Recent advances in the molecular mechanism of thalidomide teratogenicity - 30/05/20
, Shichao Wang b, Ruihua Fan a, Jieying Hu a, ⁎ Bienvenue sur EM-consulte, la référence des professionnels de santé.
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Graphical abstract |
Highlights |
• | Thalidomide hijacks CRL4CRBN E3 ligase to ubiquitinate and degrade cellular proteins. |
• | Thalidomide-induced degradation of SALL4 and p63 very likely plays a critical role in thalidomide embryopathy. |
• | Neosubstrate degradation and other mechanisms are not mutually exclusive and may cause thalidomide embryopathy together. |
Abstract |
Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the pleiotropic properties of this class of drugs, including their anti-inflammatory, antiangiogenic and immunomodulatory activities. Based on their notable activities, thalidomide and its analogues, lenalidomide and pomalidomide, have been repurposed to treat erythema nodosum leprosum, multiple myeloma and other haematological malignancies. Thalidomide analogues were recently found to hijack CRL4CRBN ubiquitin ligase to target a number of cellular proteins for ubiquitination and proteasomal degradation. Thalidomide-mediated degradation of SALL4 and p63, transcription factors essential for embryonic development, very likely plays a critical role in thalidomide embryopathy. In this review, we provide a brief retrospective summary of thalidomide-induced teratogenesis, the mechanism of thalidomide activity, and the latest advances in the molecular mechanism of thalidomide-induced birth malformations.
Le texte complet de cet article est disponible en PDF.Abbreviations : CRL4, DRRS, ESCs, HOS, IMiDs, MDS, MM, NO, ROS, SALL4, TNF-α
Keywords : Thalidomide, Teratogenicity, CRL4CRBN, SALL4, p63, Ubiquitination
Plan
Vol 127
Article 110114- juillet 2020 Retour au numéro
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