2015
DOI: 10.1038/nature14610
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Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

Abstract: SummaryLenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the CRL4CRBN E3 ubiquitin ligase, resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for lenalidomide's therapeutic window in del… Show more

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Cited by 711 publications
(731 citation statements)
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References 38 publications
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“…Thus, the protein interaction, in addition to the regulatory effect of Y384 and W386 on Rabex-5 binding, is conserved between humans and mice. However, consistent with other reports, only human Cereblon is responsive to IMiD binding (13,17).…”
Section: Significancesupporting
confidence: 93%
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“…Thus, the protein interaction, in addition to the regulatory effect of Y384 and W386 on Rabex-5 binding, is conserved between humans and mice. However, consistent with other reports, only human Cereblon is responsive to IMiD binding (13,17).…”
Section: Significancesupporting
confidence: 93%
“…Here, we have identified Rabex-5 as a Cereblon-interacting protein and IMiD target molecule. Our observations on the disruption of Cereblon-Rabex-5 binding differ substantially from previously identified interactions with Ikaros, CK1α, GS, or MEIS2 (10,17,(20)(21)(22). In particular, protein levels of Rabex-5 were not affected by loss of Cereblon binding.…”
Section: Discussioncontrasting
confidence: 56%
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“…A potential mechanism of action of lenalidomide involves the degradation of casein kinase 1A1 (CK1α). 57 In fact, del5q MDS patients possess a heterozygous deletion CK1α. 58 Collectively, our data is in line with Ades and colleagues 39 and suggest that the mechanisms of action of lenalidomide on AML may depend on cell intrinsic/autonomous genetic makeup, further pinpointing genetic and biological heterogeneity in AML.…”
Section: Discussionmentioning
confidence: 99%
“…4c). IMiD-binding by CRL4 CRBN prevents engagement of its endogenous substrate MEIS2; it also re-directs effective recruitment and CRBN-dependent degradation of the transcription factors Ikaros and Aiolos as well as Casein kinase 1α (CK1α) [57][58][59][60]. Additionally, lenalidomide derivative CC-885 was shown to induce recruitment and degradation of the translation termination factor GSPT1 [61].…”
Section: Small-molecule Dependent Degronsmentioning
confidence: 99%