Tumor suppressor properties of the splicing regulatory factor RBM10

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 genera...

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Detalles Bibliográficos
Autores: Hernández, Jordi, Bechara, Elias, Schlesinger, Doerte, Delgado Blanco, Javier, Serrano Pubull, Luis, 1982-, Valcárcel, J. (Juan)
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/26874
Acceso en línea:http://hdl.handle.net/10230/26874
http://dx.doi.org/10.1080/15476286.2016.1144004
Access Level:acceso abierto
Palabra clave:Pulmons -- Càncer
Lung cancer
NUMB
Notch
RBM10
Splicing
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spelling Tumor suppressor properties of the splicing regulatory factor RBM10Hernández, JordiBechara, EliasSchlesinger, DoerteDelgado Blanco, JavierSerrano Pubull, Luis, 1982-Valcárcel, J. (Juan)Pulmons -- CàncerLung cancerNUMBNotchRBM10SplicingRBM10 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.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.Wiley-Blackwell201620162016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/26874http://dx.doi.org/10.1080/15476286.2016.1144004reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésRNA Biology. 2016; 13(4): 466-472© 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.http://creativecommons.org/licenses/by-nc/3.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/268742026-06-12T07:21:37Z
dc.title.none.fl_str_mv Tumor suppressor properties of the splicing regulatory factor RBM10
title Tumor suppressor properties of the splicing regulatory factor RBM10
spellingShingle Tumor suppressor properties of the splicing regulatory factor RBM10
Hernández, Jordi
Pulmons -- Càncer
Lung cancer
NUMB
Notch
RBM10
Splicing
title_short Tumor suppressor properties of the splicing regulatory factor RBM10
title_full Tumor suppressor properties of the splicing regulatory factor RBM10
title_fullStr Tumor suppressor properties of the splicing regulatory factor RBM10
title_full_unstemmed Tumor suppressor properties of the splicing regulatory factor RBM10
title_sort Tumor suppressor properties of the splicing regulatory factor RBM10
dc.creator.none.fl_str_mv Hernández, Jordi
Bechara, Elias
Schlesinger, Doerte
Delgado Blanco, Javier
Serrano Pubull, Luis, 1982-
Valcárcel, J. (Juan)
author Hernández, Jordi
author_facet Hernández, Jordi
Bechara, Elias
Schlesinger, Doerte
Delgado Blanco, Javier
Serrano Pubull, Luis, 1982-
Valcárcel, J. (Juan)
author_role author
author2 Bechara, Elias
Schlesinger, Doerte
Delgado Blanco, Javier
Serrano Pubull, Luis, 1982-
Valcárcel, J. (Juan)
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Pulmons -- Càncer
Lung cancer
NUMB
Notch
RBM10
Splicing
topic Pulmons -- Càncer
Lung cancer
NUMB
Notch
RBM10
Splicing
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/26874
http://dx.doi.org/10.1080/15476286.2016.1144004
url http://hdl.handle.net/10230/26874
http://dx.doi.org/10.1080/15476286.2016.1144004
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv RNA Biology. 2016; 13(4): 466-472
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley-Blackwell
publisher.none.fl_str_mv Wiley-Blackwell
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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