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Nature DOI:10.1038/nature14610

Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.

Publication TypeJournal Article
Year of Publication2015
AuthorsKrönke, J, Fink, EC, Hollenbach, PW, MacBeth, KJ, Hurst, SN, Udeshi, ND, Chamberlain, PP, Mani, DR, Man, HWah, Gandhi, AK, Svinkina, T, Schneider, RK, McConkey, M, Järås, M, Griffiths, E, Wetzler, M, Bullinger, L, Cathers, BE, Carr, SA, Chopra, R, Ebert, BL
JournalNature
Volume523
Issue7559
Pages183-8
Date Published2015 Jul 09
ISSN1476-4687
KeywordsAmino Acid Sequence, Animals, Casein Kinase I, Cell Line, Gene Expression Regulation, HEK293 Cells, Humans, Immunologic Factors, Jurkat Cells, K562 Cells, Mice, Molecular Sequence Data, Myelodysplastic Syndromes, Peptide Hydrolases, Proteolysis, Sequence Alignment, Sequence Deletion, Species Specificity, Thalidomide, Ubiquitin-Protein Ligases, Ubiquitination
Abstract

Lenalidomide 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 E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), 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 the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.

URLhttp://dx.doi.org/10.1038/nature14610
DOI10.1038/nature14610
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26131937?dopt=Abstract

Alternate JournalNature
PubMed ID26131937
PubMed Central IDPMC4853910
Grant ListP01CA108631 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
11566 / / Cancer Research UK / United Kingdom
R01HL082945 / HL / NHLBI NIH HHS / United States