小脑
沙利度胺
来那度胺
酪蛋白激酶1
平方毫米
癌症研究
泛素连接酶
泛素
生物
多发性骨髓瘤
化学
激酶
基因
生物化学
免疫学
蛋白激酶A
作者
Jan Krönke,Emma C. Fink,Paul W. Hollenbach,Kyle J. MacBeth,Slater N. Hurst,Namrata D. Udeshi,Philip P. Chamberlain,D. R. Mani,Hon Wah Man,Anita K. Gandhi,Tanya Svinkina,Rebekka K. Schneider,Marie McConkey,Marcus Järås,Elizabeth A. Griffiths,Meir Wetzler,Lars Bullinger,Brian E. Cathers,Steven A. Carr,Rajesh Chopra,Benjamin L. Ebert
出处
期刊:Nature
[Springer Nature]
日期:2015-07-01
卷期号:523 (7559): 183-188
被引量:630
摘要
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.
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