Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
Science. 2010 Mar 12;327(5971):1345-50. 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.
半个世纪前，沙利度胺曾被广泛开给孕妇作为镇静剂，但后来发现它具有致畸性，会导致多种出生缺陷。如今，尽管尚不清楚沙利度胺如何导致肢体畸形和其他发育缺陷，但它仍被用于治疗麻风病和多发性骨髓瘤。在这里，我们鉴定出 cereblon（CRBN）是沙利度胺结合蛋白。CRBN 与受损 DNA 结合蛋白 1（DDB1）和 Cul4A 形成 E3 泛素连接酶复合物，对于斑马鱼和小鸡的肢体生长和成纤维细胞生长因子 Fgf8 的表达很重要。沙利度胺通过与 CRBN 结合并抑制相关的泛素连接酶活性来启动其致畸作用。本研究揭示了沙利度胺致畸性的基础，并可能有助于开发无致畸活性的新沙利度胺衍生物。
