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

Darren J. Baker, Carmen Perez-Terzic, Fang Jin, Kevin Pitel, Nicolas J. Niederländer, Karthik Jeganathan, Satsuki Yamada, Santiago Reyes, Lois Rowe, H. Jay Hiddinga, Norman L. Eberhardt, Andre Terzic, Jan M. van Deursen

Research output: Contribution to journalArticle

220 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)825-836
Number of pages12
JournalNature Cell Biology
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2008

ASJC Scopus subject areas

  • Cell Biology

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