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Teratogenic effects of thalidomide: molecular mechanisms

Cellular and Molecular Life Sciences volume 68, pages 1569–1579 (2011)Cite this article

Abstract

Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

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Acknowledgments

We thank Drs. Yuki Yamaguchi, Toshihiko Ogura and Takayuki Suzuki for aiding us in our research. Our research was supported by the Global COE (Center of Excellence) Program from the Japan Ministry of Education, Culture, Sports, Science, and Technology; and by a grant for Research and Development Projects in Cooperation with Academic Institutions from the New Energy and Technology Development Organization; and by Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency (JST).

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  1. Solutions Research Laboratory, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama, 226-8503, Japan

    Takumi Ito & Hiroshi Handa

  2. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuda-cho, Midori-ku, Yokohama, 226-8501, Japan

    Hideki Ando & Hiroshi Handa

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  1. Takumi Ito
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  2. Hideki Ando
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Correspondence to Hiroshi Handa.

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Ito, T., Ando, H. & Handa, H. Teratogenic effects of thalidomide: molecular mechanisms. Cell. Mol. Life Sci. 68, 1569–1579 (2011). https://doi.org/10.1007/s00018-010-0619-9

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  • DOI: https://doi.org/10.1007/s00018-010-0619-9

Keywords

  • Thalidomide
  • Teratogenicity
  • Oxidative stress
  • Anti-angiogenesis
  • Cereblon
  • Fibroblast growth factor 8