Abstract
EWS-WT1 is a chimeric transcription factor resulting from fusion of the N-terminal domain of the Ewing sarcoma gene EWS to the three C-terminal zinc fingers of the Wilms tumor suppressor WT1. This translocation underlies desmoplastic small round cell tumor (DSRCT), which is noted for the abundance of reactive stroma surrounding islets of tumor cells, suggestive of paracrine signals contributing to tumor cell proliferation. Hybridization to high-density oligonucleotide microarrays can be used to identify targets of EWS-WT1. Expression of EWS-WT1 from a tetracycline-regulated promoter leads to the induction of growth-associated genes, of which the most remarkable is the beta-chain of the interleukin-2/15 receptor (IL-2/15Rbeta). Potent transcriptional activation by the chimeric protein maps to two bindings sites within the IL-2/15Rbeta promoter. Analysis of primary DSRCT tumor specimens demonstrates high levels of IL-2/15Rbeta within the tumor cells, along with expression of IL-2 and IL-15 by the abundant hyperplastic endothelial cells within the reactive stroma. Activation of this cytokine signaling pathway is consistent with the nuclear localization of its downstream effectors, phosphorylated STAT3 and STAT5. These observations suggest that the transcriptional induction of a cytokine receptor by a tumor-associated translocation product enables a proliferative response of epithelial cancer cells to ligands secreted by the surrounding stroma.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abdominal Neoplasms / genetics
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Abdominal Neoplasms / metabolism
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Abdominal Neoplasms / pathology
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Carcinoma, Small Cell / genetics
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Carcinoma, Small Cell / metabolism
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Carcinoma, Small Cell / pathology
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DNA-Binding Proteins / metabolism
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Electrophoretic Mobility Shift Assay
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Gene Expression Regulation, Neoplastic*
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Humans
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Immunohistochemistry
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Interleukin-2 / metabolism
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Interleukin-2 Receptor beta Subunit
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Interleukin-5 / metabolism
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Janus Kinase 1
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Janus Kinase 3
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Male
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Milk Proteins*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Promoter Regions, Genetic
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interleukin / biosynthesis
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Receptors, Interleukin / genetics*
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Receptors, Interleukin / metabolism
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Receptors, Interleukin-15
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Receptors, Interleukin-2 / metabolism
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Response Elements / genetics
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Signal Transduction
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Trans-Activators / metabolism
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Transcription, Genetic
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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EWS1-WT1 fusion protein, human
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IL15RA protein, human
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IL2RB protein, human
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Interleukin-2
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Interleukin-2 Receptor beta Subunit
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Interleukin-5
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Milk Proteins
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Oncogene Proteins, Fusion
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-15
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Receptors, Interleukin-2
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Trans-Activators
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK3 protein, human
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Janus Kinase 1
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Janus Kinase 3