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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\u2010angiogenesis 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\u2010glycidyl methacrylate beads that enable magnetic separation and efficient purification of ligand\u2010binding 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\u2010deficient mutant of cereblon suppressed thalidomide\u2010induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild\u2010type 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.<\/jats:p>","DOI":"10.1111\/j.1741-4520.2011.00351.x","type":"journal-article","created":{"date-parts":[[2011,12,2]],"date-time":"2011-12-02T22:55:43Z","timestamp":1322866543000},"page":"1-7","source":"Crossref","is-referenced-by-count":46,"title":["Deciphering the mystery of thalidomide teratogenicity"],"prefix":"10.1111","volume":"52","author":[{"given":"Takumi","family":"Ito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Handa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,2,21]]},"reference":[{"key":"e_1_2_3_2_1","first-page":"1964","article-title":"Thalidomide 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