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      Genomic alterations during p53-dependent apoptosis induced by γ-irradiation of Molt-4 leukemia cells

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          Abstract

          Molt-4 leukemia cells undergo p53-dependent apoptosis accompanied by accumulation of de novo ceramide after 14 hours of γ-irradiation. In order to identify the potential mediators involved in ceramide accumulation and the cell death response, differentially expressed genes were identified by Affymetrix Microarray Analysis. Molt-4-LXSN cells, expressing wild type p53, and p53-deficient Molt-4-E6 cells were irradiated and harvested at 3 and 8 hours post-irradiation. Human genome U133 plus 2.0 array containing >47,000 transcripts was used for gene expression profiling. From over 10,000 probes, 281 and 12 probes were differentially expressed in Molt-4-LXSN and Molt-4-E6 cells, respectively. Data analysis revealed 63 (upregulated) and 20 (downregulated) genes (>2 fold) in Molt-4-LXSN at 3 hours and 140 (upregulated) and 21 (downregulated) at 8 hours post-irradiation. In Molt-4-E6 cells, 5 (upregulated) genes each were found at 3 hours and 8 hours, respectively. In Molt-4-LXSN cells, a significant fraction of the genes with altered expression at 3 hours were found to be involved in apoptosis signaling pathway ( BCL2L11), p53 pathway ( PMAIP1, CDKN1A and FAS) and oxidative stress response ( FDXR, CROT and JUN). Similarly, at 8 hours the genes with altered expression were involved in the apoptosis signaling pathway ( BAX, BIK and JUN), p53 pathway ( BAX, CDKN1A and FAS), oxidative stress response ( FDXR and CROT) and p53 pathway feedback loops 2 ( MDM2 and CDKN1A). A global molecular and biological interaction map analysis showed an association of these altered genes with apoptosis, senescence, DNA damage, oxidative stress, cell cycle arrest and caspase activation. In a targeted study, activation of apoptosis correlated with changes in gene expression of some of the above genes and revealed sequential activation of both intrinsic and extrinsic apoptotic pathways that precede ceramide accumulation and subsequent execution of apoptosis. One or more of these altered genes may be involved in p53-dependent ceramide accumulation.

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          Most cited references 39

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          Linear models and empirical bayes methods for assessing differential expression in microarray experiments.

          The problem of identifying differentially expressed genes in designed microarray experiments is considered. Lonnstedt and Speed (2002) derived an expression for the posterior odds of differential expression in a replicated two-color experiment using a simple hierarchical parametric model. The purpose of this paper is to develop the hierarchical model of Lonnstedt and Speed (2002) into a practical approach for general microarray experiments with arbitrary numbers of treatments and RNA samples. The model is reset in the context of general linear models with arbitrary coefficients and contrasts of interest. The approach applies equally well to both single channel and two color microarray experiments. Consistent, closed form estimators are derived for the hyperparameters in the model. The estimators proposed have robust behavior even for small numbers of arrays and allow for incomplete data arising from spot filtering or spot quality weights. The posterior odds statistic is reformulated in terms of a moderated t-statistic in which posterior residual standard deviations are used in place of ordinary standard deviations. The empirical Bayes approach is equivalent to shrinkage of the estimated sample variances towards a pooled estimate, resulting in far more stable inference when the number of arrays is small. The use of moderated t-statistics has the advantage over the posterior odds that the number of hyperparameters which need to estimated is reduced; in particular, knowledge of the non-null prior for the fold changes are not required. The moderated t-statistic is shown to follow a t-distribution with augmented degrees of freedom. The moderated t inferential approach extends to accommodate tests of composite null hypotheses through the use of moderated F-statistics. The performance of the methods is demonstrated in a simulation study. Results are presented for two publicly available data sets.
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            Apoptosis: a review of programmed cell death.

            The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.
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              Tumor necrosis factor signaling.

              A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50,000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: Visualization
                Role: Methodology
                Role: Methodology
                Role: MethodologyRole: SoftwareRole: Visualization
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 December 2017
                2017
                : 12
                : 12
                Affiliations
                [1 ] Department of Biology, Faculty of Sciences, Lebanese University, Hadath, Lebanon
                [2 ] Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
                [3 ] Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
                [4 ] Department of Pediatrics and Adolescent Medicine, Center for Infectious Diseases Research, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
                Virginia Commonwealth University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-34833
                10.1371/journal.pone.0190221
                5741252
                29272311
                © 2017 Hage-Sleiman et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 7, Tables: 2, Pages: 17
                Product
                Funding
                Funded by: Medical Practice Plan (MPP) at AUB-FM and Lebanese National Center for Scientific Research (LNCSR)
                Award Recipient :
                This research was supported by funding from the Medical Practice Plan (MPP) at AUB-FM and the Lebanese National Center for Scientific Research (LNCSR) to GD. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Cyclins
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Gene Ontologies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Gene Ontologies
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Gene Mapping
                Research and Analysis Methods
                Molecular Biology Techniques
                Gene Mapping
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized

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