The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ

Oncogene. 2009 Jan 15;28(2):270-8. doi: 10.1038/onc.2008.378. Epub 2008 Oct 13.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / biosynthesis
  • Acute-Phase Proteins / genetics
  • Binding Sites
  • CCAAT-Enhancer-Binding Proteins / physiology
  • Cell Line, Tumor / metabolism
  • Cell Nucleus / metabolism
  • Cell Nucleus / ultrastructure
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology
  • Humans
  • I-kappa B Proteins
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics*
  • Lipocalin-2
  • Lipocalins / biosynthesis
  • Lipocalins / genetics
  • Liposarcoma, Myxoid / genetics*
  • Liposarcoma, Myxoid / pathology
  • NF-kappa B / physiology*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nuclear Proteins / physiology*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Interaction Mapping
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • RNA-Binding Protein FUS / genetics
  • RNA-Binding Protein FUS / physiology
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / physiology
  • Transcription, Genetic

Substances

  • Acute-Phase Proteins
  • CCAAT-Enhancer-Binding Proteins
  • DDIT3 protein, human
  • FUS-DDIT3 fusion protein, human
  • I-kappa B Proteins
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • NF-kappa B
  • NFKBIZ protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • RNA-Binding Protein FUS
  • Transcription Factor CHOP