Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anti-Bacterial Agents / pharmacology
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Bone Neoplasms / enzymology
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Bone Neoplasms / genetics
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Cell Division / physiology
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Cell Survival / physiology
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Cell Transformation, Neoplastic
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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DNA Primers / chemistry
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Fibroblasts / cytology*
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Gene Expression Profiling
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Humans
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Infant, Newborn
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Mutation
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / physiology*
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Proto-Oncogene Protein c-fli-1
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RNA-Binding Protein EWS
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Retroviridae / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sarcoma, Ewing / enzymology
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Sarcoma, Ewing / genetics
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Tetracyclines
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Transcription Factors / physiology*
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Transfection
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Anti-Bacterial Agents
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DNA Primers
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EWS-FLI fusion protein
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Oncogene Proteins, Fusion
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Proto-Oncogene Protein c-fli-1
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RNA-Binding Protein EWS
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Tetracyclines
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Transcription Factors
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Tumor Suppressor Protein p53