The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ.
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.
Lundberg Laboratory for Cancer Research (LLCR), Department of Pathology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
M
M
Göransson
M K
MK
Andersson
C
C
Forni
A
A
Ståhlberg
C
C
Andersson
A
A
Olofsson
R
R
Mantovani
P
P
Aman
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000235:genetics; D018208:Liposarcoma, Myxoid / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000502:physiology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
D000209:Acute-Phase Proteins; D048868:Adaptor Proteins, Signal Transducing; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; C532377:FUS-DDIT3 fusion protein, human; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; C417234:NFKBIZ protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D034702:RNA-Binding Protein FUS; D051742:Transcription Factor CHOP