Ewingʼs sarcoma and peripheral primitive neuroectodermal tumors after their genetic union

Kovar, Heinrich

doi:10.1097/00001622-199807000-00010

Cited by 88 publications

(45 citation statements)

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“…The HD region at 9p21 included the CDKN2A/B loci, confirming the role of this tumour suppressor gene in ES pathogenesis (Kovar, 1998). Among the other HD, the 1p36 region contains a substantial numbers of putative tumour suppressor genes (Table 1) and it has been shown to be deleted in other tumours, such as neuroblastoma (Thompson et al, 2001).…”

Section: Resultsmentioning

confidence: 79%

“…Ewing's sarcoma (ES) is the second most common malignant bone tumour in children and young adults (Kovar, 1998), and belongs to a wider group of neuroectodermal tumours known as ES Family of Tumours (Ushigome et al, 2002). Their genetic hallmark is the presence of the reciprocal t(11;22)(q24;q12) translocation (Aurias et al, 1984;Mugneret et al, 1988), or other less frequent variant translocations t(21;22)(q12;q12) and t(7;22)(p22;q12), and their morphology falls in the smallblue-round-cells category.…”

Section: Introductionmentioning

confidence: 99%

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Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma

et al. 2007

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Section: Resultsmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma

et al. 2007

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“…1 Ewing tumors are characterized by specific balanced chromosomal translocations, leading to the formation of chimeric proteins that join the N-terminal region from the EWS gene product in frame with the C-terminal portion of out of five different members of the ETS family of transcription factors: FLI1, ERG or FEV (ERG subfamily) and E1AF or ETV1 (PEA3 subfamily). The EWS/FLI1 combination is most frequent and is present in nearly 85% of all cases.…”

mentioning

confidence: 99%

The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors

Mendiola¹,

Carrillo²,

García³

et al. 2005

Int. J. Cancer

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The Ewing family of tumors harbors chromosomal translocations that join the N-terminal region of the EWS gene with the C-terminal region of several transcription factors of the ETS family, mainly FLI1, resulting in chimeric transcription factors that play a pivotal role in the pathogenesis of Ewing tumors. To identify downstream targets of the EWS/FLI1 fusion protein, we established 293 cells expressing constitutively either the chimeric EWS/ FLI1 or wild type FLI1 proteins and used cDNA arrays to identify genes differentially regulated by EWS/FLI1. DAX1 (NR0B1), an unusual orphan nuclear receptor involved in gonadal development, sex determination and steroidogenesis, showed a consistent up-regulation by EWS/FLI1 oncoprotein, but not by wild type FLI1. Specific induction of DAX1 by EWS/FLI1 was confirmed in two independent cell systems with inducible expression of EWS/ FLI1. We also analyzed the expression of DAX1 in Ewing tumors and derived cell lines, as well as in other nonrelated small round cell tumors. DAX1 was expressed in all Ewing tumor specimens analyzed, and in seven out of eight Ewing tumor cell lines, but not in any neuroblastoma or embryonal rhabdomyosarcoma. Furthermore, silencing of EWS/FLI1 by RNA interference in a Ewing tumor cell line markedly reduced the levels of DAX1 mRNA and protein, confirming that DAX1 up-regulation is dependent upon EWS/FLI1 expression. The high levels of DAX1 found in Ewing tumors and its potent transcriptional repressor activity suggest that the oncogenic effect of EWS/FLI1 may be mediated, at least in part, by the up-regulation of DAX1 expression. ' 2005 Wiley-Liss, Inc.Key words: Ewing tumors; EWS/FLI1 oncoprotein; orphan nuclear receptor DAX1; cDNA arrays Ewing sarcoma and peripheral primitive neuroectodermal tumors (PNETs) are referred to as the Ewing family of tumors, a group of highly malignant tumors arising in children, adolescents and young adults. 1 Ewing tumors are characterized by specific balanced chromosomal translocations, leading to the formation of chimeric proteins that join the N-terminal region from the EWS gene product in frame with the C-terminal portion of out of five different members of the ETS family of transcription factors: FLI1, ERG or FEV (ERG subfamily) and E1AF or ETV1 (PEA3 subfamily). The EWS/FLI1 combination is most frequent and is present in nearly 85% of all cases. 2 A large body of evidence has shown the oncogenic potential of EWS/FLI1 protein. Thus, the ectopic expression of EWS/FLI1 in murine fibroblasts promotes anchorage-independent growth in vitro 3 and accelerates tumorigenesis in vivo. 4 Moreover, EWS/FLI1 knock-down using a variety of techniques inhibits the growth of Ewing tumor-derived cell lines both in vitro and in vivo. 5-9 These data, together with the observation that EWS/ETS chimeric proteins are present in virtually all Ewing tumors, have provided strong evidence that these fusion genes are necessary for the development of these neoplasms. However, EWS/FLI1 appears to be toxic for mouse embryo fibroblasts 10 and p...

