Identification of a primary target of thalidomide teratogenicity.
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.
Ito
Takumi
T
Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Ando
Hideki
H
Suzuki
Takayuki
T
Ogura
Toshihiko
T
Hotta
Kentaro
K
Imamura
Yoshimasa
Y
Yamaguchi
Yuki
Y
Handa
Hiroshi
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002642:Chick Embryo; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005552:Forelimb / Q000002:abnormalities / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D013792:Thalidomide / Q000378:metabolism / Q000633:toxicity*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054875:Ubiquitination; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D050505:Mutant Proteins; C479529:RBX1 protein, human; D013723:Teratogens; D029961:Zebrafish Proteins; C517774:fgf8a protein, zebrafish; D013792:Thalidomide; D005346:Fibroblast Growth Factors; D044767:Ubiquitin-Protein Ligases; C548021:CRBN protein, zebrafish; D010447:Peptide Hydrolases