KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.

In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we...

Descripción completa

Detalles Bibliográficos
Autores: Salmón, Marina, Paniagua, Guillem, Fernández-García, Fernando, Zarzuela, Eduardo, Álvarez-Díaz, Ruth, Musteanu, Mónica, Muñoz, Javier, Drosten, Matthias, Lechuga, Carmen G, Guerra, Carmen, Caleiras, E, Ortega Jimenez, Sagrario, Barbacid, Mariano
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/14703
Acceso en línea:http://hdl.handle.net/20.500.12105/14703
Access Level:acceso abierto
Palabra clave:Adenocarcinoma of Lung
Animals
Apoptosis
Cell Proliferation
Female
Humans
Lung Neoplasms
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Protein Isoforms
Proto-Oncogene Proteins p21(ras)
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
id ES_952aee256e2b9ef204db5bb4e99ea0bd
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/14703
network_acronym_str ES
network_name_str España
repository_id_str
spelling KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.Salmón, MarinaPaniagua, GuillemFernández-García, FernandoZarzuela, EduardoÁlvarez-Díaz, RuthMusteanu, MónicaMuñoz, JavierDrosten, MatthiasLechuga, Carmen GGuerra, CarmenCaleiras, EOrtega Jimenez, SagrarioBarbacid, MarianoAdenocarcinoma of LungAnimalsApoptosisCell ProliferationFemaleHumansLung NeoplasmsMaleMiceMice, Inbred C57BLMice, KnockoutMutationProtein IsoformsProto-Oncogene Proteins p21(ras)Tumor Cells, CulturedXenograft Model Antitumor AssaysIn mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.Nature Publishing GroupUnión Europea. Comisión Europea. European Research Council (ERC)Unión Europea. Comisión EuropeaMinisterio de Economía, Industria y Competitividad (España)Comunidad de Madrid (España)CRIS contra el CáncerFundación AXA20222022-07-1320212021-07-2720212021-07-27journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/14703reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566open accesshttp://purl.org/coar/access_right/c_abf2Atribución-NoComercial-CompartirIgual 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/147032026-06-12T12:43:37Z
dc.title.none.fl_str_mv KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
title KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
spellingShingle KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
Salmón, Marina
Adenocarcinoma of Lung
Animals
Apoptosis
Cell Proliferation
Female
Humans
Lung Neoplasms
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Protein Isoforms
Proto-Oncogene Proteins p21(ras)
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
title_short KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
title_full KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
title_fullStr KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
title_full_unstemmed KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
title_sort KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.
dc.creator.none.fl_str_mv Salmón, Marina
Paniagua, Guillem
Fernández-García, Fernando
Zarzuela, Eduardo
Álvarez-Díaz, Ruth
Musteanu, Mónica
Muñoz, Javier
Drosten, Matthias
Lechuga, Carmen G
Guerra, Carmen
Caleiras, E
Ortega Jimenez, Sagrario
Barbacid, Mariano
author Salmón, Marina
author_facet Salmón, Marina
Paniagua, Guillem
Fernández-García, Fernando
Zarzuela, Eduardo
Álvarez-Díaz, Ruth
Musteanu, Mónica
Muñoz, Javier
Drosten, Matthias
Lechuga, Carmen G
Guerra, Carmen
Caleiras, E
Ortega Jimenez, Sagrario
Barbacid, Mariano
author_role author
author2 Paniagua, Guillem
Fernández-García, Fernando
Zarzuela, Eduardo
Álvarez-Díaz, Ruth
Musteanu, Mónica
Muñoz, Javier
Drosten, Matthias
Lechuga, Carmen G
Guerra, Carmen
Caleiras, E
Ortega Jimenez, Sagrario
Barbacid, Mariano
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Unión Europea. Comisión Europea. European Research Council (ERC)
Unión Europea. Comisión Europea
Ministerio de Economía, Industria y Competitividad (España)
Comunidad de Madrid (España)
CRIS contra el Cáncer
Fundación AXA
dc.subject.none.fl_str_mv Adenocarcinoma of Lung
Animals
Apoptosis
Cell Proliferation
Female
Humans
Lung Neoplasms
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Protein Isoforms
Proto-Oncogene Proteins p21(ras)
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
topic Adenocarcinoma of Lung
Animals
Apoptosis
Cell Proliferation
Female
Humans
Lung Neoplasms
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Protein Isoforms
Proto-Oncogene Proteins p21(ras)
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
description In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a Kras FSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras +/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras +/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-07-27
2021
2021-07-27
2022
2022-07-13
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/14703
url http://hdl.handle.net/20.500.12105/14703
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución-NoComercial-CompartirIgual 4.0 Internacional
http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869413784382078976
score 15,81155

Similares en LA Referencia