The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts.
Ewing's sarcoma is associated with a fusion between the EWS and FLI1 genes, forming an EWS/FLI fusion protein. We developed a system for the identification of cooperative mutations in this tumor through expression of EWS/FLI in primary human fibroblasts. Gene expression profiling demonstrated that this system recapitulates many features of Ewing's sarcoma. EWS/FLI-expressing cells underwent growth arrest, suggesting that growth arrest-abrogating collaborative mutations may be required for tumorigenesis. Expression profiling identified transcriptional upregulation of p53, and the growth arrest was rescued by inhibition of p53. These data support a role for p53 as a tumor suppressor in Ewing's sarcoma and demonstrate the use of transcriptional profiling of model systems in the identification of cooperating mutations in human cancer.
Lessnick
Stephen L
SL
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Dacwag
Caroline S
CS
Golub
Todd R
TR
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005347:Fibroblasts / Q000166:cytology*; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000201:enzymology / Q000235:genetics; D013754:Tetracyclines; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D017931:DNA Primers; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D013754:Tetracyclines; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53