p63 is a cereblon substrate involved in thalidomide teratogenicity
p63 is a cereblon substrate involved in thalidomide teratogenicity
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DOI：
10.1038/s41589-019-0366-7
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发表时间：
2019-11-01
影响因子：
14.8
通讯作者：
Handa, Hiroshi
中科院分区：
文献类型：
--
作者：
Asatsuma-Okumura, Tomoko;Ando, Hideki;Handa, Hiroshi
Cereblon（CRBN）是沙利度胺的主要靶点，并介导其多种药理学活性，包括致畸和抗骨髓瘤活性。CRBN作为E3泛素连接酶CRL 4的底物受体发挥作用，其底物特异性由沙利度胺及其类似物调节。尽管最近已经鉴定了许多CRL4（CRBN）底物，但涉及沙利度胺致畸性的底物尚不清楚。在这里，我们表明，p63亚型是沙利度胺依赖性CRL4（CRBN）的neosubstrates负责，至少部分，其致畸作用。p53家族成员p63与多种发育过程相关。Delta Np63 alpha对肢体发育至关重要，而TAp63 alpha对耳蜗发育和听力至关重要。使用斑马鱼模型，我们表明，沙利度胺通过诱导三角洲Np63 α和TAp63 α的降解，分别对胸鳍和耳泡发挥其致畸作用。这些结果可能有助于发明新的沙利度胺类似物缺乏致畸活性。
Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4(CRBN) substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4(CRBN) neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. Delta Np63 alpha is essential for limb development, while TAp63 alpha is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of Delta Np63 alpha and TAp63 alpha, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.