title: Deciphering the mystery of thalidomide teratogenicity.
abstract: Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ≈ 10,000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a clinically effective, albeit strictly restricted, drug for the treatment of leprosy and multiple myeloma. Investigators have studied thalidomide teratogenicity for half a century, proposing over 30 hypotheses to account for its actions. Among these, the anti-angiogenesis and oxidative stress models have gained widespread support. Nonetheless, the precise molecular mechanisms and direct targets of thalidomide have not heretofore been elucidated. We developed ferrite-glycidyl methacrylate beads that enable magnetic separation and efficient purification of ligand-binding molecules; the beads were recently employed to identify cereblon as a primary target of thalidomide. Cereblon forms an E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of fibroblast growth factor 8, an essential regulator of limb development. Expression of a drug binding-deficient mutant of cereblon suppressed thalidomide-induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild-type cereblon, inhibiting the function of the associated E3 ubiquitin ligase. The present review summarizes the teratogenicity of thalidomide, including existing models for its mode of action, and discusses the identification of cereblon as a key molecule for deciphering the longstanding mystery of thalidomide teratogenicity.
authors.affiliation: Solutions Research Laboratory, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002642:Chick Embryo; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D006801:Humans; D017880:Limb Deformities, Congenital / Q000139:chemically induced; D008689:Methacrylates / Q000737:chemistry; D009101:Multiple Myeloma / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D010447:Peptide Hydrolases / Q000378:metabolism; D011247:Pregnancy; D013723:Teratogens / Q000494:pharmacology*; D013792:Thalidomide / Q000009:adverse effects*; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D008689:Methacrylates; D013723:Teratogens; D025801:Ubiquitin; D051524:Fibroblast Growth Factor 8; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases