EWS/Fli-1 chimeric protein is a transcriptional activator.
Fli-1, an ets related gene, was found to be rearranged in 75% of erythroleukemias induced by Friend murine leukemia virus. We have shown previously that the Fli-1 gene codes for a sequence specific transcriptional activator which contains two autonomous transcriptional activation domains, one at the amino terminal region and the other at the carboxy terminal region. Recently human Fli-1 gene was shown to be involved in Ewing's sarcoma and related subtypes of primitive neuroectodermal tumors which share t(11;22) (q24;q12) chromosome translocation. In these tumors the carboxyl terminal region of Fli-1 was found to be fused with the amino terminal region of a putative RNA binding protein, EWS. Because part of the amino terminal transcriptional activation domain of Fli-1 was replaced with the amino terminal domain of the EWS (NTD-EWS) which shares homology with RNA polymerase II, it was speculated that NTD-EWS may interfere with RNA pol II function. Alternatively, NTD-EWS could also contribute to the transcriptional activation function of EWS/Fli-1 chimeric protein by providing either a modulatory/regulatory domain or a novel transcriptional activation domain. Here we show that EWS/Fli-1 chimeric protein functions as a transcriptional activator. Deletion analysis reveals that the EWS domain functions as a modulatory/regulatory domain for the transcriptional activation properties of the carboxy terminal transcriptional activation domain of EWS/Fli-1. We therefore propose that replacement of the amino terminal transcriptional activation domain of the Fli-1 protein with the regulatory domain of NTD-EWS results in the activation of the carboxy terminal transcriptional activation domain of Fli-1 which may be the molecular mechanism involved in these human tumors.
Ohno
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Department of Microbiology and Immunology, Jefferson Cancer Institute, Philadelphia, Pennsylvania 19107-5541.
Rao
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VN
Reddy
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ES
D016475:3T3 Cells; D000818:Animals; D018076:DNA, Complementary / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D012261:Ribonucleoproteins / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497426:Fli1 protein, mouse; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009687:Nuclear Proteins; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; D015534:Trans-Activators