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Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development

Oncogene volume 23, pages 8931–8940 (2004)Cite this article

Abstract

The tumor suppressor p19ARF inhibits Mdm2, which restricts the activity of p53. Complicated feedback and control mechanisms regulate ARF, Mdm2, and p53 interactions. Here we report that ARF haploinsufficiency completely rescued the p53-dependent effects of Mdm2 haploinsufficiency on B-cell development, survival, and transformation. In contrast to Mdm2+/− B cells, Mdm2+/− B cells deficient in ARF were similar to wild-type B cells in their rates of growth and apoptosis and activation of p53. Consequently, the profoundly reduced numbers of B cells in Mdm2+/−Eμ-myc transgenic mice were restored to normal levels in ARF+/−Mdm2+/−Eμ-myc transgenics. Additionally, ARF+/−Mdm2+/−Eμ-myc transgenics developed lymphomas at rates analogous to those observed for wild-type Eμ-myc transgenics, demonstrating that loss of one allele of ARF rescued the protracted lymphoma latency in Mdm2+/−Eμ-myc transgenics. Importantly, in ARF+/−Mdm2+/−Eμ-myc transgenic lymphomas, p53 was inactivated at the frequency observed in lymphomas of wild-type Eμ-myc transgenics. Collectively, these results support a model whereby the stoichiometry of Mdm2 and ARF controls apoptosis and tumor development, which should have significant implications in the treatment of malignancies that have inactivated ARF.

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Acknowledgements

We thank Drs John Cleveland and Hua Xiao for critically reviewing the manuscript, Drs Guillermina Lozano, Martine Roussel, Charles Sherr, Alan Harris, and Charles Sidman for kindly providing breeder mice that were essential for these studies, Dr Jane Meza for the Kaplan–Meier analysis, and the personnel in the Eppley Institute's animal facility. This work was supported by NCI grant CA098139, the Wanda Rizzo memorial fund, the Eppley Institute for Research in Cancer, and NIH training grant T32 CA09476 (JRA). CME is a Leukemia and Lymphoma Society Scholar.

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  1. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Christine M Eischen, Jodi R Alt & Peng Wang

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Christine M Eischen & Jodi R Alt

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  1. Christine M Eischen
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Correspondence to Christine M Eischen.

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Eischen, C., Alt, J. & Wang, P. Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development. Oncogene 23, 8931–8940 (2004). https://doi.org/10.1038/sj.onc.1208052

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