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.
Göransson
M
M
Lundberg Laboratory for Cancer Research (LLCR), Department of Pathology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Andersson
M K
MK
Forni
C
C
Ståhlberg
A
A
Andersson
C
C
Olofsson
A
A
Mantovani
R
R
Aman
P
P
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