EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis In vivo

EJ Sohn, H Li, K Reidy, LF Beers, BL Christensen… - Cancer research, 2010 - AACR
EJ Sohn, H Li, K Reidy, LF Beers, BL Christensen, SB Lee
Cancer research, 2010AACR
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 …
Abstract
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. Cancer Res; 70(3); 1154–63
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