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IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.

Cironi L, Riggi N, Provero P, Wolf N, Suvà ML, Suvà D, Kindler V, Stamenkovic I - PLoS ONE (2008)

Bottom Line: 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.However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Pathology, Institute of Pathology CHUV, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

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.

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Related in: MedlinePlus

Venn diagrams indicating the extent of overlap of the transcription profiles of MPCs expressing the three ESFT- associated fusion proteins, ERG-1, FLI-1, the EWS-FLI-1 R340N mutant and the AML-associated FUS-ERG fusion protein.A white asterisk marks the areas where Igf1 is commonly present.
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pone-0002634-g005: Venn diagrams indicating the extent of overlap of the transcription profiles of MPCs expressing the three ESFT- associated fusion proteins, ERG-1, FLI-1, the EWS-FLI-1 R340N mutant and the AML-associated FUS-ERG fusion protein.A white asterisk marks the areas where Igf1 is commonly present.

Mentions: Transcriptional changes were analysed 36 hours and 4 days following infection, when expression of all of the fusion proteins and that of the corresponding wild type ets family proteins was comparable. No significant difference in the gene expression profile induced by the various fusion genes at 36 hours and 4 days was observed (data not shown). The number of genes observed to be induced and repressed differed among cells expressing the three fusion proteins, with a higher number of genes being affected by EWS-FLI-1 and FUS-ERG than by EWS-ERG. Using a 5% false discovery rate, cells expressing EWS-ERG displayed 67 repressed and 144 induced genes, whereas EWS-FLI-1 and FUS-ERG expressing cells had 199 and 172 repressed and 250 and 208 induced transcripts, respectively (Table S1, Figure 5).


IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.

Cironi L, Riggi N, Provero P, Wolf N, Suvà ML, Suvà D, Kindler V, Stamenkovic I - PLoS ONE (2008)

Venn diagrams indicating the extent of overlap of the transcription profiles of MPCs expressing the three ESFT- associated fusion proteins, ERG-1, FLI-1, the EWS-FLI-1 R340N mutant and the AML-associated FUS-ERG fusion protein.A white asterisk marks the areas where Igf1 is commonly present.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2481291&req=5

pone-0002634-g005: Venn diagrams indicating the extent of overlap of the transcription profiles of MPCs expressing the three ESFT- associated fusion proteins, ERG-1, FLI-1, the EWS-FLI-1 R340N mutant and the AML-associated FUS-ERG fusion protein.A white asterisk marks the areas where Igf1 is commonly present.
Mentions: Transcriptional changes were analysed 36 hours and 4 days following infection, when expression of all of the fusion proteins and that of the corresponding wild type ets family proteins was comparable. No significant difference in the gene expression profile induced by the various fusion genes at 36 hours and 4 days was observed (data not shown). The number of genes observed to be induced and repressed differed among cells expressing the three fusion proteins, with a higher number of genes being affected by EWS-FLI-1 and FUS-ERG than by EWS-ERG. Using a 5% false discovery rate, cells expressing EWS-ERG displayed 67 repressed and 144 induced genes, whereas EWS-FLI-1 and FUS-ERG expressing cells had 199 and 172 repressed and 250 and 208 induced transcripts, respectively (Table S1, Figure 5).

Bottom Line: 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.However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Pathology, Institute of Pathology CHUV, University of Lausanne, Lausanne, Switzerland.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus