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 Posted: Tue Oct 07, 2008 6:52 pm Post subject: Opposing roles for p16Ink4a and p19Arf in senescence and age |
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Nat Cell Biol. 2008 Jul;10(7):825-36. Epub 2008 May 30. Links
Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused
by BubR1 insufficiency.Baker DJ, Perez-Terzic C, Jin F, Pitel K,
Niederländer NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ,
Eberhardt NL, Terzic A, van Deursen JM.
Department of Pediatric and Adolescent Medicine, Mayo Clinic College
of Medicine, Rochester, MN 55905, USA.
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.
PMID: 18516091 [PubMed - indexed for MEDLINE] |
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| Posted: Tue Oct 07, 2008 6:53 pm Post subject: Re: Opposing roles for p16Ink4a and p19Arf in senescence and |
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Cell Cycle. 2008 Sep 15;7(18):2795-802. Epub 2008 Sep 28. Links
The yin and yang of the Cdkn2a locus in senescence and aging.Baker DJ,
Jin F, van Deursen JM.
Department of Pediatric and Adolescent Medicine, Mayo Clinic College
of Medicine, Rochester, Minnesota 55905, USA.
Senescence of cultured cells involves activation of the p19(Arf)-p53
and the p16(Ink4a)-Rb tumor suppressor pathways. This, together with
the observation that p19(Arf) 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 p16(Ink4a) and p19(Arf) expression in skeletal muscle and fat.
Inactivation of p16(Ink4a) in BubR1 mutant mice delays both cellular
senescence and aging specifically in these tissues. Surprisingly,
however, inactivation of p19(Arf) has the opposite effect; it
exacerbates in vivo senescence and aging in skeletal muscle and fat.
These mouse studies suggest that p16(Ink4a) is indeed an effector of
aging and in vivo senescence, but p19(Arf) an attenuator. Thus, the
role of the p19(Arf)-p53 pathway in aging and in vivo senescence seems
far more complex than previously anticipated.
PMID: 18769141 [PubMed - in process] |
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