Article abstract
Nature Cell Biology 10, 825 - 836 (2008)
Published online: 30 May 2008 | doi:10.1038/ncb1744
Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency
Darren J. Baker1, Carmen Perez-Terzic2, Fang Jin1, Kevin Pitel1, Nicolas J. Niederländer3, Karthik Jeganathan1, Satsuki Yamada3, Santiago Reyes3, Lois Rowe3, H. Jay Hiddinga4, Norman L. Eberhardt4, Andre Terzic3 & Jan M. van Deursen1,4
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.
- Department of Pediatric and Adolescent Medicine Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
- Department of Physical Medicine and Rehabilitation Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
- Department of Medicine Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
- Department of Biochemistry and Molecular Biology Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Correspondence to: Jan M. van Deursen1,4 e-mail: vandeursen.jan@mayo.edu
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