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Decreased Mdm2 expression inhibits tumor development induced by loss of ARF

Oncogene volume 25, pages 3708–3718 (2006)Cite this article

Abstract

The tumor suppressor p14/p19ARF regulates Mdm2, which is known for controlling the p53 tumor suppressor. Here we report that loss of one allele of Mdm2 in cells that lack ARF resulted in a decreased rate of proliferation, fewer chromosomal aberrations, and suppression of Ras-induced transformation. Moreover, a haploinsufficiency of Mdm2 inhibited spontaneous tumor development in ARF-null mice. Remarkably, Mdm2+/−ARF−/− mice survived an average of 6 months longer than Mdm2+/+ARF−/− mice. The spectrum of tumors that arose in Mdm2+/−ARF−/− mice did not significantly differ from those that developed in mice lacking only ARF. However, the extended tumor latency allowed for the emergence of multiple primary tumors in a third of the Mdm2+/−ARF−/− mice, as compared to the single tumor type that arose in ARF-null only mice. Therefore, a decrease in Mdm2 levels restored regulation of critical cellular processes that are altered during transformation and that occur in the absence of ARF. Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach.

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Acknowledgements

We would like to thank Jane Kennedy, Silvia Plaza, and Gregg Cochran for expert technical assistance with the mice, genotyping, and immunohistochemisty, respectively, Dr Jane Meza for Kaplan–Meier analysis, Drs Hua Xiao and Timothy McKeithan for helpful discussion, Dr Guillermina Lozano for the Mdm2+/− breeder mice and Drs Martine Roussel and Charles Sherr for ARF−/− breeder mice. This work was supported by NCI grant CA098139, the Eppley Institute for Research in Cancer, and the Wanda Rizzo Memorial fund. TCG is a Mantle Cell Lymphoma grantee of the Lymphoma Research Foundation. CME is a Leukemia & Lymphoma Society Scholar.

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  1. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA

    P Wang, T Lushnikova & C M Eischen

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

    T C Greiner & C M Eischen

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  1. P Wang
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Correspondence to C M Eischen.

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Wang, P., Greiner, T., Lushnikova, T. et al. Decreased Mdm2 expression inhibits tumor development induced by loss of ARF. Oncogene 25, 3708–3718 (2006). https://doi.org/10.1038/sj.onc.1209411

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