p63 is a cereblon substrate involved in thalidomide teratogenicity
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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Thalidomide-induced degradation of SALL4, and to some extent PLZF and p63, was confirmed as the root cause of teratogenic deformities.
“thalidomide-induced degradation of SAll4, and to some extent PlZF and p63 (Asatsuma-Okumura et al. 2019;yamanaka et al. 2021), was confirmed as the root cause of the teratogenic deformities affecting thousands of babies (Matyskiela et al. 2018).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Asatsuma-Okumura et al. 2019
GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [15]
Over a dozen proteins, including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα, have been identified as substrates for CRBN.
“To date, over a dozen proteins including Ikaros, Aiolos, GSPT1, CK1α, glutamine synthetase, MEIS2, KCNMA1/SLO1, CLC1, and AMPKα have been identified as substrates for CRBN3,11–16,24–28.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [15]
The transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus.
“The subcellular localizations of these factors differ: the transcription factors Ikaros, Aiolos, and MEIS2 are localized to the nucleus, whereas GSPT1, CK1α, and glutamine synthetase reside in the cytoplasm.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [15]
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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
- Venue
- Nature Chemical Biology
- Published
- 2019-10-07
- Volume
- 15
- Issue
- 11
- Pages
- 1077-1084
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- 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
- 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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