What question did this study set out to answer?

To identify the direct molecular target and biochemical mechanism responsible for thalidomide-induced teratogenicity and embryonic limb defects.

March 11, 2010Science

Identification of a Primary Target of Thalidomide Teratogenicity

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Authors

TITakumi Ito HAHideki Ando TSTakayuki Suzuki

Discussion

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Overview

Preclinical study reveals cereblon as the primary target of thalidomide teratogenicity in animal models, suggesting a path toward designing non-teratogenic drug derivatives.

Key Points

To identify the direct molecular target and biochemical mechanism responsible for thalidomide-induced teratogenicity and embryonic limb defects.
Purified and isolated cellular proteins displaying direct binding affinity to thalidomide.
Characterized the multiprotein E3 ubiquitin ligase complex containing the identified target protein, DDB1, and Cul4A.
Investigated the effects of thalidomide-mediated inhibition on limb outgrowth and Fgf8 expression in zebrafish and chick embryonic models.
Identified cereblon (CRBN) as the primary thalidomide-binding protein that associates with DDB1 and Cul4A to form an active E3 ubiquitin ligase complex.
Demonstrated that thalidomide binds directly to CRBN, inhibiting its intrinsic ubiquitin ligase activity and disrupting Fgf8 expression required for normal limb outgrowth.

Cite This Study

Ito et al. (2010) studied this question.

synapsesocial.com/papers/69d817eba2a48916bbbeef64 https://doi.org/10.1126/science.1177319

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March 11, 2010Science

Identification of a Primary Target of Thalidomide Teratogenicity

View Full Paper

Ask AI

Bookmark

Authors

TITakumi Ito HAHideki Ando TSTakayuki Suzuki

Discussion

Member takes

Overview

Preclinical study reveals cereblon as the primary target of thalidomide teratogenicity in animal models, suggesting a path toward designing non-teratogenic drug derivatives.

Key Points

To identify the direct molecular target and biochemical mechanism responsible for thalidomide-induced teratogenicity and embryonic limb defects.
Purified and isolated cellular proteins displaying direct binding affinity to thalidomide.
Characterized the multiprotein E3 ubiquitin ligase complex containing the identified target protein, DDB1, and Cul4A.
Investigated the effects of thalidomide-mediated inhibition on limb outgrowth and Fgf8 expression in zebrafish and chick embryonic models.
Identified cereblon (CRBN) as the primary thalidomide-binding protein that associates with DDB1 and Cul4A to form an active E3 ubiquitin ligase complex.
Demonstrated that thalidomide binds directly to CRBN, inhibiting its intrinsic ubiquitin ligase activity and disrupting Fgf8 expression required for normal limb outgrowth.

Cite This Study

Ito et al. (2010) studied this question.

synapsesocial.com/papers/69d817eba2a48916bbbeef64 https://doi.org/10.1126/science.1177319

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