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Pathways of aging: comparative analysis of gene signatures in replicative senescence and stress induced premature senescence

Show simple item record Kural, Kamil Can Tandon, Neetu Skoblov, Mikhail Kel-Margoulis, Olga V. Baranova, Ancha 2019-02-08T16:00:08Z 2019-02-08T16:00:08Z 2016-12-28
dc.description.abstract Background In culturing normal diploid cells, senescence may either happen naturally, in the form of replicative senescence, or it may be a consequence of external challenges such as oxidative stress. Here we present a comparative analysis aimed at reconstruction of molecular cascades specific for replicative (RS) and stressinduced senescence (SIPS) in human fibroblasts. Results An involvement of caspase-3/keratin-18 pathway and serine/threonine kinase Aurora A/ MDM2 pathway was shared between RS and SIPS. Moreover, stromelysin/MMP3 and N-acetylglucosaminyltransferase enzyme MGAT1, which initiates the synthesis of hybrid and complex Nglycans, were identified as key orchestrating components in RS and SIPS, respectively. In RS only, Aurora-B driven cell cycle signaling was deregulated in concert with the suppression of anabolic branches of the fatty acids and estrogen metabolism. In SIPS, Aurora-B signaling is deprioritized, and the synthetic branches of cholesterol metabolism are upregulated, rather than downregulated. Moreover, in SIPS, proteasome/ubiquitin ligase pathways of protein degradation dominate the regulatory landscape. This picture indicates that SIPS proceeds in cells that are actively fighting stress which facilitates premature senescence while failing to completely activate the orderly program of RS. The promoters of genes differentially expressed in either RS or SIPS are unusually enriched by the binding sites for homeobox family proteins, with particular emphasis on HMX1, IRX2, HDX and HOXC13. Additionally, we identified Iroquois Homeobox 2 (IRX2) as a master regulator for the secretion of SPP1-encoded osteopontin, a stromal driver for tumor growth that is overexpressed by both RS and SIPS fibroblasts. The latter supports the hypothesis that senescence-specific de-repression of SPP1 aids in SIPS-dependent stromal activation. Conclusions Reanalysis of previously published experimental data is cost-effective approach for extraction of additional insignts into the functioning of biological systems. en_US
dc.language.iso en_US en_US
dc.publisher BMC Genomics en_US
dc.rights Attribution 3.0 United States *
dc.rights.uri *
dc.subject Genes en_US
dc.subject Aging en_US
dc.title Pathways of aging: comparative analysis of gene signatures in replicative senescence and stress induced premature senescence en_US
dc.type Article en_US
dc.identifier.doi 10.1186/s12864-016-3352-4

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