Opposing roles for p16(Ink4a) and p19(Arf) in senescence and ageing caused by BubR1 insufficiency

作者：Baker Darren J; Perez Terzic Carmen; Jin Fang; Pitel Kevin; Niederlaender Nicolas J; Jeganathan Karthik; Yamada Satsuki; Reyes Santiago; Rowe Lois; Hiddinga H Jay; Eberhardt Norman L; Terzic Andre; van Deursen Jan M^*

来源：Nature Cell Biology, 2008, 10(7): 825-836.

DOI：10.1038/ncb1744

Expression of p16(Ink4a) and p19(Arf) 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 p16(Ink4a) or p19(Arf) 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 p16(Ink4a) and p19(Arf). Inactivation of p16(Ink4a) in BubR1-insufficient mice attenuates both cellular senescence and premature ageing in these tissues. Conversely, p19(Arf) 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 p16(Ink4a) is an effector and p19(Arf) an attenuator of senescence and ageing in these tissues.

• 出版日期2008-7