Cited by 137Protein Degradation and InhibitorsPharmacological Effects and Toxicity StudiesDevelopmental Biology and Gene Regulation

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p63 is a cereblon substrate involved in thalidomide teratogenicity

Asatsuma-Okumura, Tomoko, Ando, Hideki, De Simone, Marco, Yamamoto, Junichi, Sato, Tomomi, Shimizu, Nobuyuki, Asakawa, Kazuhide, Yamaguchi, Yuki, Ito, Takumi, Guerrini, Luisa, Handa, Hiroshi·2019·Nature Chemical Biology

DOI 10.1038/s41589-019-0366-7

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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 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.

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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.
Affiliations: Tokyo Medical University (JP)
Tokyo Institute of Technology (JP)
University of Milan (IT)
Corresponding author: Guerrini, Luisa
Handa, Hiroshi
ORCID: Asatsuma-Okumura, Tomoko
Yamamoto, Junichi
Sato, Tomomi
Shimizu, Nobuyuki
Asakawa, Kazuhide
Yamaguchi, Yuki
Ito, Takumi
Guerrini, Luisa
Handa, Hiroshi
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2019-10-07
Volume: 15
Issue: 11
Pages: 1077-1084
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/s41589-019-0366-7
OpenAlex: W2978105110
Cited by: 134
References: 50
Citations by year: 2026: 6 · 2025: 23 · 2024: 14 · 2023: 19 · 2022: 23 · 2021: 24 · 2020: 25
FWCI: 5.96
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
Funders: MEXT | Japan Society for the Promotion of Science (15H04288, 17K14996, 17H06112, S1411011)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: thalidomide, cereblon, p63, teratogenicity, p53 family, ΔNp63α, TAp63α, limb development, cochlear development, zebrafish, thalidomide analogues
MeSH terms: Humans, Membrane Proteins, Substrate Specificity, Teratogens, Thalidomide, HEK293 Cells

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p63 is a cereblon substrate involved in thalidomide teratogenicity

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