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Science 327 (5971): 1345-1350

Copyright © 2010 by the American Association for the Advancement of Science

Identification of a Primary Target of Thalidomide Teratogenicity

Takumi Ito,1,* Hideki Ando,2,* Takayuki Suzuki,3,4 Toshihiko Ogura,3 Kentaro Hotta,2 Yoshimasa Imamura,5 Yuki Yamaguchi,2 Hiroshi Handa1,2,{dagger}

Abstract: Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.

1 Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
2 Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
3 Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
4 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency (JST), Saitama 332-0012, Japan.
5 Drug Discovery Research, Astellas Pharma Inc., Ibaraki 305-8585, Japan.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: handa.h.aa{at}m.titech.ac.jp

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