The yin and yang of the Cdkn2a locus in senescence and aging

Research output: Contribution to journalReview articlepeer-review

25 Scopus citations

Abstract

Senescence of cultured cells involves activation of the p19 Arf-p53 and the p16Ink4a-Rb tumor suppressor pathways. This, together with the observation that p19Arf and p16 Ink4a expression increases with age in many tissues of humans and rodents, led to the speculation that these pathways drive in vivo senescence and natural aging. However, it has been difficult to test this hypothesis using a mammalian model system because inactivation of either of these pathways results in early death from tumors. One approach to bypass this problem would be to inactivate these pathways in a murine segmental progeria model such as mice that express low amounts of the mitotic checkpoint protein BubR1 (BubR1 hypomorphic mice). These mice have a five-fold reduced lifespan and develop a variety of early-aging associated phenotypes including cachetic dwarfism, skeletal muscle degeneration, cataracts, arterial stiffening, (subcutaneous) fat loss, reduced stress tolerance and impaired wound healing. Importantly, BubR1 hypomorphism elevates both p16Ink4a and p19Arf expression in skeletal muscle and fat. Inactivation of p16Ink4a in BubR1 mutant mice delays both cellular senescence and aging specifically in these tissues. Surprisingly, however, inactivation of p19Arf has the opposite effect; it exacerbates in vivo senescence and aging in skeletal muscle and fat. These mouse studies suggest that p16Ink4a is indeed an effector of aging and in vivo senescence, but p19Arf an attenuator. Thus, the role of the p19Arf-p53 pathway in aging and in vivo senescence seems far more complex than previously anticipated.

Original languageEnglish (US)
Pages (from-to)2795-2802
Number of pages8
JournalCell Cycle
Volume7
Issue number18
DOIs
StatePublished - Sep 15 2008

Keywords

  • BubR1
  • Cellular senescence
  • Premature aging
  • Spindle assembly checkpoint
  • p16
  • p19

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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