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Vol. 17, No. 2, pp. 201-213, January 15, 2003
Genetics of Development and Diseases Branch, National Institutes of
Diabetes and Digestive and Kidney Diseases, National Institutes of
Health, Bethesda, Maryland 20892, USA
Senescence may function as a two-edged sword that brings unexpected
consequences to organisms. Here we provide evidence to support this
theory by showing that the absence of the Brca1 full-length isoform
causes senescence in mutant embryos and cultured cells as well as aging
and tumorigenesis in adult mice. Haploid loss of p53 overcame embryonic
senescence but failed to prevent the adult mutant mice from prematurely
aging, which included decreased life span, reduced body fat deposition,
osteoporosis, skin atrophy, and decreased wound healing. We further
demonstrate that mutant cells that escaped senescence had undergone
clonal selection for faster proliferation and extensive
genetic/molecular alterations, including overexpression of cyclin D1
and cyclin A and loss of p53. These observations provide the first in
vivo evidence that links cell senescence to aging due to impaired
function of Brca1 at the expense of tumorigenesis.
[Key Words: p53; p21; senescence; aging; tumorigenesis]
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