Identification of a Primary Target of Thalidomide Teratogenicity

Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Science (Impact Factor: 33.61). 03/2010; 327(5971):1345-50. DOI: 10.1126/science.1177319
Source: PubMed


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.

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