title: Transcription factor IKZF1 is degraded during the apoptosis of multiple myeloma cells induced by kinase inhibition.
abstract: Immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide exhibit high responsive rates for newly identified or relapsed multiple myeloma patients. However, their mechanisms of action are not completely understood. One mechanism involves the ubiquitination and degradation of two transcription factors, IKZF1 and IKZF3. Whether there are other degradation pathways for IKZF1 in myeloma cells remains unknown. Here, we found that although IKZF1 ubiquitination was reduced, its stability was also significantly reduced in MM1.S and OPM2 cells treated with kinase inhibitors, 5,6-dichlorobenzimidazole riboside (DRB) or roscovitine. Through pharmacological inhibition and biochemical approaches we demonstrated that instead of undergoing the ubiquitin-proteasome pathway, IKZF1 was degraded through apoptosis induced by kinase inhibition. This result may provide a new direction in developing therapeutic treatments for myeloma patients.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yaobin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Xian
authors.initials: X
authors.lastname: He
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Sui
authors.affiliation: Department of Oncology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, China. Electronic address: gux2002@suda.edu.cn.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D015151:Immunoblotting; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D013997:Time Factors; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C497239:IKZF1 protein, human; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051740:Ikaros Transcription Factor; D004004:Dichlororibofuranosylbenzimidazole
keywords: Apoptosis; Degradation; IKZF1; Kinase inhibitor; Multiple myeloma; Ubiquitination