GPMDB00194OtherKroenke J, et al.InstrumentNot AvailableNot availableHomo_sapiens_viruses, Humanclauser@broad.mit.edu24292625Brigham and Women-s Hospital, 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availableGPMDBLenalidomide 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.Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.Krönke Jan J,Udeshi Namrata D ND,Narla Anupama A,Grauman Peter P,Hurst Slater N SN,McConkey Marie M,Svinkina Tanya T,Heckl Dirk D,Comer Eamon E,Li Xiaoyu X,Ciarlo Christie C,Hartman Emily E,Munshi Nikhil N,Schenone Monica M,Schreiber Stuart L SL,Carr Steven A SA,Ebert Benjamin L BL,Krönke Jan J, Udeshi Namrata D ND, Narla Anupama A, Grauman Peter P, Hurst Slater N SN, McConkey Marie M, Svinkina Tanya T, Heckl Dirk D, Comer Eamon E, Li Xiaoyu X, Ciarlo Christie C, Hartman Emily E, Munshi Nikhil N, Schenone Monica M, Schreiber Stuart L SL, Carr Steven A SA, Ebert Benjamin L BLPlasma-Cell Myelomas, multicellular organismal catabolic process, single-organism catabolic process, Disease, Zfpn1a3, Myelomas, Revimid, degradation, Zfpn1a1, ZNFN1A1, Hs.54452, Myeloma, Multiple myeloma (disorder), ZNFN1A3, Kahler's disease, Multiple myeloma without mention of having achieved remission, RGD1562979, Cell Myelomas, Myeloma Multiple, Myeloma-Multiples, Myeloma-Multiple, PPP1R92, MM, multiple myeloma, Kahler, Multiple Myelomas, IKAROS, hlk-1, AIO, 5832432G11Rik, [M]Plasma cell myeloma, Aiolos, Myelomatoses, Znfn1a3, 2, Znfn1a1, NOS, Cell., Ikaros, Myelomatosis, PRO0758, 6-Piperidinedione, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), AIOLOS, Plasma-Cell, Plasma-Cell Myeloma, 3-(4-amino-1, CC5013, Plasmacytic myeloma, 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2, Plasma, 5830411O07Rik, MULT MYE W/O ACHV RMSON, breakdown, Multiple myeloma, CC 5013, catabolism, IK1, Plasma Cell Myelomas, myeloma, Kahler Disease, LYF1, Multiple myeloma without mention of remission, CC-5013, Multiple, 6-dione, no ICD-O subtype, Cell Myeloma, Plasma Cell Myeloma, no ICD-O subtype (morphologic abnormality), 3-dihydro-1-oxo-2H- isoindol-2-yl)-, Multiple myeloma (clinical), mKIAA4227, Plasma Cell, LyF-1, Revlimid, Kahler disease, IMiD3 cpdmulticellular organismal catabolic process, single-organism catabolic process, B Cells, Zfpn1a3, CRL4, EVI27, Zfpn1a1, Bursa-Dependent Lymphocytes, Hs.54452, Multiple myeloma (disorder), Kahler's disease, Multiple myeloma without mention of having achieved remission, Neoplasms, Cell Myelomas, B cell, Benign Neoplasm, number, Substitution, ATP Dependent Proteolysis Factor 1, Ubiquitin carboxyl extension protein 80, Tumor, Myeloma-Multiples, Malignant, Transcription Factor, Myeloma-Multiple, presence, NEOPL, Human, Multiple Myelomas, IKAROS, hlk-1, AIO, inhibition of cell growth, [M]Plasma cell myeloma, resistance, Aiolos, Myelomatoses, Znfn1a3, 2, Znfn1a1, HMG-20, ubiquitin-like protein modifier, CC5013, Plasmacytic myeloma, 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2, 5830411O07Rik, down-regulation of cell growth, Transcription, B-cell, Ubiquitylation, Multiple myeloma, High Mobility Protein 20, Malignancy, catabolism, IK1, IL17BR, down regulation of cell growth, Plasma Cell Myelomas, myeloma, Ubiquitin-related 1, Sciences, tumour, Neoplasias, APF-1, CC-5013, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), 40S ribosomal protein S27a, drugs, 6-dione, Cell Myeloma, B lymphocyte, medicine, no ICD-O subtype (morphologic abnormality), ubiquitin, 