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A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function
Author(s) -
Liu Yaobin,
Huang Xiangao,
He Xian,
Zhou Yanqing,
Jiang Xiaogang,
ChenKiang Selina,
Jaffrey Samie R.,
Xu Guoqiang
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-274050
Subject(s) - cereblon , ubiquitin ligase , thalidomide , ubiquitin , cullin , pomalidomide , chemistry , ubiquitin protein ligases , microbiology and biotechnology , dna ligase , cancer research , multiple myeloma , biology , biochemistry , gene , immunology
ABSTRACT The immunomodulatory drug (IMiD) thalidomide and its structural analogs lenalidomide and pomalidomide are highly effective in treating clinical indications. Thalidomide binds to cereblon (CRBN), a substrate receptor of the cullin‐4 really interesting new gene (RING) E3 ligase complex. Here, we examine the effect of thalidomide and its analogs on CRBN ubiquitination and its functions in human cell lines. We find that the ubiquitin modification of CRBN includes K48‐linked polyubiquitin chains and that thalidomide blocks the formation of CRBN‐ubiquitin conjugates. Furthermore, we show that ubiquitinated CRBN is targeted for proteasomal degradation. Treatment of human myeloma cell lines such as MM1.S, OPM2, and U266 with thalidomide (100 μM) and its structural analog lenalidomide (10 μM) results in stabilization of CRBN and elevation of CRBN protein levels. This in turn leads to the reduced level of CRBN target proteins and enhances the sensitivity of human multiple myeloma cells to IMiDs. Our results reveal a novel mechanism by which thalidomide and its analogs modulate the CRBN function in cells. Through inhibition of CRBN ubiquitination, thalidomide and its analogs allow CRBN to accumulate, leading to the increased cullin‐4 RING E3 ligase‐mediated degradation of target proteins.—Liu, Y., Huang, X., He, X., Zhou, Y., Jiang, X., Chen‐Kiang, S., Jaffrey, S. R., Xu, G. A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function. FASEB J. 29, 4829–4839 (2015). www.fasebj.org