A novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.

TitleA novel effect of thalidomide and its analogs: suppression of cereblon ubiquitination enhances ubiquitin ligase function.
Publication TypeJournal Article
Year of Publication2015
AuthorsLiu Y, Huang X, He X, Zhou Y, Jiang X, Chen-Kiang S, Jaffrey SR, Xu G
JournalFASEB J
Volume29
Issue12
Pagination4829-39
Date Published2015 Dec
ISSN1530-6860
KeywordsAdaptor Proteins, Signal Transducing, Cell Line, Tumor, HEK293 Cells, Humans, Lenalidomide, Multiple Myeloma, Peptide Hydrolases, Thalidomide, Ubiquitin-Protein Ligases, Ubiquitination
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.

DOI10.1096/fj.15-274050
Alternate JournalFASEB J
PubMed ID26231201
PubMed Central IDPMC4653049
Grant ListR01 CA188794 / CA / NCI NIH HHS / United States
R21 MH086128 / MH / NIMH NIH HHS / United States
MH086128 / MH / NIMH NIH HHS / United States
Related Faculty: 
Selina Chen-Kiang, Ph.D.

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