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Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo

Oncogene volume 22, pages 5055–5059 (2003)Cite this article

Abstract

Deletion of the INK4a/ARF locus at 9p21 is detected with high frequency in human melanoma. Within a short genomic distance, this locus encodes several proteins with established tumor-suppressor roles in a broad spectrum of cancer types. Several lines of evidence support the view that p16INK4a and p19ARF exert the tumor-suppressor activities of this locus, although their relative importance in specific cancer types such as melanoma has been less rigorously documented on the genetic level. Here, we exploit a well-defined mouse model of RAS-induced melanomas to examine the impact of germline p16INK4a or p19ARF nullizygosity on melanoma formation. We demonstrate that loss of either Ink4a/Arf product can cooperate with RAS activation to produce clinically indistinguishable melanomas. In line with the common phenotypic end point, we further show that RAS+ p16INK4a−/− melanomas sustain somatic inactivation of p19ARF-p53 and, correspondingly, that RAS+ p19ARF−/− melanomas experience high-frequency loss of p16INK4a. These genetic studies provide definitive proof that p16INK4a and p19ARF cooperate to suppress the development of melanoma in vivo.

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Acknowledgements

We wish to thank A Houghton and J Sage for reagents, and N Bardeesy and G Merlino for advice and critical reading of the manuscript. NES and MB are supported by grants from the NIH and the Howard Hughes Medical Institute. This work was supported in part by grants to LC from the NIH, the Claudia Adams Barr Program in Cancer Research and the Rockefeller Brothers Fund. LC is a Charles E Culpeper Medical Scholar.

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Author notes

  1. Norman Edward Sharpless

    Present address: The Lineberger Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599-7295, USA

  2. Marcus Wolfram Bosenberg

    Present address: Department of Pathology, University of Vermont, Burlington, VT, 05405, USA

  3. Norman Edward Sharpless and Karuppiah Kannan: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street (M413), Boston, 02115, MA, USA

    Norman Edward Sharpless, Karuppiah Kannan, Jin Xu, Marcus Wolfram Bosenberg & Lynda Chin

  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 44 Binney Street (M413), Boston, 02115, MA, USA

    Marcus Wolfram Bosenberg

  3. Department of Dermatology, Harvard Medical School, 44 Binney Street (M413), Boston, 02115, MA, USA

    Lynda Chin

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Correspondence to Lynda Chin.

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Sharpless, N., Kannan, K., Xu, J. et al. Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo. Oncogene 22, 5055–5059 (2003). https://doi.org/10.1038/sj.onc.1206809

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