p63 is a cereblon substrate involved in thalidomide teratogenicity

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 CRL4^CRBN 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 CRL4^CRBN.

Main Results:

• p63 isoforms, including ∆Np63α and TAp63α, were identified as thalidomide-dependent CRL4^CRBN 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.