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

Authors: Baker DJ; Perez-Terzic C; Jin F; Pitel KS; Niederländer NJ; Jeganathan K; Yamada S; Reyes S; Rowe L; Hiddinga HJ; Eberhardt NL; Terzic A; van Deursen JM

Abstract: 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.

Keywords: Adipose Tissue/anatomy & histology/metabolism; Aging/*physiology; Animals; Biological Markers/metabolism; *Cell Aging; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism; Eye/anatomy & histology/metabolism; Fibroblasts/cytology/metabolism; Genotype; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal/cytology/metabolism/pathology; Neoplasms/metabolism/pathology; Protein-Serine-Threonine Kinases/genetics/*metabolism; Survival Rate; Tissue Distribution
Journal: Nature cell biology
Volume: 10
Issue: 7
Pages: 825-36
Date: June 3, 2008
PMID: 18516091
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Citation:

Baker DJ, Perez-Terzic C, Jin F, Pitel KS, Niederländer NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ, Eberhardt NL, Terzic A, van Deursen JM (2008) Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature cell biology 10: 825-36.


Lifespan Factors:
  • Bub1b budding uninhibited by benzimidazoles 1 homolog, beta (S. cerevisiae)


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