Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice

Aging is a highly complex biological process that is believed to involve multiple mechanisms. Mice that have small amounts of the mitotic checkpoint protein BubR1 age much faster than normal mice, but whether other mitotic checkpoint genes function to prevent the early onset of aging is unknown. In...

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Published inThe Journal of cell biology Vol. 172; no. 4; pp. 529 - 540
Main Authors Baker, Darren J, Jeganathan, Karthik B, Malureanu, Liviu, Perez-Terzic, Carmen, Terzic, Andre, van Deursen, Jan M.A
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 13.02.2006
The Rockefeller University Press
Subjects
Age
Aging
Aging, Premature - genetics
Aneuploidy
Animals
Cell Cycle Proteins - genetics
Cellular biology
Cellular senescence
Chromosomal Proteins, Non-Histone
Chromosomes
Genes
Genotype & phenotype
Haplotypes
Mice
Mice, Knockout
Mice, Mutant Strains
Mitosis
Mutation
Neoplasms - physiopathology
Nuclear Matrix-Associated Proteins - genetics
Nucleocytoplasmic Transport Proteins - genetics
Phenotype
Phenotypes
Ploidies
Poly-ADP-Ribose Binding Proteins
Proteins
Rodents
Tumors
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Summary:Aging is a highly complex biological process that is believed to involve multiple mechanisms. Mice that have small amounts of the mitotic checkpoint protein BubR1 age much faster than normal mice, but whether other mitotic checkpoint genes function to prevent the early onset of aging is unknown. In this study, we show that several aging-associated phenotypes appear early in mice that are double haploinsufficient for the mitotic checkpoint genes Bub3 and Rae1 but not in mice that are single haploinsufficient for these genes. Mouse embryonic fibroblasts (MEFs) from Bub3/Rae1 haploinsufficient mice undergo premature senescence and accumulate high levels of p19, p53, p21, and p16, whereas MEFs from single haploinsufficient mice do not. Furthermore, although BubR1 hypomorphic mice have less aneuploidy than Bub3/Rae1 haploinsufficient mice, they age much faster. Our findings suggest that early onset of aging-associated phenotypes in mice with mitotic checkpoint gene defects is linked to cellular senescence and activation of the p53 and p16 pathways rather than to aneuploidy.
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Correspondence to Jan M.A. van Deursen: vandeursen.jan@mayo.edu
Abbreviations used in this paper: APC, anaphase-promoting complex; DMBA, dimethylbenzanthrene; MEF, mouse embryonic fibroblast; MVA, mosaic variegated aneuploidy; NEBD, nuclear envelope breakdown; PI, propidium iodide; PMSCS, premature sister chromatid separation; SA, senescence associated.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200507081