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.
p63 is a cereblon substrate involved in thalidomide teratogenicity / T. Asatsuma-Okumura, H. Ando, M. De Simone, J. Yamamoto, T. Sato, N. Shimizu, K. Asakawa, Y. Yamaguchi, T. Ito, L. Guerrini, H. Handa. - In: NATURE CHEMICAL BIOLOGY. - ISSN 1552-4469. - 15:11(2019 Nov 15), pp. 1077-1084.
|Titolo:||p63 is a cereblon substrate involved in thalidomide teratogenicity|
DE SIMONE, MARCO [Investigation]
GUERRINI, LUISA FRANCESCA (Ultimo) [Writing – Review & Editing] (Corresponding)
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||15-nov-2019|
|Data ahead of print / Data di stampa:||7-ott-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41589-019-0366-7|
|Appare nelle tipologie:||01 - Articolo su periodico|