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Differential oncogenic potential of activated RAS isoforms in melanocytes

Oncogene volume 26, pages 4563–4570 (2007)Cite this article

Abstract

RAS genes are mutated in approximately 30% of all human cancers. Interestingly, there exists a strong bias in favor of mutation of only one of the three major RAS genes in tumors of different cellular origins. NRAS mutations occur in approximately 20% of human melanomas, whereas HRAS and KRAS mutations are rare in this disease. To define the mechanism(s) responsible for this preference in melanocytes, we compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. Although both NRAS and KRAS activate mitogen-activated protein kinase signaling, only NRAS enhances MYC activity in these cells. Our data suggest that the activity of specific RAS isoforms is context-dependent and provide a possible explanation for the prevalence of NRAS mutations in melanoma. In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways.

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Acknowledgements

We thank Dr Vincent Hearing for providing the anti-PEP7 antibody, Dr Stephen Hughes for the RCASBP(M2C)797-8 virus and Dr Brian Lewis for the RCASBP(A)MYC virus. We thank Bryn Eagleson, Elissa Boguslawski, Dawna Dylewski and the vivarium staff for assistance with the animal experiments. We thank Dr Kyle Furge and Karl Dykema (Laboratory of Computational Biology) for technical assistance and helpful comments. We also thank David Nadziejka for critical review of the manuscript. This work was supported by funds from the Melanoma Research Foundation, the James A Schlipmann Melanoma Cancer Foundation and the Van Andel Research Institute. Lastly, the authors wish to dedicate this work to the memory of Dr Han-Mo Koo, who made significant contributions to the scientific community and especially to cancer research.

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Authors and Affiliations

  1. Molecular Medicine and Virology Group, Van Andel Research Institute, Grand Rapids, MI, USA

    T Whitwam, M E Russo & S L Holmen

  2. Laboratory of Pharmacogenetics, Van Andel Research Institute, Grand Rapids, MI, USA

    M W VanBrocklin & H-M Koo

  3. Laboratory of Microarray Technology, Van Andel Research Institute, Grand Rapids, MI, USA

    P T Haak & J H Resau

  4. Department of Mathematical Sciences, Northern Illinois University, DeKalb, IL, USA

    D Bilgili

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  1. T Whitwam
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  2. M W VanBrocklin
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  3. M E Russo
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  4. P T Haak
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  6. J H Resau
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  7. H-M Koo
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  8. S L Holmen
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Correspondence to S L Holmen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Whitwam, T., VanBrocklin, M., Russo, M. et al. Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene 26, 4563–4570 (2007). https://doi.org/10.1038/sj.onc.1210239

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