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Wildtype Kras2 can inhibit lung carcinogenesis in mice

Nature Genetics volume 29, pages 25–33 (2001)Cite this article

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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Figure 1: Lung tumor bioassays using heterozygous K ras2-deficient mice.
Figure 2: Lung tumors from heterozygous K ras2-deficient mice.
Figure 3: Growth suppression by wildtype K ras2 in a transformed NIH/3T3 cell line (R16).
Figure 4: Growth suppression by wildtype Kras2 in a mouse lung tumor cell line (LM2).
Figure 5: Activation status of Kras2 and ERK in LM2 cells expressing wildtype Kras2.
Figure 6: Nude mouse tumorigenicity assays of wildtype Kras2 transfected tumor cells.
Figure 7: LOH on chromosome 6 in mouse lung tumors.

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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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  1. Zhongqiu Zhang and Yian Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Human Cancer Genetics, The Ohio State University Comprehensive Cancer Center, 420 West 12th Avenue, Columbus, Ohio, USA

    Zhongqiu Zhang, Gongjie Liu, Jie Li & Ming You

  2. School of Public Health, The Ohio State University Comprehensive Cancer Center, 420 West 12th Avenue, Columbus, Ohio, USA

    Yian Wang

  3. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Haris G. Vikis & Kun-Liang Guan

  4. Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Leisa Johnson & Tyler Jacks

  5. Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA

    Marshall W. Anderson

  6. Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

    Robert C. Sills & H.L. Hong

  7. Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

    Theodora R. Devereux

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Correspondence to Yian Wang or Ming You.

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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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