Early differential responses elicited by BRAFV600E in adult mouse models
Abstract The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAFV600E) which in turn sustains continuous cell proliferation. The study of BRAFV600E murine models has been mainly fo...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04597-z |
| _version_ | 1828857101542227968 |
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| author | Giuseppe Bosso Pablo Lanuza-Gracia Sergio Piñeiro-Hermida Merve Yilmaz Rosa Serrano Maria A. Blasco |
| author_facet | Giuseppe Bosso Pablo Lanuza-Gracia Sergio Piñeiro-Hermida Merve Yilmaz Rosa Serrano Maria A. Blasco |
| author_sort | Giuseppe Bosso |
| collection | DOAJ |
| description | Abstract The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAFV600E) which in turn sustains continuous cell proliferation. The study of BRAFV600E murine models has been mainly focused on the role of BRAFV600E in tumor development but little is known on the early molecular impact of BRAFV600E expression in vivo. Here, we study the immediate effects of acute ubiquitous BRAFV600E activation in vivo. We find that BRAFV600E elicits a rapid DNA damage response in the liver, spleen, lungs but not in thyroids. This DNA damage response does not occur at telomeres and is accompanied by activation of the senescence marker p21CIP1 only in lungs but not in liver or spleen. Moreover, in lungs, BRAFV600E provokes an acute inflammatory state with a tissue-specific recruitment of neutrophils in the alveolar parenchyma and macrophages in bronchi/bronchioles, as well as bronchial/bronchiolar epithelium transdifferentiation and development of adenomas. Furthermore, whereas in non-tumor alveolar type II (ATIIs) pneumocytes, acute BRAFV600E induction elicits rapid p53-independent p21CIP1 activation, adenoma ATIIs express p53 without resulting in p21CIP1 gene activation. Conversely, albeit in Club cells BRAFV600E-mediated proliferative cue is more exacerbated compared to that occurring in ATIIs, such oncogenic stimulus culminates with p21CIP1-mediated cell cycle arrest and apoptosis. Our findings indicate that acute BRAFV600E expression drives an immediate induction of DNA damage response in vivo. More importantly, it also results in rapid differential responses of cell cycle and senescence-associated proteins in lung epithelia, thus revealing the early molecular changes emerging in BRAFV600E-challenged cells during tumorigenesis in vivo. |
| first_indexed | 2024-12-13T01:29:00Z |
| format | Article |
| id | doaj.art-165b8f8dc3e345ff9878676c8caeb0c1 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-13T01:29:00Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-165b8f8dc3e345ff9878676c8caeb0c12022-12-22T00:04:02ZengNature Publishing GroupCell Death and Disease2041-48892022-02-0113211510.1038/s41419-022-04597-zEarly differential responses elicited by BRAFV600E in adult mouse modelsGiuseppe Bosso0Pablo Lanuza-Gracia1Sergio Piñeiro-Hermida2Merve Yilmaz3Rosa Serrano4Maria A. Blasco5Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3Abstract The BRAF gene is frequently mutated in cancer. The most common genetic mutation is a single nucleotide transition which gives rise to a constitutively active BRAF kinase (BRAFV600E) which in turn sustains continuous cell proliferation. The study of BRAFV600E murine models has been mainly focused on the role of BRAFV600E in tumor development but little is known on the early molecular impact of BRAFV600E expression in vivo. Here, we study the immediate effects of acute ubiquitous BRAFV600E activation in vivo. We find that BRAFV600E elicits a rapid DNA damage response in the liver, spleen, lungs but not in thyroids. This DNA damage response does not occur at telomeres and is accompanied by activation of the senescence marker p21CIP1 only in lungs but not in liver or spleen. Moreover, in lungs, BRAFV600E provokes an acute inflammatory state with a tissue-specific recruitment of neutrophils in the alveolar parenchyma and macrophages in bronchi/bronchioles, as well as bronchial/bronchiolar epithelium transdifferentiation and development of adenomas. Furthermore, whereas in non-tumor alveolar type II (ATIIs) pneumocytes, acute BRAFV600E induction elicits rapid p53-independent p21CIP1 activation, adenoma ATIIs express p53 without resulting in p21CIP1 gene activation. Conversely, albeit in Club cells BRAFV600E-mediated proliferative cue is more exacerbated compared to that occurring in ATIIs, such oncogenic stimulus culminates with p21CIP1-mediated cell cycle arrest and apoptosis. Our findings indicate that acute BRAFV600E expression drives an immediate induction of DNA damage response in vivo. More importantly, it also results in rapid differential responses of cell cycle and senescence-associated proteins in lung epithelia, thus revealing the early molecular changes emerging in BRAFV600E-challenged cells during tumorigenesis in vivo.https://doi.org/10.1038/s41419-022-04597-z |
| spellingShingle | Giuseppe Bosso Pablo Lanuza-Gracia Sergio Piñeiro-Hermida Merve Yilmaz Rosa Serrano Maria A. Blasco Early differential responses elicited by BRAFV600E in adult mouse models Cell Death and Disease |
| title | Early differential responses elicited by BRAFV600E in adult mouse models |
| title_full | Early differential responses elicited by BRAFV600E in adult mouse models |
| title_fullStr | Early differential responses elicited by BRAFV600E in adult mouse models |
| title_full_unstemmed | Early differential responses elicited by BRAFV600E in adult mouse models |
| title_short | Early differential responses elicited by BRAFV600E in adult mouse models |
| title_sort | early differential responses elicited by brafv600e in adult mouse models |
| url | https://doi.org/10.1038/s41419-022-04597-z |
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