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

Göransson, Melker; Elias, Erik; Ståhlberg, Anders; Olofsson, Anita; Andersson, Christian X.; Åman, Pierre

doi:10.1002/ijc.20893

Cited by 43 publications

(45 citation statements)

References 31 publications

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“…The NF-kB-controlled genes MMP1 and LCN2 are upregulated in FUS-DDIT3-expressing cell lines MMP1 and LCN2, both genes involved in extracellular matrix remodeling, were found to be upregulated in FUS-DDIT3-GFP cells, whereas DDIT3 had very little effect (Go¨ransson et al, 2005). The expression patterns were confirmed here by real-time PCR (Table 1).…”

Section: Physical Interaction Between Nfkbiz and Fus-ddit3supporting

confidence: 71%

“…NF-kB is a major factor controlling IL8 transcription in FUS-DDIT3-expressing cells DDIT3 and FUS-DDIT3 give opposite effects on the IL8 transcription in HT1080 cells (Go¨ransson et al, 2005). To study the mechanism behind this difference, we expressed luciferase reporter constructs containing the C/EBP-NF-kB composite site of the IL8 promoter, or mutant forms of this construct in genetically modified HT1080 cells (Figure 1).…”

Section: Resultsmentioning

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: Physical Interaction Between Nfkbiz and Fus-ddit3supporting

confidence: 71%

Section: Resultsmentioning

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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“…These results are in line with those of studies in other human cancers, which have demonstrated that the main effect of C/EBPβ over-expression is induction of uncontrolled proliferation. 13,[21][22][23] Additionally, the role of several major NPM-ALK activated signaling pathways in C/EBPβ expression and activation was explored. Through the use of gene silencing experiments, we were able to dissect several mechanisms through which NPM-ALK exerts its control on C/EBPβ.…”

Section: Discussionmentioning

confidence: 99%

C/EBP expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway

Anastasov

Bonzheim²,

Rudelius³

et al. 2009

Haematologica

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BackgroundAnaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma is characterized by the t(2;5) chromosomal translocation, resulting in the expression of a fusion protein formed of nucleophosmin (NPM) and ALK. Recently, we reported the abnormal expression of the transcription factor CCAAT/enhancer binding protein-beta (C/EBPβ) in ALK-positive anaplastic large cell lymphomas, and demonstrated its dependence on NPM-ALK activity. Design and MethodsIn this study, the role of C/EBPβ in proliferation and survival of ALK-positive anaplastic large cell lymphomas was investigated, as well as the mechanism of its expression and activity. Highly effective short hairpin RNA sequences and/or pharmacological inhibitors were used to abrogate the expression or activity of C/EBPβ, signal transducer and activator of transcription 3 (STAT3), AKT, extracellular signal-related kinase 1/2 (ERK1/2) and mammalian target of rapamycin (mTOR). ResultsInterference with C/EBPβ expression resulted in a dramatic decrease in cell proliferation in ALK-positive anaplastic large cell lymphomas, with a mild induction of apoptosis after 6 days. Down-regulation of STAT3 resulted in a marked decrease in C/EBPβ mRNA and protein levels with impairment in cell proliferation and viability, underscoring the important role of these two proteins in ALK-mediated oncogenesis. Additionally, we demonstrated that reduction of ERK1/2 activity led to C/EBPβ Thr 235 dephosphorylation and moderate growth retardation. The AKT/mTOR signaling pathway did not have any influence on C/EBPβ expression or C/EBPβ phosphorylation. ConclusionsThese findings reveal the convergence of STAT3 and ERK1/2 signaling pathways activated by NPM-ALK in mediating the regulation of C/EBPβ expression, a transcription factor central to NPM-ALK transformation.Key words: anaplastic large cell lymphoma (ALCL), C/EBPβ, STAT3, RNA interference, cell proliferation. STAT3 signaling pathway. Haematologica 2010;95:760-767. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Anastasov N, Bonzheim I, Rudelius M, Klier M, Dau T, Angermeier D, Duyster J, Pittaluga S, Fend F, Raffeld M, and Quintanilla-Martinez L. C/EBPβ expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the C/EBPβ expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway

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“…Immunoadsorbed DNA was analyzed by PCR using the following primers: IL-6 promoter (5 ¶-AGCACTGGCAGCACAAGGCAAAC-3 ¶ and 5 ¶-CAAGCCTGGGATTAT-GAAGAAGG-3 ¶), Cyp1a1 enhancer (5 ¶-TAAGAGCCCCGCCCCGACTTCCT-3 ¶ and 5 ¶-TAGCTTGCGTGCGCCGGCGACAT-3 ¶). Cyp1a1 and IL-6 ChIP primers are previously published (25,26).…”

Section: Methodsmentioning

confidence: 99%

Inflammatory Signaling and Aryl Hydrocarbon Receptor Mediate Synergistic Induction of Interleukin 6 in MCF-7 Cells

et al. 2008

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The pleiotropic cytokine interleukin 6 (IL-6) is involved in immune cell homeostasis. Additionally, IL-6 expression and signaling in tumor cells have been shown to elicit both protumor and antitumor properties. There is a plethora of mechanistic knowledge regarding how IL-6 signal transduction translates to biological responses. However, there is little understanding as to what factors control IL-6 expression within a tumor cell environment. The studies presented herein show that, in MCF-7 breast and ECC-1 endocervical cancer cells, the stimulation of aryl hydrocarbon receptor (AHR) activity, in combination with IL-1B or phorbol 12-myristate 13-acetate (PMA) treatment, results in a marked synergistic induction of IL-6 levels over what is seen without AHR activation. Chromatin immunoprecipitation experiments suggest that the regulation of IL-6 mRNA expression occurs at the chromatin level, as AHR presence on the IL-6 promoter was observed in response to treatment with AHR ligand. Synergistic induction of IL-6 expression was sustained for 72 hours, with accumulation of IL-6 protein reaching levels 4.8-fold above IL-1B treatment alone. In addition, transcriptional regulation of the prototypic AHR responsive gene Cyp1a1 was negatively regulated by PMA and IL-1B treatment. Silencing of RELA expression alleviated IL-1B-mediated repression of AHR transcriptional activity, whereas PMA-mediated repression was maintained. Additionally, small interfering RNA studies reveal that AHR and RELA are necessary for synergistic induction of IL-6. The findings presented here reveal the AHR as a potential therapeutic target for selective modulation of IL-6 expression in some tumor cell types. The data also suggest a possible previously unrecognized mechanism of AHRmediated tumor promotion. [Cancer Res 2008;68(10):3609-17]

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

Cited by 43 publications

References 31 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

C/EBP expression in ALK-positive anaplastic large cell lymphomas is required for cell proliferation and is induced by the STAT3 signaling pathway

Inflammatory Signaling and Aryl Hydrocarbon Receptor Mediate Synergistic Induction of Interleukin 6 in MCF-7 Cells

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