Related Experiment Video

Updated: Jan 6, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.7K

p63 is a cereblon substrate involved in thalidomide teratogenicity

Tomoko Asatsuma-Okumura1, Hideki Ando1, Marco De Simone2

  • 1Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Nature Chemical Biology
|October 9, 2019
PubMed

Insights

Thalidomide causes birth defects by degrading p63 proteins, essential for development. Targeting these p63 isoforms could lead to safer thalidomide analogs without teratogenic effects.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Pharmacology

Background:

  • Cereblon (CRBN) mediates thalidomide's effects, acting as a substrate receptor for the CRL4 E3 ubiquitin ligase.
  • While CRBN substrates are known, the specific one causing thalidomide's teratogenicity remains unidentified.

Purpose of the Study:

  • To identify the specific substrate of CRL4CRBN responsible for thalidomide's teratogenic effects.
  • To elucidate the mechanism by which thalidomide induces developmental abnormalities.

Main Methods:

  • Utilized a zebrafish model to study thalidomide's teratogenic impact.
  • Investigated the role of p63 isoforms as thalidomide-dependent neosubstrates of CRL4CRBN.

Main Results:

  • p63 isoforms, including ∆Np63α and TAp63α, were identified as thalidomide-dependent CRL4CRBN neosubstrates.
  • Thalidomide induced degradation of ∆Np63α in pectoral fins and TAp63α in otic vesicles, causing teratogenic effects in zebrafish.
  • p63 isoform degradation is implicated in thalidomide-induced limb and cochlea developmental defects.

Conclusions:

  • p63 isoforms are key mediators of thalidomide's teratogenic activity.
  • Understanding this mechanism may facilitate the development of safer thalidomide analogs.
  • This research provides insights into the molecular basis of thalidomide teratogenicity.

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