The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
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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In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
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Self-citationp63 is a p53 homologue required for limb and epidermal morphogenesis
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Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
Krönke, J., Udeshi, N. D., Narla, A., Grauman, P., Hurst, S. N., McConkey, M., Svinkina, T., Heckl, D., Comer, E., Li, X., et al. (2014) · Science · doi:10.1126/science.1244851 · Cited by 1,879
Phthalimide conjugation as a strategy for in vivo target protein degradation
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The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins
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Induced protein degradation: an emerging drug discovery paradigm
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Advancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 680
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 520
Proteolysis‐targeting chimeras in drug development: A safety perspective
Moreau, K., Coen, M., Zhang, A. X., Pachl, F., Castaldi, M. P., Dahl, G., Boyd, H., Scott, C., & Newham, P. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15014 · Cited by 229
Targeted protein degradation for cancer therapy
Hinterndorfer, M., Spiteri, V. A., Ciulli, A., & Winter, G. E. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00817-8 · Cited by 245
Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
Luh, L. M., Scheib, U., Juenemann, K., Wortmann, L., Brands, M., & Cromm, P. M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004310 · Cited by 203
Metadata
- 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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