Abstract
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Neoplasms / genetics*
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cell Adhesion
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Gene Expression Regulation, Neoplastic*
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Humans
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Keratin-17 / genetics*
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Keratin-17 / metabolism*
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Mice
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Mice, Nude
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Proto-Oncogene Protein c-fli-1 / genetics
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Proto-Oncogene Protein c-fli-1 / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA-Binding Protein EWS / genetics
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RNA-Binding Protein EWS / metabolism
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Sarcoma, Ewing / genetics*
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Sarcoma, Ewing / metabolism
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Sarcoma, Ewing / pathology
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Signal Transduction
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Zinc Finger Protein GLI1
Substances
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EWS-FLI fusion protein
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GLI1 protein, human
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Keratin-17
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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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Transcription Factors
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Zinc Finger Protein GLI1
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Proto-Oncogene Proteins c-akt