1. Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors.
- Author
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Erkizan HV, Scher LJ, Gamble SE, Barber-Rotenberg JS, Sajwan KP, Üren A, and Toretsky JA
- Subjects
- Amino Acid Sequence, Cell Cycle Checkpoints, Cell Line, Tumor, Humans, Kinetics, Oncogene Proteins, Fusion antagonists & inhibitors, Oncogene Proteins, Fusion genetics, Peptide Library, Protein Binding, Proto-Oncogene Protein c-fli-1 antagonists & inhibitors, Proto-Oncogene Protein c-fli-1 genetics, RNA-Binding Protein EWS antagonists & inhibitors, RNA-Binding Protein EWS genetics, Recombinant Fusion Proteins antagonists & inhibitors, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Surface Plasmon Resonance, Transcriptional Activation, Oncogene Proteins, Fusion metabolism, Peptides metabolism, Proto-Oncogene Protein c-fli-1 metabolism, RNA-Binding Protein EWS metabolism, Sarcoma, Ewing pathology
- Abstract
Ewing tumor is driven by the oncogenic EWS-FLI1 fusion protein that functions as an aberrant transcription factor. The identification of EWS-FLI1 protein partners is essential to enhance its vulnerability as a therapeutic target. We utilized phage display library screening against recombinant EWS-FLI1 protein. We identified 27 unique Ewing sarcoma binding peptides. The cytotoxicity evaluation of these peptides with in EWS-FLI1 containing cell lines yielded one potent peptide called ESAP1 (TMRGKKKRTRAN). ESAP1 binds EWS-FLI1 with 0.202 micromolar affinity as measured in surface plasmon resonance. The minimal interaction region of ESAP1 is characterized and found that the lysine residues are critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 as well as disrupts cell cycle kinetics in Ewing Tumor cells. These findings provide both a novel experimental probe and a potential therapeutic scaffold for Ewing Tumor., (© 2011 Landes Bioscience)
- Published
- 2011
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