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Molecular Models of Aging: Comparative Analysis of Gene Signatures in Replicative Senescence and Stress Induced Premature Senescence

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dc.contributor.advisor Baranova, Ancha
dc.contributor.author Kural, Kamil Can
dc.creator Kural, Kamil Can
dc.date 2016-12-09
dc.date.accessioned 2018-05-25T19:31:16Z
dc.date.available 2018-05-25T19:31:16Z
dc.identifier doi:10.13021/G8VH76
dc.identifier.uri http://hdl.handle.net/1920/10989
dc.description.abstract 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. In this work, a comparative analysis design has been used that aims to reconstruct the molecular cascades which are specific for replicative senescence (RS) and stress-induced senescence (SIPS) in human fibroblasts. The results indicate the involvement of caspase-3/keratin-18 pathway and serine/threonine kinase Aurora A/ MDM2 pathway commonly shared between RS and SIPS. Moreover, stromelysin/MMP3 and N-acetyl glucosaminyl transferase enzyme MGAT1, which initiates the synthesis of hybrid and complex N-glycans, 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, while 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, Iroquois Homeobox 2 (IRX2) was identified 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. en_US
dc.language.iso en en_US
dc.subject aging en_US
dc.subject stress en_US
dc.subject replicative en_US
dc.subject senescence en_US
dc.subject microarray en_US
dc.subject bioinformatics en_US
dc.title Molecular Models of Aging: Comparative Analysis of Gene Signatures in Replicative Senescence and Stress Induced Premature Senescence en_US
dc.type Thesis en_US
thesis.degree.name Master of Science in Bioinformatics and Computational Biology en_US
thesis.degree.level Master's en_US
thesis.degree.discipline Bioinformatics and Computational Biology en_US
thesis.degree.grantor George Mason University en_US


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