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Age (Dordr). 2013 Jun;35(3):549-62. doi: 10.1007/s11357-011-9378-2. Epub 2012 Jan 15.

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress.

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1
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, MBC #03-66, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Abstract

Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H2O2 as compared to their younger counterparts. In response to γ-rays and H2O2, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.

PMID:
22252435
PMCID:
PMC3636406
DOI:
10.1007/s11357-011-9378-2
[Indexed for MEDLINE]
Free PMC Article
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