title: Tumor suppressor properties of the splicing regulatory factor RBM10.
abstract: RBM10 is an RNA binding protein and alternative splicing regulator frequently mutated in lung adenocarcinomas. Recent results indicate that RBM10 inhibits proliferation of lung cancer cells by promoting skipping of exon 9 of the gene NUMB, a frequent alternative splicing change in lung cancer generating a negative regulator of Notch signaling. Complementing these observations, we show that knock down of RBM10 in human cancer cells enhances growth of mouse tumor xenografts, confirming that RBM10 acts as a tumor suppressor, while knock down of an oncogenic mutant version of RBM10 reduces xenograft tumor growth. A RBM10 mutation found in lung cancer cells, V354E, disrupts RBM10-mediated regulation of NUMB alternative splicing, inducing the cell proliferation-promoting isoform. We now show that 2 natural RBM10 isoforms that differ by the presence or absence of V354 in the second RNA Recognition Motif (RRM2), display similar regulatory effects on NUMB alternative splicing, suggesting that V354E actively disrupts RBM10 activity. Structural modeling localizes V354 in the outside surface of one α-helix opposite to the RNA binding surface of RBM10, and we show that the mutation does not compromise binding of the RRM2 domain to NUMB RNA regulatory sequences. We further show that other RBM10 mutations found in lung adenocarcinomas also compromise regulation of NUMB exon 9. Collectively, our previous and current results reveal that RBM10 is a tumor suppressor that represses Notch signaling and cell proliferation through the regulation of NUMB alternative splicing.
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.|b Universitat Pompeu Fabra , Dr. Aiguader 88, 08003 Barcelona , Spain.
authors: Jordi
authors: J
authors: Hernández
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.|b Universitat Pompeu Fabra , Dr. Aiguader 88, 08003 Barcelona , Spain.
authors: Elias
authors: E
authors: Bechara
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.
authors: Doerte
authors: D
authors: Schlesinger
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.|b Universitat Pompeu Fabra , Dr. Aiguader 88, 08003 Barcelona , Spain.
authors: Javier
authors: J
authors: Delgado
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.|b Universitat Pompeu Fabra , Dr. Aiguader 88, 08003 Barcelona , Spain.|c Institució Catalana de Recerca i Estudis Avançats (ICREA) , Passeig Lluis Companys 23, 08010 Barcelona , Spain.
authors: Luis
authors: L
authors: Serrano
authors: a Centre de Regulació Genòmica, The Barcelona Institute of Science and Technology , Dr. Aiguader 88, 08003 Barcelona , Spain.|b Universitat Pompeu Fabra , Dr. Aiguader 88, 08003 Barcelona , Spain.|c Institució Catalana de Recerca i Estudis Avançats (ICREA) , Passeig Lluis Companys 23, 08010 Barcelona , Spain.
authors: Juan
authors: J
authors: Valcárcel
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D009154:Mutation; D016601:RNA-Binding Proteins / Q000502:physiology*
chemical_list: C512260:RBM10 protein, human; D016601:RNA-Binding Proteins
keywords: Lung cancer; NUMB; Notch; RBM10; splicing