Publication Date:
2010-03-13
Description:
Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takumi -- Ando, Hideki -- Suzuki, Takayuki -- Ogura, Toshihiko -- Hotta, Kentaro -- Imamura, Yoshimasa -- Yamaguchi, Yuki -- Handa, Hiroshi -- New York, N.Y. -- Science. 2010 Mar 12;327(5971):1345-50. doi: 10.1126/science.1177319.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Integrated Research Institute, Tokyo Institute of Technology, Yokohama 226-8503, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20223979" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Carrier Proteins/metabolism
;
Chick Embryo
;
Cullin Proteins/metabolism
;
DNA-Binding Proteins/*metabolism
;
Embryo, Nonmammalian/drug effects
;
Embryonic Development/drug effects
;
Fibroblast Growth Factors/genetics/metabolism
;
Forelimb/abnormalities/embryology
;
Gene Expression Regulation, Developmental
;
HeLa Cells
;
Humans
;
Mutant Proteins/metabolism
;
Peptide Hydrolases/genetics/*metabolism
;
Teratogens/metabolism/*toxicity
;
Thalidomide/metabolism/*toxicity
;
Ubiquitin-Protein Ligases/antagonists & inhibitors/*metabolism
;
Ubiquitination
;
Zebrafish/embryology/genetics
;
Zebrafish Proteins/genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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