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 subset of ets transcription factor family members, most commonly the FLI1 gene and less frequently ERG, ETV1, E1A-F, or FEV. These fusion proteins are thought 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. Genet., 23: 222-227, 1999) that the transforming growth factor beta (TGF-beta) type II receptor (TGF-beta RII), a putative tumor suppressor gene, is a target of the EWS-FLI1 fusion protein. Here, we also examined effects of EWS-ETV1 and EWS-ERG on expression of the TGF-beta RII gene. We show that relative to the control, NIH-3T3 cell lines stably transfected with the EWS-FLI1, EWS-ERG, or EWS-ETV1 gene fusion express reduced levels of TGF-beta RII mRNA and protein, and that these cell lines have reduced TGF-beta sensitivity. Cotransfection of these fusion genes and the TGF-beta RII promoter suppresses TGF-beta RII promoter activity and also FLI1-, ERG-, or ETV1-induced promoter activity. These results indicate that transcriptional repression of TGF-beta RII is an important target of the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene, and that EWS-ets fusion proteins may function as dominant negative forms of ets transcription factors.
Im
Y H
YH
Laboratory of Cell Regulation and Carcinogenesis, DBS, National Cancer Institute, Bethesda, Maryland 20892-5055, USA.
Kim
H T
HT
Lee
C
C
Poulin
D
D
Welford
S
S
Sorensen
P H
PH
Denny
C T
CT
Kim
S J
SJ
D016475:3T3 Cells; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034802:RNA-Binding Protein EWS; D011869:Radioligand Assay; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C072312:ERG protein, human; C122140:EWS-ETV1 fusion protein, human; C106031:EWS-FLI fusion protein; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D016212:Transforming Growth Factor beta; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II