title: Activation of c-Abl Kinase Potentiates the Anti-myeloma Drug Lenalidomide by Promoting DDA1 Protein Recruitment to the CRL4 Ubiquitin Ligase.
abstract: Cullin-RING ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates the cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Tyr-316 to recruit a small regulatory protein, DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3, in lenalidomide-treated multiple myeloma cells. Importantly, panobinostat, a recently approved anti-myeloma drug, and dexamethasone enhance lenalidomide-induced substrate degradation and cytotoxicity by activating c-Abl, therefore providing a mechanism underlying their combination with lenalidomide to treat multiple myeloma.
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China and.
authors.forename: Shaobing
authors.initials: S
authors.lastname: Gao
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China and.
authors.forename: Chenlu
authors.initials: C
authors.lastname: Geng
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China and.
authors.forename: Tianyu
authors.initials: T
authors.lastname: Song
authors.affiliation: the Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Xuanru
authors.initials: X
authors.lastname: Lin
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China and.
authors.forename: Jiye
authors.initials: J
authors.lastname: Liu
authors.affiliation: the Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.affiliation: From the Life Sciences Institute and Innovation Center for Cell Signaling Networks, Zhejiang University, Hangzhou, Zhejiang 310058, China and cangyong@zju.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D000077767:Panobinostat; D011485:Protein Binding; D059748:Proteolysis; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D053722:Receptors, Interleukin-17
chemical_list: D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D006877:Hydroxamic Acids; D007211:Indoles; D000077269:Lenalidomide; D000077767:Panobinostat; D016315:Proto-Oncogene Proteins c-abl; D013792:Thalidomide; D014443:Tyrosine; D044767:Ubiquitin-Protein Ligases; C541165:DDA1 protein, human; C091435:DDB1 protein, human; C408922:IL17RB protein, human; D053722:Receptors, Interleukin-17
keywords: CRL4; DDA1; c-Abl; cancer biology; cancer therapy; lenalidomide; molecular cell biology; ubiquitin ligase; ubiquitylation (ubiquitination)