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

Abstract

BackgroundIn 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.ResultsAn 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.ConclusionsReanalysis of previously published experimental data is cost-effective approach for extraction of additional insignts into the functioning of biological systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3352-4) contains supplementary material, which is available to authorized users.

The emerging role of cellular senescence in renal diseases

“…8 Senescent cells are alive but display typical features of an enlarged, flattened morphology, senescence-associated heterochromatin marks, accumulation of lipofuscin granules, expression of β-galactosidase and lack of mitogenic responses. 9 An important characteristic of senescent cells is their production of a series of proteins named as the senescence-associated secretory phenotype (SASP). 9 An important characteristic of senescent cells is their production of a series of proteins named as the senescence-associated secretory phenotype (SASP).…”

“…1 Cellular senescence can be classified into two different types according to the presence or the absence of telomere shortening: replicative senescence caused by shortening of telomeres and premature senescence caused by other stress signals such as aberrant oncogene activation and genomic damage. 9 An important characteristic of senescent cells is their production of a series of proteins named as the senescence-associated secretory phenotype (SASP). 10 Through the SASP, senescent cells can affect surrounding cells by secreting various inflammatory cytokines, chemokines, growth factors and extracellular matrix remodelling factors such as interleukin 1α (IL-1α), interleukin 6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), TGF-β, connective tissue growth factor (CTGF) and monocyte chemoattractant protein-1 (MCP-1).…”

“…SIPS can be induced by many stress signals, including radiation, oxidative stress, chemical toxicants, DNA damage, oncogenic mutation and nutrient deficiency. 9 The stimuli-induced DNA damage response (DDR) is involved in the activation of p16/ phosphorylated retinoblastoma (pRb) pathway, especially in epithelial cells.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…Currently, two major types of cellular senescence are considered: replicative senescence and stress-induced premature senescence (SIPS). In general, these types of senescence are distinguished by the number of divisions at which the senescence occurs [32].…”

Computational genomics at BGRS\SB-2016: introductory note

“…The work by Kural et al [6] considers molecular genomics models of aging. 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.…”