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Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma

Oncogene volume 22, pages 1–9 (2003)Cite this article

Abstract

The chromosomal translocation specifically linked to the Ewing sarcoma family results in the generation of fusion proteins comprising the amino terminal portion of EWS and the DNA-binding domain of ets transcription factors. The EWS/ets chimeric proteins act as aberrant transcription factors leading to tumorigenic processes. We searched for genes specifically activated in Ewing sarcoma cells but not in other tumor cell lines using the gene array technique, and found significantly enhanced expression of the Id2 gene. High levels of Id2 transcripts were detected in Ewing sarcoma cell lines and tumor tissues. The EWS/ets chimeric proteins activated the Id2 gene via the 5′-upstream promoter sequence. Chromatin-immunoprecipitation revealed a direct interaction of EWS/Fli-1 with the promoter regions of the Id2, TGF-β type II receptor, cyclin D1, and c-myc genes. Since EWS/Fli-1 transactivates c-myc, a cooperative action of the chimeric protein and c-myc leads to overexpression of Id2. In the present study, we suggest that Id2 is a target of the chimeric proteins and that the c-myc/Id2 pathway plays a pivotal role in the tumorigenic processes provoked by EWS/ets proteins.

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Acknowledgements

The EWS/ERG expression vector are gifts from T Ohno (Gifu University, School of Medicine). We thank T Fukasawa (Keio University School of Medicine) for reviewing this manuscript, and the staff of Department of Pathology, Keio University School of Medicine for technical assistance. We are grateful to K Saito, S Asai, J Osegawa and K Abe for joining this research as undergraduate students.

This work was partly supported by a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, as well as a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS).

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  1. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Mariko Fukuma, Hajime Okita, Jun-ichi Hata & Akihiro Umezawa

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  1. Mariko Fukuma
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  2. Hajime Okita
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Correspondence to Akihiro Umezawa.

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Fukuma, M., Okita, H., Hata, Ji. et al. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene 22, 1–9 (2003). https://doi.org/10.1038/sj.onc.1206055

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