p63 is a cereblon substrate involved in thalidomide teratogenicity

• Published in: Nature chemical biology Vol. 15; no. 11; pp. 1077 - 1084
• Main Authors: Asatsuma-Okumura, Tomoko, Ando, Hideki, De Simone, Marco, Yamamoto, Junichi, Sato, Tomomi, Shimizu, Nobuyuki, Asakawa, Kazuhide, Yamaguchi, Yuki, Ito, Takumi, Guerrini, Luisa, Handa, Hiroshi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2019; Nature Publishing Group
• Subjects: 631/136; 631/136/334/1874/763; 631/154/570; 631/92/555; Analogs; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Birth defects; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cochlea; Congenital diseases; Fins; HEK293 Cells; Humans; Isoforms; Membrane Proteins - metabolism; Mutation; p53 Protein; Proteins; Stem cells; Substrate Specificity; Substrates; Teratogenicity; Teratogens - toxicity; Thalidomide; Thalidomide - toxicity; Ubiquitin; Ubiquitin-protein ligase; Zebrafish
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/s41589-019-0366-7

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. ∆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. Zebrafish p63 isoforms were identified as thalidomide-dependent neosubstrates of the cereblon-containing E3 ligase complex. ∆Np63α and TAp63α are responsible for thalidomide-induced malformations of pectoral fins and otic vesicles, respectively.