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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2021 |
| Country: | España |
| Institution: | Instituto de Salud Carlos III (ISCIII) |
| Repository: | Repisalud |
| Language: | English |
| OAI Identifier: | oai:repisalud.isciii.es:20.500.12105/14703 |
| Online Access: | http://hdl.handle.net/20.500.12105/14703 |
| Access Level: | Open access |
| Keyword: | 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 |
| _version_ | 1878736775897153536 |
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| author | Salmón, Marina |
| 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 |
| author_browse | Barbacid, Mariano Caleiras, E Drosten, Matthias Fernández-García, Fernando Guerra, Carmen Lechuga, Carmen G Musteanu, Mónica Muñoz, Javier Ortega Jimenez, Sagrario Paniagua, Guillem Salmón, Marina Zarzuela, Eduardo Álvarez-Díaz, Ruth |
| 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 |
| collection | Repisalud |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_952aee256e2b9ef204db5bb4e99ea0bd |
| institution | Instituto de Salud Carlos III (ISCIII) |
| instname_str | Instituto de Salud Carlos III (ISCIII) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repisalud.isciii.es:20.500.12105/14703 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Nature Publishing Group |
| publisherStr | Nature Publishing Group |
| reponame_str | Repisalud |
| spelling | KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform. 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 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 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. Nature Publishing Group http://hdl.handle.net/20.500.12105/14703 |
| 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 | 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_short | 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. |
| 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 |
| topic_facet | 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 |
| url | http://hdl.handle.net/20.500.12105/14703 |