title: Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells.
abstract: The transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp-1) has crucial roles in the control of plasma cell differentiation and in maintaining survival of plasma cells. However, how Blimp-1 ensures the survival of plasma cell malignancy, multiple myeloma (MM), has remained elusive. Here we identified Aiolos, an anti-apoptotic transcription factor of MM cells, as a Blimp-1-interacting protein by mass spectrometry. ChIP coupled with DNA microarray was used to profile the global binding of Aiolos and Blimp-1 to endogenous targets in MM cells, which revealed their co-binding to a large number of genes, including apoptosis-related genes. Accordingly, Blimp-1 and Aiolos regulate similar transcriptomes in MM cells. Analysis of the binding motifs for Blimp-1 and Aiolos uncovered a partial motif that was similar across sites for both proteins. Aiolos promotes the binding of Blimp-1 to target genes and thereby enhances Blimp-1-dependent transcriptional repression. Furthermore, treatment with an anti-MM agent, lenalidomide, caused ubiquitination and proteasomal degradation of Blimp-1, leading to the de-repression of a new Blimp-1 direct target, CULLIN 4A (CUL4A), and reduced Aiolos levels. Accordingly, lenalidomide-induced cell death was partially rescued by reintroduction of Blimp-1 or knockdown of CUL4A. Thus, we demonstrated the functional impacts and underlying mechanisms of the interaction between Aiolos and Blimp-1 in maintaining MM cell survival. We also showed that interruption of Blimp-1/Aiolos regulatory pathways contributes to lenalidomide-mediated anti-MM activity.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: K-H
authors.initials: KH
authors.lastname: Hung
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: S-T
authors.initials: ST
authors.lastname: Su
authors.affiliation: Department of Bio-Industrial Mechatronics Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Life Science, National Taiwan Ocean University and Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
authors.forename: P-H
authors.initials: PH
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Wu
authors.affiliation: Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.
authors.forename: M-J M
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: P-C
authors.initials: PC
authors.lastname: Wu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: F-R
authors.initials: FR
authors.lastname: Lin
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: M-D
authors.initials: MD
authors.lastname: Tsai
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Lin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000906:Antibodies; C114234:CUL4A protein, human; D044842:Cullin Proteins; C106285:IKZF3 protein, human; D034741:RNA, Small Interfering; D051740:Ikaros Transcription Factor; D013792:Thalidomide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000077269:Lenalidomide
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