EWS/FLI1 oncogene activates caspase 3 transcription and triggers apoptosis in vivo.
EWS/FLI1 is a fusion gene product generated by a chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS/FLI1 encodes an aberrant transcription factor with oncogenic properties in vitro. Paradoxically, expression of EWS/FLI1 in nontransformed primary cells results in apoptosis, but the exact mechanism remains unclear. In primary mouse embryonic fibroblasts derived from conditional EWS/FLI1 knock-in embryos, expression of EWS/FLI1 resulted in apoptosis with concomitant increase in the endogenous Caspase 3 (Casp3) mRNA. EWS/FLI1 directly bound and activated the CASP3 promoter, whereas small interfering RNA-mediated knockdown of EWS/FLI1 led to a marked decrease in CASP3 transcripts in Ewing sarcoma cell lines. Ectopic expression of EWS/FLI1 resulted in an increased expression of CASP3 protein in heterologous cell lines. Importantly, expression of EWS/FLI1 in the mouse triggered an early onset of apoptosis in kidneys and acute lethality. These findings suggest that EWS/FLI1 induces apoptosis, at least partially, through the activation of CASP3 and show the cell context-dependent roles of EWS/FLI1 in apoptosis and tumorigenesis.
Pubmed ID: 20103643 RIS Download
Animals | Antineoplastic Agents, Hormonal | Apoptosis | Base Sequence | Binding Sites | Caspase 3 | Cell Line, Tumor | Cells, Cultured | Embryo, Mammalian | Fibroblasts | Gene Expression | Heart | Humans | Kidney | Lung | Mice | Mice, Transgenic | Myocardium | Oncogene Proteins, Fusion | Pancreas | Promoter Regions, Genetic | Protein Binding | Proto-Oncogene Protein c-fli-1 | RNA Interference | RNA-Binding Protein EWS | Tamoxifen | Transcription, Genetic