Identification of a Primary Target of Thalidomide Teratogenicity

• Published in: Science (American Association for the Advancement of Science) Vol. 327; no. 5971; pp. 1345 - 1350
• Main Authors: Ito, Takumi, Ando, Hideki, Suzuki, Takayuki, Ogura, Toshihiko, Hotta, Kentaro, Imamura, Yoshimasa, Yamaguchi, Yuki, Handa, Hiroshi
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 12.03.2010; The American Association for the Advancement of Science
• Subjects: Animals; Binding sites; Biological and medical sciences; Birth defects; Carrier Proteins - metabolism; Cellular immunity; Chick Embryo; Cullin Proteins - metabolism; Danio rerio; Delta cells; Developmental biology; DNA damage; DNA-Binding Proteins - metabolism; Drug toxicity and drugs side effects treatment; Embryo, Nonmammalian - drug effects; Embryology: invertebrates and vertebrates. Teratology; Embryonic Development - drug effects; Embryos; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Forelimb - abnormalities; Forelimb - embryology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; HeLa Cells; Humans; Medical sciences; Messenger RNA; Miscellaneous (drug allergy, mutagens, teratogens...); Mutant Proteins - metabolism; Pectorals; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Pharmacology; Pharmacology. Drug treatments; Receptors; Research Article; Substrate specificity; Teratogenicity; Teratogens - metabolism; Teratogens - toxicity; Teratology. Teratogens; Thalidomide - metabolism; Thalidomide - toxicity; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Ubiquitins; Zebrafish - embryology; Zebrafish - genetics; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Embryo; Toxicity; Anti-Tumor Necrosis Factor-alpha; Site of action; Binding protein; Vertebrata; Brachydanio rerio; Malformation; Pisces; Animal; Limb; Fibroblast growh factor 8; Chicken; Teratogen; Aves; Mechanism of action; Thalidomide
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1177319

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.