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BRCA2 and Smad3 synergize in regulation of gene transcription

Oncogene volume 21, pages 5660–5664 (2002)Cite this article

Abstract

Smad3 is an essential component in the intracellular signaling of transforming growth factor-β (TGFβ), which is a potent inhibitor of tumor cell proliferation. BRCA2 is a tumor suppressor involved in early onset of breast, ovarian and prostate cancer. Both Smad3 and BRCA2 possess transcription activation domains. Here, we show that Smad3 and BRCA2 interact functionally and physically. We found that BRCA2 forms a complex with Smad3 in vitro and in vivo, and that both MH1 and MH2 domains of Smad3 contribute to the interaction. TGFβ1 stimulates interaction of endogenous Smad3 and BRCA2 in non-transfected cells. BRCA2 co-activates Smad3-dependent transcriptional activation of luciferase reporter and expression of plasminogen activator inhibitor-1 (PAI-1). Smad3 increases the transcriptional activity of BRCA2 fused to the DNA-binding domain (DBD) of Gal4, and reciprocally, BRCA2 co-activates DBD-Gal4-Smad3. Thus, our results show that BRCA2 and Smad3 form a complex and synergize in regulation of transcription.

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Acknowledgements

We are thankful to Johan Ericsson for valuable discussions, and to Francois Fuks, Tony Kouzarides and Inder Verma for BRCA2 constructs. This work was supported in part by grants of the Royal Swedish Academy of Sciences, the INSERM/MFR/VR and the EU-program on angiogenesis to Serhiy Souchelnytskyi. Takashi Kanamoto was supported by the Swedish Foundation for International Cooperation in Research and Higher Education (STINT).

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Box 595, Husargatan, 3, Uppsala, SE-751 24, Sweden

    Olena Preobrazhenska, Mariya Yakymovych, Takashi Kanamoto, Ihor Yakymovych, Carl-Henrik Heldin & Serhiy Souchelnytskyi

  2. Institute of Cell Biology of Acad. of Sci. of Ukraine, Drahomanova str., 14/16, Lviv, UA-79005, Ukraine

    Olena Preobrazhenska, Mariya Yakymovych & Rostyslav Stoika

  3. Department of Ophthalmology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minani-ku, Hiroshima, 734-8551, Japan

    Takashi Kanamoto

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  1. Olena Preobrazhenska
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  2. Mariya Yakymovych
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  7. Serhiy Souchelnytskyi
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Correspondence to Serhiy Souchelnytskyi.

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Preobrazhenska, O., Yakymovych, M., Kanamoto, T. et al. BRCA2 and Smad3 synergize in regulation of gene transcription. Oncogene 21, 5660–5664 (2002). https://doi.org/10.1038/sj.onc.1205732

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