Identification of a Primary Target of Thalidomide Teratogenicity
Identification of a Primary Target of Thalidomide Teratogenicity
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DOI：
10.1126/science.1177319
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发表时间：
2010-03-12
期刊：
影响因子：
56.9
通讯作者：
Handa, Hiroshi
中科院分区：
文献类型：
--
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
半个世纪前，沙利度胺作为镇静剂被广泛用于孕妇，但被发现具有致畸性，导致多种出生缺陷。今天，沙利度胺仍然用于治疗麻风病和多发性骨髓瘤，尽管它如何导致肢体畸形和其他发育缺陷尚不清楚。在这里，我们确定cereblon（CRBN）作为沙利度胺结合蛋白。CRBN与受损的DNA结合蛋白1（DDB1）和Cul4A形成E3泛素连接酶复合物，其对于斑马鱼和小鸡中的肢体生长和成纤维细胞生长因子Fgf8的表达是重要的。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。这项研究揭示了沙利度胺致畸性的基础，并可能有助于开发新的沙利度胺衍生物没有致畸活性。
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.