Faculty Collaboration Database

Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001 Dec 15;15(24):3249-62

Date

12/26/2001

Pubmed ID

11751631

Pubmed Central ID

PMC312852

DOI

10.1101/gad.947701

Scopus ID

2-s2.0-0035893318 (requires institutional sign-in at Scopus site)   536 Citations

Abstract

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.

Author List

Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Adenoma
Animals
Apoptosis
Bromodeoxyuridine
Cyclin-Dependent Kinase Inhibitor p16
DNA Primers
Gene Expression Regulation, Neoplastic
Genes, Tumor Suppressor
Genes, ras
Genotype
In Situ Nick-End Labeling
Lung Neoplasms
Mice
Mice, Knockout
Mice, Transgenic
Models, Genetic
Neoplasm Recurrence, Local
Reverse Transcriptase Polymerase Chain Reaction
Tetracycline
Transgenes
Tumor Suppressor Protein p53