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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

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

Fingerprint

Yin-Yang
Aging of materials
Skeletal Muscle
Cell Aging
Muscle
Fats
Progeria
Tumors
M Phase Cell Cycle Checkpoints
Dwarfism
Tissue
Subcutaneous Fat
Wound Healing
Cataract
Cultured Cells
Rodentia
Neoplasms
Phenotype
Chemical activation
Cells

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

The yin and yang of the Cdkn2a locus in senescence and aging. / Baker, Darren J; Jin, Fang; Van Deursen, Jan.

In: Cell Cycle, Vol. 7, No. 18, 15.09.2008, p. 2795-2802.

Research output: Contribution to journalArticle

@article{584cdc027fbc4d009526954b85c9f32c,
title = "The yin and yang of the Cdkn2a locus in senescence and aging",
abstract = "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.",
keywords = "BubR1, Cellular senescence, p16, p19, Premature aging, Spindle assembly checkpoint",
author = "Baker, {Darren J} and Fang Jin and {Van Deursen}, Jan",
year = "2008",
month = "9",
day = "15",
language = "English (US)",
volume = "7",
pages = "2795--2802",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "18",

}

TY - JOUR

T1 - The yin and yang of the Cdkn2a locus in senescence and aging

AU - Baker, Darren J

AU - Jin, Fang

AU - Van Deursen, Jan

PY - 2008/9/15

Y1 - 2008/9/15

N2 - 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.

AB - 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.

KW - BubR1

KW - Cellular senescence

KW - p16

KW - p19

KW - Premature aging

KW - Spindle assembly checkpoint

UR - http://www.scopus.com/inward/record.url?scp=51849157424&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=51849157424&partnerID=8YFLogxK

M3 - Article

C2 - 18769141

AN - SCOPUS:51849157424

VL - 7

SP - 2795

EP - 2802

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 18

ER -