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“…It is more likely that only specific ets-EWS recombinations generate hybrid proteins that recognize specific targets that subsequently promote tumor formation. [35][36][37][38] It is likely that specific ets domains recognize unique cellular targets. This hypothesis is also supported by our finding that the FLI1/ ERF hybrid, but not wt ERF, is able to suppress the ES phenotype, despite their similarities in expression level and subcellular compartmentalization.…”

Section: Discussionmentioning

confidence: 99%

Suppression of the Ewing’s sarcoma phenotype by FLI1/ERF repressor hybrids

et al. 2000

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Fusion of the 5Ј half of the Ewing's sarcoma (ES) gene EWS with the DNA-binding domain of several transcription factors has been detected in many human tumors. The t(11;22)(q24;q12) chromosomal translocation is specifically linked to ES and primitive neuroectodermal tumors and results, in the majority of cases, in the fusion of the amino terminus of the EWS gene to the carboxyl-terminal DNA-binding domain of the FLI1 gene. The chimeric protein has been shown to be oncogenic, a potent transcriptional activator, and necessary for the maintenance of the Ewing's phenotype, making it an attractive target for gene therapy. In this study, we demonstrate that the ES transformed phenotype can be suppressed by chimeric transcriptional repressors containing the DNA-binding domain of FLI1 and the regulatory and repressor domain of ERF, a transcription suppressor and member of the ets gene family. The hybrid repressor is expressed at levels comparable with EWS/FLI1, does not affect EWS/FLI1 expression, and exhibits similar DNA-binding specificity but suppresses transcriptional activity. The FLI1/ERF repressor, like the wild-type ERF, is regulated by mitogen-activated protein kinase-dependent subcellular localization. Our data suggest that transformation by EWS/FLI1 may partially be due to activation of specific EWS/FLI1-regulated genes involved in cell proliferation. A berrant expression and/or structural alteration of transcription factors have been suggested to be critical events in tumorigenic transformation. 1,2 The t(11;22)(q24;q12) chromosomal translocation, detected in the majority of Ewing's sarcoma (ES) and primitive neuroectodermal tumors, fuses the amino terminus of the EWS gene to the carboxyl terminus of the ets transcription factor family member FLI1. 3 In other ES and primitive neuroectodermal tumors, analogous translocations fuse the EWS gene to other members of the ets family, including ERG, 4 ETV-1, 5 E1AF, 6 and FEV, 7 members of the ERG and PEA3 subclasses of the family. 8,9 In all of these fusions, the transactivating domain of the EWS gene is fused to the DNA-binding domain of an ets gene. It has been shown that the EWS/FLI1 fusion protein is a more potent transcriptional activator than FLI1 10,11 and, in contrast to FLI1, is a transforming gene. 10 Both the transactivation domain of EWS and the ets-DNA-binding domain are required for transformation, 10 and the transactivation efficiency of different classes of EWS-FLI1 fusions has been reported to correlate with the behavior of tumors in vivo. 12 Furthermore, the transforming phenotype can be suppressed by blocking EWS-FLI1 production. [13][14][15] The parental EWS protein contains an RNA-binding domain and a transactivation domain and is similar to the TLS/FUS and hTAF II 68 members of the TET family of proteins that are able to interact with both TFIID and RNA polymerase II. 16 The EWS-FLI1 hybrid, however, does not appear to be capable of similar functions, 17 suggesting that different mechanisms may be involved in EWS-FLI1-induced tumorigenesis.The...

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Ewingʼs sarcoma and peripheral primitive neuroectodermal tumors after their genetic union

Cited by 88 publications

References 0 publications

Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma

Array CGH and gene-expression profiling reveals distinct genomic instability patterns associated with DNA repair and cell-cycle checkpoint pathways in Ewing's sarcoma

The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors

Suppression of the Ewing’s sarcoma phenotype by FLI1/ERF repressor hybrids

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