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Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency

Nature Cell Biology volume 10, pages 825–836 (2008)Cite this article

A Corrigendum to this article was published on 30 May 2012

This article has been updated

Abstract

Expression of p16Ink4a and p19Arf increases with age in both rodent and human tissues. However, whether these tumour suppressors are effectors of ageing remains unclear, mainly because knockout mice lacking p16Ink4a or p19Arf die early of tumours. Here, we show that skeletal muscle and fat, two tissues that develop early ageing-associated phenotypes in response to BubR1 insufficiency, have high levels of p16Ink4a and p19Arf. Inactivation of p16Ink4a in BubR1-insufficient mice attenuates both cellular senescence and premature ageing in these tissues. Conversely, p19Arf inactivation exacerbates senescence and ageing in BubR1 mutant mice. Thus, we identify BubR1 insufficiency as a trigger for activation of the Cdkn2a locus in certain mouse tissues, and demonstrate that p16Ink4a is an effector and p19Arf an attenuator of senescence and ageing in these tissues.

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Figure 1: Ablation of p16Ink4a in BubR1H/H mice extends lifespan and attenuates sarcopaenia.
Figure 2: Inverse correlation between BubR1 and p16Ink4a expression levels with ageing.
Figure 3: p16Ink4a disruption attenuates selective progeroid features of BubR1 hypomorphic mice.
Figure 4: p16Ink4a induction in BubR1H/H mice promotes cellular senescence.
Figure 5: p19Arf is elevated in BubR1 hypomorphic tissues with high p16Ink4a.
Figure 6: Accelerated ageing in BubR1H/H mouse tissues with increased p16Ink4a expression when p19Arf is lacking.
Figure 7: Senescence increases in BubR1H/H tissues with high p16Ink4a when p19Arf is lacking.
Figure 8: Ablation of p16Ink4a accelerates lung tumorigenesis in BubR1 insufficient mice.

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  • 27 April 2012

    In the version of this Article originally published, an initial was omitted for Kevin Pitel. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Paul Galardy, Rick Bram, Randy Faustino, Amy Tang, Robin Ricke and Jim Kirkland for critical reading of the manuscript or helpful discussions. We would like to thank Mariano Barbacid for the generous gift of anti-p15Ink4b antibody. This work was supported by grants from the National Institutes of Health, the Ted Nash Foundation and the Ellison Medical Foundation to J.v.D.

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Authors and Affiliations

  1. Department of Pediatric and Adolescent Medicine Mayo Clinic College of Medicine, Rochester, 55905, MN, USA

    Darren J. Baker, Fang Jin, Kevin S. Pitel, Karthik Jeganathan & Jan M. van Deursen

  2. Department of Physical Medicine and Rehabilitation Mayo Clinic College of Medicine, Rochester, 55905, MN, USA

    Carmen Perez-Terzic

  3. Department of Medicine Mayo Clinic College of Medicine, Rochester, 55905, MN, USA

    Nicolas J. Niederländer, Satsuki Yamada, Santiago Reyes, Lois Rowe & Andre Terzic

  4. Department of Biochemistry and Molecular Biology Mayo Clinic College of Medicine, Rochester, 55905, MN, USA

    H. Jay Hiddinga, Norman L. Eberhardt & Jan M. van Deursen

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Contributions

D.J.B., C.P.T., F.J., K.P., N.J.N., K.J., S.Y., S.R., L.R., H.J.H. and N.L.E. conducted experiments, prepared the figures and analysed the data; D.J.B., A.T. and J.M.v.D. planned the project and wrote the manuscript; J.M.v.D. supervised the project.

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Correspondence to Jan M. van Deursen.

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Supplementary Figures S1, S2, S3, S4, S5, S6, Supplementary Table S1 and Discussion (PDF 1768 kb)

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Baker, D., Perez-Terzic, C., Jin, F. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 10, 825–836 (2008). https://doi.org/10.1038/ncb1744

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