p63 and mutations involved in developmental syndrome, a tale that connects to thalidomide

Cibio Seminar

May 29th
Versione stampabile

Luisa Guerrini
Dept of BioSciences, University of Milano

11.30 a.m. - Aula A203
Via Sommarive 5 - Povo, Trento

Severe developmental malformations were detected in human fetus in the 1950s when women used the anti-nausea and sedative drug Thalidomide in the first trimester of pregnancy1. The molecular mechanisms underlying Thalidomide teratogenicity were unknown after almost 6o years from its withdrawal from the market. Further studies revealed new potential therapeutic activities of thalidomide and its derivatives, leading to the approval of thalidomide for the treatment of leprosy and multiple myeloma. Cereblon (CRBN) is the primary target of thalidomide teratogenicity2. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4. Thalidomide and other ligands modulate substrate specificity of CRL4CRBN, but the substrate responsible for thalidomide teratogenicity was unknown. The striking similarities between the phenotypic abnormalities of babies born from mother exposed to thalidomide during pregnancy and patients affected by syndromes associated with mutations in the p63 gene3, prompted us to verify whether p63 could be the substrate responsible for Thalidomide teratogenicity. Here we show that TAp63 and Np63 proteins are degraded by thalidomide by the CRBN E3 ubiquitin ligase complex. Thalidomide initiates its teratogenic effects by binding to CRBN and this enhances p63/CRBN interaction resulting in p63 degradation both in vitro and in vivo. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicle by binding to CRBN and inducing the degradation of z∆Np63α and zTAp63α, respectively4. The results shed new light on the molecular mechanisms of thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.