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The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors

Oncogene volume 21, pages 8302–8309 (2002)Cite this article

Abstract

We report here that the Id2 (inhibitor of DNA binding 2) gene is a novel target of transcriptional activation by EWS–FLI1 and EWS–ERG, two fusion proteins that characterize Ewing family tumors (EFTs). To identify downstream targets of these EWS–ETS fusion proteins, we introduced EWS–ETS fusion constructs into a human fibrosarcoma cell line by retroviral transduction. cDNA microarray analysis revealed that Id2 expression was up-regulated by introducing the EWS–ETS fusion gene but not by the normal full-length ETS gene. An Id2 promoter-luciferase reporter assay showed that transactivation by EWS–ETS involves the minimal Id2 promoter and may function in cooperation with c-Myc within the full-length regulatory region. A chromatin immunoprecipitation assay revealed direct interaction between the Id2 promoter and EWS-FLI1 fusion protein in vivo. Significantly higher expression of Id2 and c-Myc was observed in all of the six EFT cell lines examined compared to six other sarcoma cell lines. Moreover, high levels of Id2 expression were also observed in five of the six primary tumors examined. Id2 is generally thought to affect the balance between cell differentiation and proliferation in development and is highly expressed in several cancer types. Considering these previous studies, our data suggest that the oncogenic effect of EWS–ETS may be mediated in part by up-regulating Id2 expression.

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Acknowledgements

This work was partially supported by a grant from the Ministry of Education, Culture, Sport, Science, and Technology of Japan. Authors are grateful to Drs Joseph F Costello, Goichi Watanabe and Setsuko Ishida for valuable discussion.

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Authors and Affiliations

  1. Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo, 060-8556, Japan

    Hiroyuki Nishimori, Yasushi Sasaki, Koichi Yoshida, Hideto Irifune & Takashi Tokino

  2. Department of Orthopedic Surgery, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, 060-8556, Sapporo, Japan

    Hideto Irifune, Satoshi Kawaguchi & Takuro Wada

  3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Hitoshi Zembutsu, Toshihiro Tanaka & Yusuke Nakamura

  4. Institute for Frontier Medical Sciences, Kyoto University, 53 Shougoin, Kawara-machi, Sakyo-ku, 606-8507, Kyoto, Japan

    Tomoki Aoyama, Taisuke Hosaka & Junya Toguchida

  5. Department of Orthopedic Surgery, Faculty of Medicine, Kyoto University, 54 Shougoin, Kawara-machi, Sakyo-ku, 606-8507, Kyoto, Japan

    Tomoki Aoyama & Taisuke Hosaka

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

    Jun-ichi Hata

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  1. Hiroyuki Nishimori
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  14. Takashi Tokino
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Correspondence to Takashi Tokino.

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Nishimori, H., Sasaki, Y., Yoshida, K. et al. The Id2 gene is a novel target of transcriptional activation by EWS-ETS fusion proteins in Ewing family tumors. Oncogene 21, 8302–8309 (2002). https://doi.org/10.1038/sj.onc.1206025

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