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.

Keyword

Acute-Phase Proteins

biosynthesis

genetics

Binding Sites

CCAAT-Enhancer-Binding Proteins

physiology

Cell Line

Tumor

metabolism

Cell Nucleus

metabolism

ultrastructure

Fibrosarcoma

metabolism

pathology

Humans

Interleukin-6

biosynthesis

genetics

Interleukin-8

biosynthesis

genetics

Lipocalins

biosynthesis

genetics

Liposarcoma

Myxoid

genetics

pathology

NF-kappa B

physiology

Neoplasm Proteins

genetics

physiology

Nuclear Proteins

physiology

Oncogene Proteins

Fusion

genetics

physiology

Promoter Regions

Genetic

genetics

Protein Binding

Protein Interaction Mapping

Proto-Oncogene Proteins

biosynthesis

genetics

RNA-Binding Protein FUS

genetics

physiology

Transcription Factor CHOP

genetics

physiology

Transcription

Genetic

Publication and Content Type

ref (subject category)

art (subject category)