3-dihydro-1-oxo-2H- isoindol-2-yl)-, Malignancies, ubiquitination, Aiolos., Plasma Cell, protein tagging activity, Revlimid, Neoplastic Growth, Tumors, Cancer, Plasma-Cell Myelomas, data, Disease, Myelomas, Malignant Neoplasm, Revimid, degradation, B Lymphocytes, Myeloma, ZNFN1A1, ZNFN1A3, drug, RGD1562979, Myeloma Multiple, Factor, CEP52, Amino Acid Substitutions, tumours, Cell, PPP1R92, MM, multiple myeloma, Kahler, count in organism, Experiment, Ubiquitin A-52 residue ribosomal protein fusion product 1, Benign, count, Ubiquitin-related 2, 5832432G11Rik, Neoplasm, IL17RH1, NOS, Myelomatosis, Ikaros, ATP-Dependent Proteolysis Factor 1, PRO0758, 6-Piperidinedione, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), Plasma-Cell, Plasma-Cell Myeloma, AIOLOS, MRT2A, 3-(4-amino-1, Ubiquitin, Plasma, covalent modifier, Amino Acid, MULT MYE W/O ACHV RMSON, breakdown, Factors, B-Lymphocytes, CC 5013, Human Ubiquitin, Kahler Disease, Benign Neoplasms, Bursa-Equivalent Lymphocyte, Cancers, Substitutions, LYF1, Multiple myeloma without mention of remission, Malignant Neoplasms, Multiple, B-Cells, no ICD-O subtype, MRT2, IL-2 production, Plasma Cell Myeloma, 60S ribosomal protein L40, B-Lymphocyte, ligase, downregulation of cell growth, Ubiquitin-related, Multiple myeloma (clinical), quantitative, mKIAA4227, B-lymphocyte, LyF-1, NEOPLASMS BENIGN, Neoplasia, Kahler disease, IMiD3 cpd, presence or absence in organismPlasma-Cell Myelomas, multicellular organismal catabolic process, single-organism catabolic process, Disease, Zfpn1a3, Myelomas, Revimid, degradation, Zfpn1a1, ZNFN1A1, Hs.54452, Myeloma, Multiple myeloma (disorder), ZNFN1A3, Kahler's disease, Multiple myeloma without mention of having achieved remission, RGD1562979, Cell Myelomas, Myeloma Multiple, Myeloma-Multiples, Myeloma-Multiple, PPP1R92, MM, multiple myeloma, Kahler, Multiple Myelomas, IKAROS, hlk-1, AIO, 5832432G11Rik, [M]Plasma cell myeloma, Aiolos, Myelomatoses, Znfn1a3, 2, Znfn1a1, NOS, Cell., Ikaros, Myelomatosis, PRO0758, 6-Piperidinedione, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), AIOLOS, Plasma-Cell, Plasma-Cell Myeloma, 3-(4-amino-1, CC5013, Plasmacytic myeloma, 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2, Plasma, 5830411O07Rik, MULT MYE W/O ACHV RMSON, breakdown, Multiple myeloma, CC 5013, catabolism, IK1, Plasma Cell Myelomas, myeloma, Kahler Disease, LYF1, Multiple myeloma without mention of remission, CC-5013, Multiple, 6-dione, no ICD-O subtype, Cell Myeloma, Plasma Cell Myeloma, no ICD-O subtype (morphologic abnormality), 3-dihydro-1-oxo-2H- isoindol-2-yl)-, Multiple myeloma (clinical), mKIAA4227, Plasma Cell, LyF-1, Revlimid, Kahler disease, IMiD3 cpdmulticellular organismal catabolic process, single-organism catabolic process, B Cells, Zfpn1a3, CRL4, EVI27, Zfpn1a1, Bursa-Dependent Lymphocytes, Hs.54452, Multiple myeloma (disorder), Kahler's disease, Multiple myeloma without mention of having achieved remission, Neoplasms, Cell Myelomas, B cell, Benign Neoplasm, number, Substitution, ATP Dependent Proteolysis Factor 1, Ubiquitin carboxyl extension protein 80, Tumor, Myeloma-Multiples, Malignant, Transcription Factor, Myeloma-Multiple, presence, NEOPL, Human, Multiple Myelomas, IKAROS, hlk-1, AIO, conclusions, inhibition of cell growth, [M]Plasma cell myeloma, resistance, Aiolos, Myelomatoses, symptoms, Znfn1a3, 2, Znfn1a1, HMG-20, ubiquitin-like protein modifier, CC5013, Plasmacytic myeloma, 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2, 