SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate
| Autor: | Mariko Riley, Katie Stamp, Xinde Zheng, Yan Ren, Kate Blease, Chin-Chun Lu, Julia Hui, Lawrence G Hamann, Philip P Chamberlain, Gang Lu, Polat Abdubek, Mary E Matyskiela, Gondi Kumar, Maria Wang, Wei Fang, Aaron Carpenter, Thomas Clayton, Clifton Drew, Suzana Couto, Chung-Wein Lee, Mark Rolfe, Rupert Vessey, James Hartke |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Ubiquitin-Protein Ligases Transgene Induced Pluripotent Stem Cells Mice Transgenic Nerve Tissue Proteins Phocomelia Protein degradation Ligands medicine.disease_cause 01 natural sciences Mice 03 medical and health sciences SALL4 Testis Animals Humans Medicine Molecular Biology Adaptor Proteins Signal Transducing Zinc finger Mutation 010405 organic chemistry business.industry Cereblon Homozygote Zinc Fingers Cell Biology medicine.disease Immunohistochemistry eye diseases Thalidomide 0104 chemical sciences DNA-Binding Proteins Teratogens 030104 developmental biology Gene Expression Regulation Proteolysis Cancer research Rabbits business Peptide Hydrolases Transcription Factors medicine.drug |
| Zdroj: | Nature Chemical Biology. 14:981-987 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/s41589-018-0129-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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