Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma
NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-κB signalling during the past twenty...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/84606 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1846-604X |
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| author | Meylan, Etienne Feldser, David M. Shen, Lynn Turk, Erin Ouyang, Chensi Dooley, Alison L. Jacks, Tyler E |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Meylan, Etienne Feldser, David M. Shen, Lynn Turk, Erin Ouyang, Chensi Dooley, Alison L. Jacks, Tyler E |
| author_sort | Meylan, Etienne |
| collection | MIT |
| description | NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-κB signalling during the past twenty years, the requirement for NF-κB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-κB inhibition. Furthermore, the inhibition of NF-κB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-κB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53. |
| first_indexed | 2024-09-23T11:31:23Z |
| format | Article |
| id | mit-1721.1/84606 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:31:23Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/846062022-09-27T20:03:30Z Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma Meylan, Etienne Feldser, David M. Shen, Lynn Turk, Erin Ouyang, Chensi Dooley, Alison L. Jacks, Tyler E Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Meylan, Etienne Brauneis, Alison L. Feldser, David M. Shen, Lynn Turk, Erin Ouyang, Chensi Jacks, Tyler E. NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-κB signalling during the past twenty years, the requirement for NF-κB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-κB inhibition. Furthermore, the inhibition of NF-κB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-κB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53. Howard Hughes Medical Institute National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051) Leukemia & Lymphoma Society of America (Fellowship Award) 2014-01-27T20:33:54Z 2014-01-27T20:33:54Z 2009-10 2009-04 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/84606 Meylan, Etienne, Alison L. Dooley, David M. Feldser, Lynn Shen, Erin Turk, Chensi Ouyang, and Tyler Jacks. “Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma.” Nature 462, no. 7269 (October 21, 2009): 104-107. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1846-604X en_US http://dx.doi.org/10.1038/nature08462 Nature Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Meylan, Etienne Feldser, David M. Shen, Lynn Turk, Erin Ouyang, Chensi Dooley, Alison L. Jacks, Tyler E Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title | Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title_full | Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title_fullStr | Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title_full_unstemmed | Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title_short | Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma |
| title_sort | requirement for nf κb signalling in a mouse model of lung adenocarcinoma |
| url | http://hdl.handle.net/1721.1/84606 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1846-604X |
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