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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

Authors

  • Sohn EJ
  • Li H
  • Reidy K
  • Beers LF
  • Christensen BL
  • Lee SB

Journal

Cancer research

Publication Data

February 1, 2010

Associated Grants

  • Agency: Intramural NIH HHS, Id: ZIA DK056003-05

Mesh Terms

  • 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