Abstract
Ewings sarcoma and primitive neuroectodermal tumors (ES/PNET) are characterized by the fusion of the N-terminus of the EWS gene to the C-terminus of a member of the ETS family of transcription factors. While such fusion proteins are thought to play dominant oncogenic roles, it is unlikely that a single genetic alteration by itself will support cellular transformation. Given that EWS/FLI1 is only able to transform immortalized 3T3 fibroblasts and that 30% of ES/PNET tumors contain a homozygous deletion of the p16 locus, it is likely that other genetic events are required for EWS/FLI1 oncogenesis. Here we describe a complementary mechanism utilized in the establishment ES/PNET tumors. EWS/FLI1 has the capacity to induce apoptosis and growth arrest in normal MEFs. Such effects prevent the establishment of stable expression of the protein in these cells. When expressed in p16, p19ARF, or p53 deficient MEFs, the apoptotic and growth arrest effects are attenuated, creating a environment permissive for stable expression of the protein. While loss of a single tumor suppressor is sufficient to establish expression of EWS/FLI1, cellular transformation requires further genetic perturbation.
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Acknowledgements
The authors would like to thank T Jacks, R DePinho, and M Roussel for providing the MEF cell lines from p53−/−, p16−/− and wild type, and ARF−/− knockout mice, respectively. We would like to thank Steve Hebert for technical assistance in the performing of the mouse tumorigenic assays and Myles Brown for providing the SV40 Large T antigen. We appreciate the thoughtful discussion and critical manuscript review of David Chang, Scott Maul, Mike Teitell, and Scott Welford. This work was funded by a grant from the National Cancer Institute (CA 87771).
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Deneen, B., Denny, C. Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation. Oncogene 20, 6731–6741 (2001). https://doi.org/10.1038/sj.onc.1204875
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DOI: https://doi.org/10.1038/sj.onc.1204875
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