Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma

Pérez-Losada, Jesús; Sánchez-Martı́n, Manuel; Rodríguez-García, M A; Pérez-Mancera, PA; Pintado, Belén; Flores, Teresa; Battaner, E.; Sánchez-Garcı́a, Isidro

doi:10.1038/sj.onc.1204018

Cited by 77 publications

(53 citation statements)

References 22 publications

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“…The importance of the FUS N-terminal part for oncogenic activity of FUS-DDIT3 was further confirmed by NIH-3T3-based transformation assays (Zinszner et al, 1994) and in transgenic mice (Perez-Losada et al, 2000b).…”

Section: Introductionmentioning

confidence: 74%

“…All three genes form fusion oncogenes, generated by chromosome translocations in a large group of human sarcomas and leukemias (Perez-Losada et al, 2000b;Kovar, 2005). The fusion proteins consist of N-terminal parts of FUS, EWS or TAF15, which are juxtaposed to the DNA-binding parts of various transcription factors, and the chimeric proteins have been shown to act as abnormal transcription factors (Ohno et al, 1993;Sanchez Garcia and Rabbitts, 1994;Zinszner et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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-jB (NF-jB)-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-jB composite site pinpointed the importance of NF-jB for IL8 expression in FUS-DDIT3-expressing cells. We therefore probed for possible interaction of FUS-DDIT3 with members of the NF-jB 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-jB-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-jB-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.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…The importance of the FUS N-terminal part for full oncogenic capacity of the FUS-DDIT3 fusion protein has previously been shown by NIH-3T3-based transformation assays 25 and in transgenic mice. 26 Interestingly, both the normal FUS protein and C/EBP b have been shown to interact physically with the NFkB complex. 27,28 This indicates that the other major factor for IL6 expression, the NFkB system, may be involved in the upregulated expression of IL6 in FUS-DDIT3 carrying cells.…”

Section: Discussionmentioning

confidence: 99%

Myxoid liposarcoma FUS‐DDIT3 fusion oncogene induces C/EBP β‐mediated interleukin 6 expression

Göransson

Elias

Ståhlberg

et al. 2005

Intl Journal of Cancer

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The myxoid/round cell liposarcoma oncogene FUS-DDIT3 is the result of a translocation derived gene fusion between the splicing factor FUS and DDIT3. In order to investigate the downstream targets of DDIT3, and the transforming effects of the FUS-DDIT3 fusion protein, we have introduced DDIT3-GFP and FUS-DDIT3-GFP constructs into a human fibrosarcoma cell line. The gene expression profiles of stable transfectants were compared to the original fibrosarcoma cell line by microarray analysis. We here report that the NFkB and C/EBP b controlled gene IL6 is upregulated in DDIT3-and FUS-DDIT3-expressing fibrosarcoma cell lines and in myxoid liposarcoma cell lines. Strong expression of the tumor associated multifunctional cytokine interleukin 6 was confirmed both at mRNA and protein level. Knockdown experiments using siRNA against CEBPB transcripts showed that the effect of FUS-DDIT3 on IL6 expression is C/EBP b dependent. Chromatin immunoprecipitation revealed direct interaction between the IL6 promoter and the C/EBP b protein. In addition, the effect of DDIT3 and FUS-DDIT3 on the expression of other acute phase genes was examined using real-time PCR. We demonstrate for the first time that DDIT3 and FUS-DDIT3 show opposite transcriptional regulation of IL8 and suggest that FUS-DDIT3 may affect the synergistic activation of promoters regulated by C/EBP b and NFkB. 2,3 DDIT3 is a bZIP transcription factor known to form heterodimers with C/EBP-family members 4 and other bZIP subfamilies such as the AP-1 and ATF3 families. 5,6 Thus, DDIT3 and its oncogenic variant FUS-DDIT3 may act by binding to bZIP proteins and modulate their activity and/or specificity. DDIT3 was initially reported to act as a dominant negative modulator in the C/EBP system. 4 However, as DDIT3 harbors a basic DNA binding domain and binds DNA in a sequence specific manner, it was later proposed to act as a more broad transcriptional regulator. 7 Previous studies indicate that expression of the FUS-DDIT3 fusion protein is required for the development of MLS/RCLS and sufficient for initiation of tumors resembling MLS/RCLS in transgenic mice. 8 In order to understand the transformation process leading to this tumor type, it is crucial to identify downstream target genes of the FUS-DDIT3 fusion protein. We have introduced DDIT3-GFP and FUS-DDIT3-GFP fusion constructs into a human fibrosarcoma cell line and compared the gene expression profiles in stable transfectants with the original fibrosarcoma cell line by microarray analysis. The IL6 gene was found to be upregulated both at mRNA and protein level by the forced expression of DDIT3 or FUS-DDIT3. We show that upregulation at the IL6 promoter by DDIT3 and FUS-DDIT3 is C/EBP b dependent using siRNA knockdown and Chromatin Immuno Precipitation (ChIP) analysis. Further, DDIT3 and FUS-DDIT3 are found to have opposite effect on the expression of the inflammatory cytokine IL8. Material and methods Plasmid constructionThe full length coding regions of DDIT3 and FUS-DDIT3 cDNA type II 9 were cloned into the pEGFP-N...

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“…Thus, transgenic mice expressing FUS-CHOP or CHOP-FUS transgenes under the control of the ubiquitous E1Fa promoter gave rise to similar liposarcomas that resemble their human counterparts [66,67]. On the other hand, although the uncontrolled expression of CHOP after the chromosomal translocation seems to play a leading role in liposarcoma development [64], transgenic mice expressing CHOP alone do not develop any tumor [67] and the expression of FUS restores liposarcoma development in these CHOP-transgenic mice [68]. These results provide evidence that the FUS portion of FUS-CHOP also plays a specific and critical role in the pathogenesis of liposarcoma.…”

Section: Human Mscsmentioning

confidence: 99%

Modeling sarcomagenesis using multipotent mesenchymal stem cells

2011

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Because of their unique properties, multipotent mesenchymal stem cells (MSCs) represent one of the most promising adult stem cells being used worldwide in a wide array of clinical applications. Overall, compelling evidence supports the long-term safety of ex vivo expanded human MSCs, which do not seem to transform spontaneously. However, experimental data reveal a link between MSCs and cancer, and MSCs have been reported to inhibit or promote tumor growth depending on yet undefined conditions. Interestingly, solid evidence based on transgenic mice and genetic intervention of MSCs has placed these cells as the most likely cell of origin for certain sarcomas. This research area is being increasingly explored to develop accurate MSC-based models of sarcomagenesis, which will be undoubtedly valuable in providing a better understanding about the etiology and pathogenesis of mesenchymal cancer, eventually leading to the development of more specific therapies directed against the sarcoma-initiating cell. Unfortunately, still little is known about the mechanisms underlying MSC transformation and further studies are required to develop bona fide sarcoma models based on human MSCs. Here, we comprehensively review the existing MSC-based models of sarcoma and discuss the most common mechanisms leading to tumoral transformation of MSCs and sarcomagenesis.

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Liposarcoma initiated by FUS/TLS-CHOP: the FUS/TLS domain plays a critical role in the pathogenesis of liposarcoma

Cited by 77 publications

References 22 publications

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

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

Myxoid liposarcoma FUS‐DDIT3 fusion oncogene induces C/EBP β‐mediated interleukin 6 expression

Modeling sarcomagenesis using multipotent mesenchymal stem cells

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