Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Open accessAbstract
To investigate the role of an activated K-Ras gene in the initiation and maintenance of lung adenocarcinomas, we developed transgenic mice that express murine K-Ras4b G12D under the control of doxycycline in type II pneumocytes. Focal proliferative lesions of alveolar type II pneumocytes were observed as early as seven days after induction with doxycycline; after two months of induction, the lungs contained adenomas and adenocarcinomas, with focal invasion of the pleura at later stages. Removal of doxycycline caused a rapid fall in levels of mutant K-Ras RNA and concomitant apoptotic regression of both the early proliferative lesions and the tumors. Tumor burden was dramatically decreased by three days after withdrawal, and tumors were undetectable after one month. When similar experiments were performed with animals deficient in either the p53 gene or the Ink4A/Arf locus, tumors arose more quickly (within one month of exposure to doxycycline) and displayed more obvious histological features of malignancy; nevertheless, these tumors also regressed rapidly when the inducer was removed, implying that continued production of mutant K-Ras is necessary to maintain the viability of tumor cells in the absence as well as the presence of tumor suppressor genes. We also show that the appearance and regression of these pulmonary tumors can be readily monitored in anesthetized transgenic animals by magnetic resonance imaging.
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Loss of p53 or expression of dominant negative or gain-of-function Trp53 mutants co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss.
“Loss of p53 or expression of either dominant negative or dominant gain-of-function Trp53 mutants also co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss69–71, 84.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [71]
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Autocrine IGF1 Signaling Mediates Pancreatic Tumor Cell Dormancy in the Absence of Oncogenic Drivers
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- Authors
- Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E.
- Affiliations
- National Institutes of Health (US)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Varmus, Harold E.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-12-15
- Volume
- 15
- Issue
- 24
- Pages
- 3249-3262
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC312852
- OpenAlex
- W2110719738
- Cited by
- 582
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 15 · 2022: 13 · 2021: 24 · 2020: 14 · 2019: 9 · 2018: 25 · 2017: 28 · 2016: 20 · 2015: 30 · 2014: 30 · 2013: 23 · 2012: 32
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cystic Fibrosis Foundation
- Massachusetts Institute of Technology
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Human Genome Research Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- lung adenocarcinoma, KRAS, doxycycline-inducible transgene, alveolar type II cells, tumor regression, apoptosis, p53, Ink4a/Arf, tumor suppressor, transgenic mice
- MeSH terms
- Adenocarcinoma, Adenoma, Animals, Bromodeoxyuridine, Genotype, Lung Neoplasms, Mice, Transgenic, Models, Genetic, Neoplasm Recurrence, Local, Genes, ras, Tetracycline, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Apoptosis, DNA Primers, Mice, Knockout, Transgenes, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Mice
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