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PXD001733 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleLenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells
DescriptionKrönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL. Science 2014, 343, 301-305. doi:10.1126/science.1244851. Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterKarl Clauser
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListubiquitination signature dipeptidyl lysine; unknown modification: C-carbamidomethyl; unknown modification: SILAC-R0K0,R6K4,R10K8; unknown modification: Protein Nterm-Acetyl; unknown modification: M-oxidation
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02015-01-26 17:29:02ID requested
12015-01-26 18:40:46announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: lenalidomide, ubiquitin
Contact List
Steven A. Carr
lab head
Karl Clauser
contact affiliationBroad Institute of MIT and Harvard
contact emailclauser@broad.mit.edu
dataset submitter
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