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Junction region of EWS-FLI1 fusion protein has a dominant negative effect in Ewing's sarcoma in vitro.

AbstractBACKGROUND:
Ewing's sarcoma is a malignancy characterized by a specific 11:22 chromosomal translocation which generates a novel EWS-FLI1 fusion protein functioning as an aberrant transcription factor. In the present study, we have further characterized the junction region of the EWS-FLI1 fusion protein.
METHODS:
In-silico model of EWS-FLI1 fusion protein was analysed for ligand binding sites, and a putative region (amino acid (aa) 251-343 of the type 1 fusion protein) in the vicinity of the fusion junction was cloned and expressed using bacterial expression. The recombinant protein was characterized by Circular Dichroism (CD). We then expressed aa 251-280 ectopically in Ewing's sarcoma cell-line and its effect on cell proliferation, tumorigenicity and expression of EWS-FLI1 target genes were analysed.
RESULTS:
Our modelling analysis indicated that Junction region (aa 251-343) encompasses potential ligand biding sites in the EWS-FLI1 protein and when expressed in bacteria was present as soluble form. Ectopically expressing this region in Ewing's sarcoma cells inhibited tumorigenicity, and EWS-FLI1 target genes indicating a dominant negative biological effect.
CONCLUSIONS:
Junction region can be exploited further as target for drug development in future to specifically target EWS-FLI1 in Ewing's Sarcoma.
AuthorsBabu Jully, Ramshankar Vijayalakshmi, Gopisetty Gopal, Kesavan Sabitha, Thangarajan Rajkumar
JournalBMC cancer (BMC Cancer) Vol. 12 Pg. 513 (Nov 12 2012) ISSN: 1471-2407 [Electronic] England
PMID23145994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • EWS-FLI fusion protein
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins
  • MYC protein, human
  • Oncogene Proteins, Fusion
  • Peptides
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins c-myc
  • RNA-Binding Protein EWS
  • Recombinant Proteins
  • Transcription Factors
  • Zebrafish Proteins
  • Cyclin D1
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
Topics
  • Amino Acid Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Circular Dichroism
  • Cyclin D1 (genetics, metabolism)
  • Enhancer of Zeste Homolog 2 Protein
  • Epithelial-Mesenchymal Transition (genetics)
  • Gene Expression Regulation, Neoplastic
  • Homeobox Protein Nkx-2.2
  • Homeodomain Proteins (genetics, metabolism)
  • Humans
  • Immunoblotting
  • MCF-7 Cells
  • Molecular Sequence Data
  • Oncogene Proteins, Fusion (chemistry, genetics, metabolism)
  • Peptides (genetics, metabolism)
  • Polycomb Repressive Complex 2 (genetics, metabolism)
  • Proto-Oncogene Protein c-fli-1 (chemistry, genetics, metabolism)
  • Proto-Oncogene Proteins c-myc (genetics, metabolism)
  • RNA-Binding Protein EWS (chemistry, genetics, metabolism)
  • Recombinant Proteins (chemistry, metabolism)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcoma, Ewing (genetics, metabolism, pathology)
  • Transcription Factors (genetics, metabolism)
  • Transfection
  • Zebrafish Proteins

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