Tumor suppressor properties of the splicing regulatory factor RBM10
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- dc.contributor.author Hernández, Jordica
- dc.contributor.author Bechara, Eliasca
- dc.contributor.author Schlesinger, Doerteca
- dc.contributor.author Delgado Blanco, Javierca
- dc.contributor.author Serrano Pubull, Luis, 1982-ca
- dc.contributor.author Valcárcel, J. (Juan)ca
- dc.date.accessioned 2016-06-08T13:05:39Z
- dc.date.available 2016-06-08T13:05:39Z
- dc.date.issued 2016
- dc.description.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.ca
- dc.description.sponsorship EB was supported by a Marie Curie postdoctoral fellowship and JH by a La Caixa predoctoral fellowship. Work in JV and LS labs was supported by grants from Fundación Botín, Banco de Santander through its Santander Universities Global Division and by Consolider RNAREG, MICINN and AGAUR and we acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de Excelencia Severo Ochoa 2013–2017′, SEV-2012-0208.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Hernández J, Bechara E, Schlesinger D, Delgado J, Serrano L, Valcárcel J. Tumor suppressor properties of the splicing regulatory factor RBM10. RNA Biology. 2016; 13(4): 466-472. DOI 10.1080/15476286.2016.1144004ca
- dc.identifier.doi http://dx.doi.org/10.1080/15476286.2016.1144004
- dc.identifier.issn 1547-6286
- dc.identifier.uri http://hdl.handle.net/10230/26874
- dc.language.iso engca
- dc.publisher Wiley-Blackwellca
- dc.relation.ispartof RNA Biology. 2016; 13(4): 466-472
- dc.rights © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC/nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by-nc/3.0/ca
- dc.subject.keyword Lung cancer
- dc.subject.keyword NUMB
- dc.subject.keyword Notch
- dc.subject.keyword RBM10
- dc.subject.keyword Splicing
- dc.subject.other Pulmons -- Càncerca
- dc.title Tumor suppressor properties of the splicing regulatory factor RBM10ca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca