The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1.

Abstract

EWS/FLI-1 is a chimeric protein formed by a tumor-specific 11;22 translocation found in both Ewing's sarcoma and primitive neuroectodermal tumor of childhood. EWS/FLI-I has been shown to be a potent transforming gene Aberrant expression and structural alteration of transcription factors are frequent, primary molecular mechanisms in oncogenesis (11). In lower mammals and avian species, these alterations are often mediated by retroviral insertion. In humans, deregulation or structural alteration of transcription factors is frequently the result of somatic genomic rearrangement.The 11;22 chromosomal translocation found in Ewing's sarcoma and primitive neuroectodermal tumor of childhood (PNET) juxtaposes the 5' sequences from a newly described gene, termed EWS, with the 3' sequences from FLI-1, which encodes a member of the Ets transcription factor family (6). Like most Ets family members (for a review, see reference 27), the carboxyl domain of FLI-1 mediates sequencespecific DNA binding. The FLI-1 amino terminus contains a putative transcription activation domain that may interact on a protein-protein level with other transcription factors. As with other Ets proteins, it is probably the combination of protein-DNA and protein-protein binding specificities that determines which genes are transcriptionally modulated by FLI-1. As a result of the 11;22 rearrangement, the aminoterminal domain of FLI-1 is replaced by a portion of EWS containing a series of degenerate, glutamine-rich repeats. The carboxyl terminus of EWS has amino acid similarity to proteins involved in RNA synthesis and processing (6). However, the function in tumor cells of the EWS aminoterminal domain that is fused to FLI-1 is unknown.We have recently demonstrated that the EWS/FLI-1 chi-

Efficient infection and persistence of a herpesvirus saimiri-based gene delivery vector into human tumor xenografts and multicellular spheroid cultures

“…Moreover, the long-term persistence of the vector may be useful for the enhanced expression of RNAi and ribozyme constructs for the treatment of cancer. For example, the EWS-FLI1 chimeric oncogene, which results from a chromosomal translocation associated with Ewing's sarcoma, 34,35 is an ideal target for RNAi-based applications in solid tumors. 36 In addition, the establishment of a persistent latent infection in the liver suggests that HVS-based vectors may have potential for the delivery of therapeutic genes for treatment of inherited and acquired liver diseases.…”

Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor

“…First, the functions of ETS proteins are often associated with the binding of cooperative regulatory proteins which could stabilize the interactions between the ETS and DNA (Petersen et al, 1995) and are necessary for speci®c gene transactivation in particular cell types (reviewed in: Papas et al, 1997). Second, the oncogenic conversion of Fli-1, Erg and other Ets related genes via gene fusion has been reported in EWS cells (Delattre et al, 1992;May et al, 1993;Sorensen et al, 1994;Jeon et al, 1995;Peter et al, 1997). Rearrangement of these genes may result in the alteration of their transcription activator properties, For instance, it has been shown recently that EWS acts as a regulatory domain for the transcriptional activator function of the EWS/FLI1 chimeric protein (Ohno et al, 1993).…”

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

“…26,27 The gene fusion product of t (11;22) is EWS-FLI1, a gene with potent transforming capability in NIH3T3 cells. 28 p53 alterations in ES are not common (approximately 10%) but are associated with poor outcomes. [29][30][31] As in RMS, 20-25% of ES patients present with metastatic disease, which reduces 2-year survival from approximately 70 to 40%.…”