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Sustained p16INK4a expression is required to prevent IR-induced tumorigenesis in mice

Oncogene volume 36, pages 1309–1314 (2017)Cite this article

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Abstract

Exposure of murine and human tissues to ionizing radiation (IR) induces the expression of p16INK4a, a tumor suppressor gene and senescence/aging biomarker. Increased p16INK4a expression is often delayed several weeks post exposure to IR. In this context, it remains unclear if it occurs to suppress aberrant cellular growth of potentially transformed cells or is simply a result of IR-induced loss of tissue homeostasis. To address this question, we used a conditional p16INK4a null mouse model and determined the impact of p16INK4a inactivation long-term post exposure to IR. We found that, in vitro, bone marrow stromal cells exposed to IR enter DNA replication following p16INK4a inactivation. However, these cells did not resume growth; instead, they mostly underwent cell cycle arrest in G2. Similarly, delayed inactivation of p16INK4a in mice several weeks post exposure to IR resulted in increased BrdU incorporation and cancer incidence. In fact, we found that the onset of tumorigenesis was similar whether p16INK4a was inactivated before or after exposure to IR. Overall, our results suggest that IR-induced p16INK4a dependent growth arrest is reversible in mice and that sustained p16INK4a expression is necessary to protect against tumorigenesis.

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Acknowledgements

We are grateful to the members of Dr Elie Haddad’s laboratory, flow cytometry and animal facility for providing technical support. We also would like to thank Dr Francis Rodier and Mohamad El-Ariss for the critical reading of the manuscript. This work was supported by a grant from the Canadian Institute of Health Research #MOP-341566 to CMB LP has been supported by a student fellowship from the Fondation des Étoiles. CMB is supported by a scientist award from the Fonds de recherche du Québec - Santé.

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Authors and Affiliations

  1. Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine, Montréal, Canada

    L Palacio, V Krishnan, N L O Le & C M Beauséjour

  2. Département de Pharmacologie, Université de Montréal, Montréal, Canada

    L Palacio, V Krishnan & C M Beauséjour

  3. Departments of Medicine and Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    N E Sharpless

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  1. L Palacio
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  2. V Krishnan
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  3. N L O Le
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Correspondence to C M Beauséjour.

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Palacio, L., Krishnan, V., Le, N. et al. Sustained p16INK4a expression is required to prevent IR-induced tumorigenesis in mice. Oncogene 36, 1309–1314 (2017). https://doi.org/10.1038/onc.2016.298

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