Article: article from journal or magazin.
IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.
Publication Status: epublish
BACKGROUND: The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin. METHODOLOGY/PRINCIPAL FINDINGS: To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression. CONCLUSION/SIGNIFICANCE: Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis.
Animals, Gene Expression Profiling, Gene Expression Regulation, Humans, Insulin-Like Growth Factor I/metabolism, Mesenchymal Stem Cells/cytology, Mesenchymal Stem Cells/metabolism, Mice, Mice, Inbred C57BL, Models, Biological, Oncogene Proteins, Fusion/chemistry, Oncogene Proteins, Fusion/metabolism, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Protein c-fli-1/chemistry, Proto-Oncogene Protein c-fli-1/metabolism, RNA-Binding Protein FUS/metabolism, Transcription Factors/metabolism
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