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

Baker, Darren J.; Perez‐Terzic, Carmen; Jin, Fang; Pitel, Kevin S.; Niederländer, Nicolas J.; Jeganathan, Karthik B.; Yamada, Satsuki; Reyes, Santiago; Rowe, Lois A.; Hiddinga, Henry J.; Eberhardt, Norman L.; Terzic, André; Deursen, Jan M. van

doi:10.1038/ncb1744

Cited by 338 publications

(368 citation statements)

References 49 publications

Supporting

Mentioning

355

Contrasting

Unclassified

Order By: Relevance

“…2B). In contrast to plenty of the molecular association between abnormal spindle checkpoints and apoptosis, there is a limited understanding of its molecular link directly to senescence, as it has recently been reported in the cases of BubR1 insufficiency (15,16) and Bub3/Rae1 double haploinsufficiency (17). In the present study, therefore, we focused on p31 comet -induced senescence using a highly susceptible A549 cell line.…”

Section: P31 Comet Overexpression Induces Senescence-like Phenotype Amentioning

confidence: 99%

See 1 more Smart Citation

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Yun

Han

Yoon

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

Functional suppression of spindle checkpoint protein activity results in apoptotic cell death arising from mitotic failure, including defective spindle formation, chromosome missegregation, and premature mitotic exit. The recently identified p31 comet protein acts as a spindle checkpoint silencer via communication with the transient Mad2 complex. In the present study, we found that p31 comet overexpression led to two distinct phenotypic changes, cellular apoptosis and senescence. Because of a paucity of direct molecular link of spindle checkpoint to cellular senescence, however, the present report focuses on the relationship between abnormal spindle checkpoint formation and p31 comet -induced senescence by using susceptible tumor cell lines. p31 comet -induced senescence was accompanied by mitotic catastrophe with massive nuclear and chromosomal abnormalities. The progression of the senescence was completely inhibited by the depletion of p21 Waf1/Cip1 and partly inhibited by the depletion of the tumor suppressor protein p53. Notably, p21 Waf1/Cip1 depletion caused a dramatic phenotypic conversion of p31 comet -induced senescence into cell death through mitotic catastrophe, indicating that p21 Waf1/Cip1 is a major mediator of p31 comet -induced cellular senescence. In contrast to wild-type p31 comet , overexpression of a p31 mutant lacking the Mad2 binding region did not cause senescence. Moreover, depletion of Mad2 by small interfering RNA induced senescence. Here, we show that p31 comet induces tumor cell senescence by mediating p21 Waf1/Cip1 accumulation and Mad2 disruption and that these effects are dependent on a direct interaction of p31 comet with Mad2. Our results could be used to control tumor growth. (Mol Cancer Res 2009;7(3):371 -82)

show abstract

Section: P31 Comet Overexpression Induces Senescence-like Phenotype Amentioning

confidence: 99%

“…The reduced amounts of the BubR1 protein result in the early onset of cellular senescence and accelerate the aging process of mice (15,16). The combined alteration by Bub3 and Rae1 of the mitotic checkpoint also prominently affects the cellular and organismal processes of senescence and aging (17).…”

Section: Introductionmentioning

confidence: 99%

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

Yun

Han

Yoon

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…SA-b-galactosidase is associated with cellular senescence, but it is not completely specific (Debacq-Chainiaux et al 2009). Indeed, skeletal muscles of BubR1 hypomorphic mice did not stain positive for SA-b-galactosidase but expressed high levels of several senescenceassociated genes and lost proliferative potential (Baker et al 2008) (Table 2: age related phenotypes). Synthetically, our data suggest that C2C12BKD cells did not reach senescence.…”

Section: Resultsmentioning

confidence: 99%

“…These data are consistent with observations in other in vitro models (Langen et al 2001;Sharples et al 2010;Strle et al 2004;te Pas et al 2000) and indicate that the reduced expression of these markers is responsible for the loss of differentiation capacity in C2C12BKD cells (Table 2: differentiation markers). Baker et al reported that expression of p16 Ink4a in BubR1 hypomorphic mice plays a key role in the development of age-related disorders including sarcopenia (Baker et al 2008(Baker et al , 2011. Expression level of p16 INK4a in skeletal muscle derived from BubR1 hypomorphic mice was approximately 17 times higher than for the wild type (Baker et al 2011).…”

Section: Bubr1 Hypomorphic C2c12 Cells Show Impaired Myogenic Differementioning

confidence: 99%

A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

et al. 2015

View full text Add to dashboard Cite

Sarcopenia is the age-related loss of skeletal muscle mass and function with adverse outcomes that include physical disability, poor quality of life, and death. The detailed molecular mechanisms remain unknown. An in vitro muscle atrophy model is needed to enable mechanistic studies. To create such a model, we employed BubR1 insufficiency which causes premature ageing in mice. Using C2C12 cells, a recognized in vitro model of the skeletal muscle cell, we obtained the BubR1 hypomorphic C2C12 (C2C12BKD) cells by using shRNA. The resulting C2C12BKD cells displayed several characteristics of the sarcopenic muscle cell. In C2C12BKD cells, formation of myotubes, assessed by analysis of fusion index, was markedly reduced as was the expression of myogenin and MyoD, two marker genes for myogenesis. Moreover, the cells showed increased expression of the muscle-specific ubiquitin ligases Atrogin-1 and MuRF-1, indicating increased protein degradation through the ubiquitin-proteasome dependent proteolytic pathway. These results suggest that C2C12BKD cells are potentially useful as a novel in vitro model of sarcopenia.

show abstract

“…[106][107][108] The premature aging phenotype observed in BubR1 hypomorphic mice coincides with an accumulation of senescent cells. [109] Strikingly, clearing these senescent cells significantly reduces and even partially reverts the aging phenotype. [110,111] This suggests that CIN might contribute to aging by increasing the number of senescent cells in vivo.…”

Section: What Effect Do Cin and Aneuploidy Have On Aging?mentioning

confidence: 99%

CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

View full text Add to dashboard Cite

Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

show abstract

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

Cited by 338 publications

References 49 publications

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

p31comet Induces Cellular Senescence through p21 Accumulation and Mad2 Disruption

A novel in vitro model of sarcopenia using BubR1 hypomorphic C2C12 myoblasts

CIN and Aneuploidy: Different Concepts, Different Consequences

Contact Info

Product

Resources

About