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Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53

Oncogene volume 35, pages 3866–3871 (2016)Cite this article

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Abstract

The tumor suppressor p53 is mutated in ~50% of human cancers. P53 is activated by a range of stimuli and regulates several cellular processes, including apoptotic cell death, cell cycle arrest, senescence and DNA repair. P53 induces apoptosis via transcriptional induction of the BH3-only proteins PUMA (p53-upregulated modulator of apoptosis) and NOXA, and cell cycle arrest via p21. Induction of these processes was proposed to be critical for p53-mediated tumor suppression. It is therefore surprising that mice lacking PUMA, NOXA and p21, as well as mice bearing mutations in p53 that impair the transcriptional activation of these genes, are not tumor prone, unlike mice lacking p53 function, which spontaneously develop tumors with 100% incidence. These p53 target genes and the processes they regulate may, however, impact differently on tumor development depending on the oncogenic drivers. For example, loss of PUMA enhances c-MYC-driven lymphoma development in mice, but, interestingly, the acceleration was less impressive compared with that caused by the loss of even a single p53 allele. Different studies have reported that loss of p21 can accelerate, delay or have no impact on tumorigenesis. In an attempt to resolve this controversy, we examined whether loss of p21-mediated cell cycle arrest cooperates with PUMA deficiency in accelerating lymphoma development in Eμ-Myc mice (overexpressing c-MYC in B-lymphoid cells). We found that Eμ-Myc mice lacking both p21 and PUMA (Eμ-Myc;Puma−/−;p21−/−) developed lymphoma at a rate comparable to Eμ-Myc;Puma−/− animals, notably with considerably longer latency than Eμ-Myc;p53+/-mice. Loss of p21 had no impact on the numbers, cycling or survival of pre-leukemic Eμ-Myc B-lymphoid cells, even when PUMA was lost concomitantly. These results demonstrate that even in the context of deregulated c-MYC expression, p53 must suppress tumor development by activating processes apart from, or in addition to, PUMA-mediated apoptosis and p21-induced cell cycle arrest.

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Acknowledgements

The authors thank Drs GL Kelly, ARD Delbridge, BJ Aubrey, S Cory and JM Adams for discussions and gifts of mice; K Walker, J Mansheim, C Gatt, G Siciliano and S O’Connor for expert animal care; B Helbert, H Ierino, K Mackwell and C Young for help with genotyping; J Corbin and J McManus for automated blood cell analysis. This work was supported by a PhD scholarship and Postdoctoral Fellowships from the Cancer Council of Victoria to SG and LV, by Postdoctoral Fellowships from the Leukaemia Foundation Australia to SG, from the Lady Tata Memorial Trust Research Award to AJ and SG, from the Leukemia & Lymphoma Society of America and the Beatriu de Pinos Foundation to AJ and by grants from Cancer Australia and Cure Cancer Australia Foundation (grant no. 1067571), the National Health and Medical Research Council (NHMRC; program grant no. 1016701, NHMRC Senior Principal Research Fellow (SPRF) Fellowship 1020363 to AS) and the Leukemia & Lymphoma Society of America (Specialized Center of Research (SCOR) grant no. 7001-13). This work was made possible by operational infrastructure grants through the Australian Government Independent Medical Research Institutes Infrastructure Support Scheme (IRIISS) and the Victorian State Government Operational Infrastructure Support (OIS).

Author contributions

LV, SG, AJ and AS conceived the study, planned the experiments, interpreted the results and prepared the manuscript. LV, AJ, CV and SG conducted the majority of the experiments.

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  1. L J Valente

    Present address: 3Current address: Stanford University School of Medicine, Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford, CA, USA.,

  2. L J Valente, S Grabow and C J Vandenberg: Shared first authorship.

  3. A Strasser and A Janic: Shared senior authorship.

Authors and Affiliations

  1. Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne,, Victoria, Australia

    L J Valente, S Grabow, C J Vandenberg, A Strasser & A Janic

  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

    L J Valente, S Grabow, C J Vandenberg, A Strasser & A Janic

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Valente, L., Grabow, S., Vandenberg, C. et al. Combined loss of PUMA and p21 accelerates c-MYC-driven lymphoma development considerably less than loss of one allele of p53. Oncogene 35, 3866–3871 (2016). https://doi.org/10.1038/onc.2015.457

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