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- Title
Transforming activity of EWS/FLI is not strictly dependent upon DNA-binding activity.
- Authors
Jaishankar, S; Zhang, J; Roussel, M F; Baker, S J
- Abstract
In approximately 85% of Ewing sarcomas, chromosomal translocations give rise to the chimeric gene EWS/FLI, encoding the N-terminus of the RNA binding protein EWS fused to the DNA-binding domain of the ETS protein FLI-1. EWS/FLI is a stronger transcriptional activator than wild-type FLI-1, although both proteins bind to the same DNA sequences in vitro. In addition, EWS/FLI, but not FLI-1, is a transforming oncogene in NIH3T3 fibroblasts. EWS/FLI is thought to transform through its ability to deregulate the expression of target genes. We introduced several point mutations into the ETS domain of EWS/FLI that abolished DNA-binding activity. Although two of these mutations disrupted the transforming activity of EWS/FLI, one mutated protein containing a substitution of isoleucine 347 with glutamic acid (I347E) retained diminished transforming activity. In addition, EWS/FLI I347E did not activate expression of the endogenous EWS/FLI target gene manic fringe (MFNG). These studies demonstrate that a portion of the oncogenic activity of EWS/FLI is independent of FLI DNA-binding activity.
- Subjects
TRANSFORMING growth factors; SARCOMA; GENES; DNA; CELL receptors
- Publication
Oncogene, 1999, Vol 18, Issue 40, p5592
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1202940