Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

Sadaie, Mahito; Dillon, Christian; Narita, Masashi; Young, Andrew; Cairney, Claire J.; Godwin, Lauren S.; Torrance, C; Bennett, Dorothy C.; Keith, W. Nicol

doi:10.1091/mbc.e15-01-0003

Cited by 48 publications

(46 citation statements)

References 106 publications

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“…3) highlighted Iroquois Homeobox 2 (IRX2) and POU4F1 were highlighted as most likely signaling events to connect the DEGs identified by GeneXPlain-guided microarray analysis and osteopontin. In this network, suppression of Aurora kinases that normally monitor the mitotic checkpoint, centrosome separation and cytokinesis, cause catastrophic consequences and result in increase in apoptosis, thus, being in in agreement with recently published observations of senescent fibroblasts [37]. Apoptosis activated caspase-3 directly or indirectly eliminates POU4F1/Brn-3a, the prediction that is consistent with previous observation of enhanced apoptosis in the neurons derived from Brn-3a knockout mice [38].…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 91%

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

et al. 2016

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“…53 Reduced lamin B1 levels are frequently associated with altered nuclear and cell shape and increased cellular senescence. [54][55][56][57][58][59][60] Abnormal lamin localization and expression correlate with aberrant nuclear size in various disease states, notably cancer. 61 For example, lamin B1 expression is elevated in prostate cancer, and lamin B1 expression levels directly correlate with tumor stage in hepatocellular carcinoma.…”

Section: Nuclear Lamins and Nuclear Morphologymentioning

confidence: 99%

Recent advances in understanding nuclear size and shape

Mukherjee

Chen

Levy

2016

Nucleus

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Size and shape are important aspects of nuclear structure. While normal cells maintain nuclear size within a defined range, altered nuclear size and shape are associated with a variety of diseases. It is unknown if altered nuclear morphology contributes to pathology, and answering this question requires a better understanding of the mechanisms that control nuclear size and shape. In this review, we discuss recent advances in our understanding of the mechanisms that regulate nuclear morphology, focusing on nucleocytoplasmic transport, nuclear lamins, the endoplasmic reticulum, the cell cycle, and potential links between nuclear size and size regulation of other organelles. We then discuss the functional significance of nuclear morphology in the context of early embryonic development. Looking toward the future, we review new experimental approaches that promise to provide new insights into mechanisms of nuclear size control, in particular microfluidic-based technologies, and discuss how altered nuclear morphology might impact chromatin organization and physiology of diseased cells.

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“…Since progressive accumulation of G1 tetraploidy or polyploidy is a unique senescence phenotype [28], we investigated whether premature senescence was induced by SAHA treatment. By examining the signals involved in regulation of cellular senescence, we verified that levels of p53 protein and p38 phosphorylation were up-regulated 7 days after SAHA treatment in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

Suberoylanilide hydroxamic acid represses glioma stem-like cells

et al. 2016

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BackgroundGlioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.MethodsHuman GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.ResultsWe demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.ConclusionSAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0296-6) contains supplementary material, which is available to authorized users.

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Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

Cited by 48 publications

References 106 publications

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

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

Recent advances in understanding nuclear size and shape

Suberoylanilide hydroxamic acid represses glioma stem-like cells

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