Identification of a Primary Target of Thalidomide Teratogenicity

Ito, Takumi; Ando, Hideki; Suzuki, Takayuki; Ogura, Toshihiko; Hotta, Kentaro; Imamura, Yoshimasa; Yamaguchi, Yuki; Handa, Hiroshi

doi:10.1126/science.1177319

Cited by 1,707 publications

(1,625 citation statements)

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“…Following misexpression of a mutant Cereblon protein that can not bind thalidomide in embryos, thalidomide induced damage was reduced, which included Fgf8 expression being maintained (Ito et al, 2010). Several studies have demonstrated that Fgf8 signaling is reduced or lost in developing chicken and rabbit limbs, and zebrafish fins following thalidomide exposure (Hansen et al, 2002; Ito et al, 2010; Knobloch et al, 2011). However, it is unknown if regulation of Fgf8 is directly or indirectly dependent on Cereblon expression.…”

Section: Cereblonmentioning

confidence: 99%

Thalidomide‐induced teratogenesis: History and mechanisms

Vargesson

2015

Birth Defects Research Pt C

691

557

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Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Section: Cereblonmentioning

confidence: 99%

Thalidomide‐induced teratogenesis: History and mechanisms

Vargesson

2015

Birth Defects Research Pt C

691

557

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“…Bortezomib is a proteasome inhbitor [39][40][41]; the mechanism of action of thalidomide and lenalidomide is unclear, but they are considered immunomodulatory agents [42] and may require cereblon (the putative primary teratogenic target for thalidomide) [43] expression for their anti-myeloma activity [44].…”

Section: Risk-adapted Therapymentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

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“…they stabilize the interaction of the substrate-binding domain of their respective E3 ligase and specific substrates [55]. Strikingly, phthalimide immunomodulatory drugs (IMiDs) thalidomide and its second-generation derivatives lenalidomide and pomalidomide act dually as molecular glues and PPI disruptors in humans by targeting the protein cereblon (CRBN) [56]. CRBN is the substrate-binding domain of the Rbx1-Cul4-DDB1-CRBN (CRL4 CRBN ) E3 ubiquitin ligase (Fig.…”

Section: Small-molecule Dependent Degronsmentioning

confidence: 99%