title: Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress.
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.
authors.affiliation: Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, MBC #03-66, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Huda H
authors.initials: HH
authors.lastname: Al-Khalaf
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Aboussekhra
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin; D012313:RNA