title: RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation.
abstract: RBM5, a regulator of alternative splicing of apoptotic genes, and its highly homologous RBM6 and RBM10 are RNA-binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation, and its modulation recapitulates or antagonizes the effects of RBM5, 6, and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation.
authors: Centre de Regulació Genòmica, Dr. Aiguader, 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Elias G
authors: EG
authors: Bechara
authors: Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Endre
authors: E
authors: Sebestyén
authors: Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Isabella
authors: I
authors: Bernardis
authors: Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors: Eduardo
authors: E
authors: Eyras
authors: Centre de Regulació Genòmica, Dr. Aiguader, 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Dr. Aiguader, 88, 08003 Barcelona, Spain. Electronic address: juan.valcarcel@crg.es.
authors: Juan
authors: J
authors: Valcárcel
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C512260:RBM10 protein, human; C473448:RBM5 protein, human; C120511:RBM6 protein, human; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D012313:RNA