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Abstract 3989: High throughput screening highlights NFkB signaling in Ewing sarcoma
Ewing sarcoma (ES) is the second most frequent pediatric bone tumor and still remains of poor prognosis especially for metastatic patients. Genetically, ES is characterized by a chromosomal translocation between EWSR1 and ETS family members (FLI1 in 85% of cases). This leads to the expression of EWS-FLI1 chimeric oncogene transcription factor. Aiming at identifying EWS-FLI1 regulated genes with potential therapeutic targets, a genome wide method was developed to rank these potential hits by combining Ewing sarcoma transcriptome and ChIPSeq data. Accordingly, 273 selected genes were further investigated using a siRNA approa...
Source: Cancer Research - September 30, 2014 Category: Cancer & Oncology Authors: Surdez, D., Stoll, G., Tirode, F., Laud, K., Barillot, E., Delattre, O. Tags: Tumor Biology Source Type: research

Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone.
Abstract Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that the EWS/FLI1- and EWS-knockdown cells display a high incidence of ...
Source: Cell Cycle - June 19, 2014 Category: Cytology Authors: Park H, Turkalo TK, Nelson K, Folmsbee SS, Robb C, Belford B, Azuma M Tags: Cell Cycle Source Type: research

Dual targeting of EWS-FLI1 activity and the associated DNA damage response with Trabectedin and SN38 synergistically inhibits Ewing sarcoma cell growth.
CONCLUSIONS: These results provide the basis and rationale for translating this drug combination to the clinic. In addition, the study highlights an approach that utilizes a targeted agent to interfere with an oncogenic transcription factor and then exploits the resulting changes in gene expression to develop a molecularly targeted combination therapy. PMID: 24277455 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - November 25, 2013 Category: Cancer & Oncology Authors: Grohar PJ, Segars LE, Yeung C, Pommier Y, D'Incalci M, Mendoza A, Helman LJ Tags: Clin Cancer Res Source Type: research

Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis
In this study, a network linking EWS-FLI1 to cell cycle and apoptosis phenotypes was constructed through an original method of network reconstruction. Transcriptome time-series after EWS-FLI1 silencing were used to identify core modulated genes by an original scoring method based on fitting expression profile dynamics curves. Literature data mining was then used to connect these modulated genes into a network. The validity of a subpart of this network was assessed by siRNA/RT-QPCR experiments on four additional Ewing cell lines and confirmed most of the links. Based on the network and the transcriptome data, CUL1 was ident...
Source: Nucleic Acids Research - October 18, 2013 Category: Research Authors: Stoll, G., Surdez, D., Tirode, F., Laud, K., Barillot, E., Zinovyev, A., Delattre, O. Tags: Computational Biology Source Type: research

PKC{iota}/Dvl2 in Wnt3a-dependent Neurite Outgrowth Cell Biology
Previously we reported that Wnt3a-dependent neurite outgrowth in Ewing sarcoma family tumor cell lines was mediated by Frizzled3, Dishevelled (Dvl), and c-Jun N-terminal kinase (Endo, Y., Beauchamp, E., Woods, D., Taylor, W. G., Toretsky, J. A., Uren, A., and Rubin, J. S. (2008) Mol. Cell. Biol. 28, 2368–2379). Subsequently, we observed that Dvl2/3 phosphorylation correlated with neurite outgrowth and that casein kinase 1δ, one of the enzymes that mediate Wnt3a-dependent Dvl phosphorylation, was required for neurite extension (Greer, Y. E., and Rubin, J. S. (2011) J. Cell Biol. 192, 993–1004). However, the functional ...
Source: Journal of Biological Chemistry - March 29, 2013 Category: Chemistry Authors: Greer, Y. E., Fields, A. P., Brown, A. M. C., Rubin, J. S. Tags: Signal Transduction Source Type: research

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