PUBLICATION

Identification of a primary target of thalidomide teratogenicity

Authors
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., and Handa, H.
ID
ZDB-PUB-100317-2
Date
2010
Source
Science (New York, N.Y.)   327(5971): 1345-1350 (Journal)
Registered Authors
Ando, Hideki
Keywords
none
MeSH Terms
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Humans
  • Ubiquitin-Protein Ligases/antagonists & inhibitors
  • Ubiquitin-Protein Ligases/metabolism*
  • Cullin Proteins/metabolism
  • Chick Embryo
  • Carrier Proteins/metabolism
  • Animals
  • Ubiquitination
  • Embryonic Development/drug effects
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Forelimb/abnormalities
  • Forelimb/embryology
  • Gene Expression Regulation, Developmental
  • DNA-Binding Proteins/metabolism*
  • Peptide Hydrolases/genetics
  • Peptide Hydrolases/metabolism*
  • Embryo, Nonmammalian/drug effects
  • Fibroblast Growth Factors/genetics
  • Fibroblast Growth Factors/metabolism
  • Mutant Proteins/metabolism
  • HeLa Cells
  • Teratogens/metabolism
  • Teratogens/toxicity*
  • Thalidomide/metabolism
  • Thalidomide/toxicity*
(all 28)
PubMed
20223979 Full text @ Science
Abstract
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.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
y1TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    crbnMO1-crbnMRPHLNO
    cul4aMO1-cul4aMRPHLNO
    1 - 2 of 2
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    Fish
    1 - 4 of 4
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    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
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    Mapping