5830411O07Rik, down-regulation of cell growth, Transcription, B-cell, Ubiquitylation, Multiple myeloma, High Mobility Protein 20, Malignancy, catabolism, IK1, IL17BR, down regulation of cell growth, Plasma Cell Myelomas, myeloma, Ubiquitin-related 1, tumour, Neoplasias, APF-1, CC-5013, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), 40S ribosomal protein S27a, drugs, 6-dione, Cell Myeloma, B lymphocyte, medicine, no ICD-O subtype (morphologic abnormality), ubiquitin, 3-dihydro-1-oxo-2H- isoindol-2-yl)-, Malignancies, ubiquitination, Plasma Cell, protein tagging activity, Revlimid, Neoplastic Growth, Tumors, Cancer, Plasma-Cell Myelomas, screening, Disease, findings, Myelomas, Malignant Neoplasm, Revimid, degradation, B Lymphocytes, Myeloma, ZNFN1A1, ZNFN1A3, drug, RGD1562979, Myeloma Multiple, Factor, CEP52, Amino Acid Substitutions, tumours, Cell, PPP1R92, MM, multiple myeloma, Kahler, count in organism, Ubiquitin A-52 residue ribosomal protein fusion product 1, Benign, count, Ubiquitin-related 2, 5832432G11Rik, Neoplasm, IL17RH1, NOS, concluding remarks, Myelomatosis, Ikaros, ATP-Dependent Proteolysis Factor 1, PRO0758, 6-Piperidinedione, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), Plasma-Cell, Plasma-Cell Myeloma, AIOLOS, MRT2A, 3-(4-amino-1, Ubiquitin, Plasma, covalent modifier, Amino Acid, MULT MYE W/O ACHV RMSON, breakdown, Factors, B-Lymphocytes, CC 5013, conclusion, Human Ubiquitin, signs, Kahler Disease, Benign Neoplasms, Bursa-Equivalent Lymphocyte, catabolism., Cancers, Substitutions, LYF1, Multiple myeloma without mention of remission, Malignant Neoplasms, summary, Multiple, B-Cells, no ICD-O subtype, MRT2, IL-2 production, Plasma Cell Myeloma, 60S ribosomal protein L40, B-Lymphocyte, ligase, downregulation of cell growth, Ubiquitin-related, Multiple myeloma (clinical), quantitative, mKIAA4227, B-lymphocyte, LyF-1, NEOPLASMS BENIGN, Neoplasia, Kahler disease, IMiD3 cpd, presence or absence in organism1904http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32310006306dbgap_ncbi~0patentfamilies~0rfam~0merops~0complex-portal~0uniprot~0wormbaseparasite~0embl-covid19~0reactome~0emdb~0wgs_masters~0ebiweb_resources~0opentargets_genetics~0biomodels_all~0ipd-mhc~0ebiweb_teams~0taxonomy~0genome_assembly~0sc-experiments~0ebiweb_people~0enzymeportal_enzymes~0ipd-nhkir~0cellosaurus~0pdbe~0chebi~0patentproteins~0interpro7~0uniref~0chembl~0pdbekb~0gpcrdb~0hgnc~0sc-genes~0intact~0rhea~0ebiweb_training~0alphafold~0imgt-hla~0patentnucleotides~0ensemblroot~0eva_studies~0non-coding~0europepmc~0pubmed~1identifiers_registry~0pdbechem~0massive~1hpa-covid19~0eva-variants-covid19~0biosamples~0gwas_catalog~0biotools~0tls_masters~0mesh~0coding~0sra~0opentargets~0efo~0embl-pathogen~0project~0human_diseases~0geo_datasets~0embl~0treefam~0uniparc~0ols~0dgva~0intenz~0go~0tsa_masters~0biosamples-covid19~0ebiweb_corporate~0omim~0lrg~0earlycause-molecular-sequences~0ipd-kir~0empiar~0rnacentral~0orcid_data_claims~0gpmdb~2lineage-covid19~0metagenomics~0pfam~0varsite~00Resource Reanalysis0.00.00.0058605798889574340.01.0falseLenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma CellsData from Massive, ID: MSV000079017. Experiment: KGG, Rep2, file: G20121009_NU_Ebert_KGG_L-1uMLen_M-No_H-20uMThal_Rep02_bRPFxn06.mzml. Published as part of Science. 2014 Jan 17;343(6168):301-5 . From the Abstract: {{i}} 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 ... {{/i}}2015-01-29GPM3231000630624292625MSV000079017