense EWS-FLI1 in ES cell lines with the EWS- FLI1 gene fusion restores its expression. Furthermore, introduction of normal TGF-beta RII into ES cell line restores TGF-b sensitivity and blocks tumorigenicity. These results indicate that transcriptional repression of TGF-beta RII is a major target of the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene. - ets family proto-oncogenes, promoter, Transcription, Transcription Factors, Transforming growth factor-beta, Tumorigenicity,

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005617-11
Application #
6289130
Study Section
Special Emphasis Panel (LCRC)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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