SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate

被引：218

作者：

Matyskiela, Mary E. ^{[1
]}

Couto, Suzana ^{[1
]}

Zheng, Xinde ^{[1
]}

Lu, Gang ^{[1
]}

Hui, Julia ^{[1
]}

Stamp, Katie ^{[1
]}

Drew, Clifton ^{[1
]}

Ren, Yan ^{[1
]}

Wang, Maria ^{[1
]}

Carpenter, Aaron ^{[1
]}

Lee, Chung-Wein ^{[1
]}

Clayton, Thomas ^{[1
]}

Fang, Wei ^{[1
]}

Lu, Chin-Chun ^{[1
]}

Riley, Mariko ^{[1
]}

Abdubek, Polat ^{[1
]}

Blease, Kate ^{[1
]}

Hartke, James ^{[1
]}

Kumar, Gondi ^{[1
]}

Vessey, Rupert ^{[1
]}

Rolfe, Mark ^{[1
]}

Hamann, Lawrence G. ^{[1
]}

Chamberlain, Philip P. ^{[1
]}

机构：

[1] Celgene Corp, San Diego, CA 92121 USA

来源：

NATURE CHEMICAL BIOLOGY | 2018年 / 14卷 / 10期

关键词：

E3 UBIQUITIN LIGASE; RENAL-OCULAR SYNDROME; RADIAL RAY SYNDROME; OKIHIRO-SYNDROME; CONGENITAL-ABNORMALITIES; PROTEIN-DEGRADATION; MULTIPLE-MYELOMA; LENALIDOMIDE; MUTATIONS; GENE;

D O I：

10.1038/s41589-018-0129-x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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 acrorenal-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.

引用

页码：981 / +

页数：9

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