Abstract
FUS (also called TLS), EWSR1 and TAF15 (also called TAF2N) are related genes involved in tumor type-specific fusion oncogenes in human malignancies. The FUS-DDIT3 fusion oncogene results from a t(12;16)(q13;p11) chromosome translocation and has a causative role in the initiation of myxoid/round cell liposarcomas (MLS/RCLS). The FUS-DDIT3 protein induces increased expression of the CAAT/enhancer-binding protein (C/EBP) and nuclear factor-kappaB (NF-kappaB)-controlled gene IL8, and the N-terminal FUS part is required for this activation. Chromatin immunoprecipitation analysis showed that FUS-DDIT3 binds the IL8 promoter. Expression studies of the IL8 promoter harboring a C/EBP-NF-kappaB composite site pinpointed the importance of NF-kappaB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-kappaB family. The nuclear factor NFKBIZ colocalizes with FUS-DDIT3 in nuclear structures, and immunoprecipitation experiments showed that FUS-DDIT3 binds the C-terminal of NFKBIZ. We also report that additional NF-kappaB-controlled genes are upregulated at the mRNA level in FUS-DDIT3-expressing cell lines and they can be induced by NFKBIZ. Taken together, the results indicate that FUS-DDIT3 deregulates some NF-kappaB-controlled genes through interactions with NFKBIZ. Similar mechanisms may be a part of the transformation process in other tumor types carrying FUS, EWSR1 and TAF15 containing fusion oncogenes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / biosynthesis
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Acute-Phase Proteins / genetics
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Adaptor Proteins, Signal Transducing
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Binding Sites
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CCAAT-Enhancer-Binding Proteins / physiology
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Cell Line, Tumor / metabolism
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Cell Nucleus / metabolism
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Cell Nucleus / ultrastructure
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Fibrosarcoma / metabolism
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Fibrosarcoma / pathology
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Humans
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I-kappa B Proteins
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics
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Interleukin-8 / biosynthesis
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Interleukin-8 / genetics*
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Lipocalin-2
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Lipocalins / biosynthesis
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Lipocalins / genetics
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Liposarcoma, Myxoid / genetics*
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Liposarcoma, Myxoid / pathology
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NF-kappa B / physiology*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Nuclear Proteins / physiology*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Promoter Regions, Genetic / genetics
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Protein Binding
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Protein Interaction Mapping
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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RNA-Binding Protein FUS / genetics
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RNA-Binding Protein FUS / physiology
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / physiology
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Transcription, Genetic
Substances
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Acute-Phase Proteins
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Adaptor Proteins, Signal Transducing
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CCAAT-Enhancer-Binding Proteins
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DDIT3 protein, human
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FUS-DDIT3 fusion protein, human
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I-kappa B Proteins
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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LCN2 protein, human
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Lipocalin-2
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Lipocalins
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NF-kappa B
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NFKBIZ protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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RNA-Binding Protein FUS
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Transcription Factor CHOP