PUBLICATION
p63 is a cereblon substrate involved in thalidomide teratogenicity
- Authors
- Asatsuma-Okumura, T., Ando, H., De Simone, M., Yamamoto, J., Sato, T., Shimizu, N., Asakawa, K., Yamaguchi, Y., Ito, T., Guerrini, L., Handa, H.
- ID
- ZDB-PUB-191011-5
- Date
- 2019
- Source
- Nature Chemical Biology 15(11): 1077-1084 (Journal)
- Registered Authors
- Ando, Hideki, Asakawa, Kazuhide, Sato, Tomomi, Shimizu, Nobuyuki
- Keywords
- none
- MeSH Terms
-
- HEK293 Cells
- Humans
- Membrane Proteins/metabolism*
- Substrate Specificity
- Teratogens/toxicity*
- Thalidomide/toxicity*
- PubMed
- 31591562 Full text @ Nat. Chem. Biol.
Citation
Asatsuma-Okumura, T., Ando, H., De Simone, M., Yamamoto, J., Sato, T., Shimizu, N., Asakawa, K., Yamaguchi, Y., Ito, T., Guerrini, L., Handa, H. (2019) p63 is a cereblon substrate involved in thalidomide teratogenicity. Nature Chemical Biology. 15(11):1077-1084.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping