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 CRL4CRBN substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4CRBN neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. ∆Np63α is essential for limb development, while TAp63α 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 ∆Np63α and TAp63α, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.
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We thank M. Manabe, M. Akiyama, S. Shoji and K. Taneda for technical assistance. We also thank A. J. Berk for critical comments on this manuscript. This work was supported by MEXT/JSPS KAKENHI grant numbers 17H06112 (to H.H. and Y.Y.), 15H04288 (to H.A.), 17H04213 (to T.I.), 17K14996 (to J.Y.) and 18H05502 (to T.I.). This work was also supported by MEXT-Supported Program for the Strategic Research Foundation at Private Universities S1411011 (to H.H.) and by PRESTO, JST JPMJPR1531 (to T.I.).
H.H. has received research support from Celgene Corporation.
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