Abstract
Although the ras genes have long been established as proto-oncogenes, the dominant role of activated ras in cell transformation has been questioned. Previous studies have shown frequent loss of the wildtype Kras2 allele in both mouse and human lung adenocarcinomas. To address the possible tumor suppressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heterozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells and a mouse lung tumor cell line containing an activated Kras2 allele. Allelic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mouse lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inverse correlation between the level of wildtype Kras2 expression and extracellular signal–regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression.
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Acknowledgements
We are grateful to A. de la Chapelle, G. Leone, G. Stoner and H. Schut for their critical reading of this manuscript and helpful discussions. We thank A. Malkinson for LM2 cells and E. Wiley for secretarial assistance. Some of the work was performed at Medical College of Ohio (Toledo, Ohio). This work was supported by NIH grants R01CA58554 (M.Y.), R01CA78797 (Y.W.) and R01GM62694 (K.-L.-G.).
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Zhang, Z., Wang, Y., Vikis, H. et al. Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat Genet 29, 25–33 (2001). https://doi.org/10.1038/ng721
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DOI: https://doi.org/10.1038/ng721
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