小脑
沙利度胺
锌指
癌症研究
医学
细胞生物学
转录因子
生物
遗传学
多发性骨髓瘤
内科学
基因
泛素连接酶
泛素
作者
Mary E. Matyskiela,Suzana Couto,Xinde Zheng,Gang Lu,Julia Hui,Katie Stamp,Clifton P. Drew,Yan Ren,Maria Wang,Aaron Carpenter,Chung-Wein Lee,Thomas Clayton,Wei Fang,Chin-Chun Lu,Mariko Riley,Polat Abdubek,Kate Blease,James Hartke,Gondi Kumar,Rupert Vessey,Mark Rolfe,Lawrence G. Hamann,Philip P. Chamberlain
标识
DOI:10.1038/s41589-018-0129-x
摘要
Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.
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