title: The transcriptosomal response of human A549 lung cells to a hydrogen peroxide-generating system: relationship to DNA damage, cell cycle arrest, and caspase activation.
abstract: Intracellular oxidative stress is a dynamic situation characterized by the accumulation of reactive oxygen metabolites, such as hydrogen peroxide. This is traditionally associated with both macromolecular damage and adaptive changes in gene expression, aimed at preventing cellular demise. However, the overall extent of such genetic changes is not well characterized. Here we present a comprehensive analysis of altered mRNA profiles in human A549 type II lung epithelial cells in response to hydrogen peroxide, at concentrations failing to induce necrotic toxicity. The results of an Affymetrix-based screen of the steady-state levels of mRNAs for several thousand genes revealed a complex pattern of transcriptional and/or posttranscriptional response to oxidative stress, which can be functionally related to both the oxidation and repair of damaged DNA, the induction and permanency of cell cycle arrest, and caspase-3 activation. Many of the genetic events can be related to activation of the p53/p21 pathway, but many other novel inductions and suppressions were detected, revealing the intricacy of the response. The data also disclosed a potential interaction between hydrogen peroxide treatment and increased sensitivity to cell killing by TRAIL, which could be functionally confirmed at the level of induction of caspase-3 activity.
authors.affiliation: Division of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Dandrea
authors.forename: Heike
authors.initials: H
authors.lastname: Hellmold
authors.forename: Carina
authors.initials: C
authors.lastname: Jonsson
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Tim
authors.initials: T
authors.lastname: Hofer
authors.forename: Lars
authors.initials: L
authors.lastname: Wärngård
authors.forename: Ian
authors.initials: I
authors.lastname: Cotgreave
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D001681:Biological Assay; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D005949:Glucose Oxidase / Q000494:pharmacology; D055436:Growth Differentiation Factor 15; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000493:pharmacokinetics; D018384:Oxidative Stress / Q000235:genetics; D054645:Protein Phosphatase 1; D011506:Proteins / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053671:Syndecan-4; D053221:TNF-Related Apoptosis-Inducing Ligand; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000493:pharmacokinetics; D025521:Tumor Suppressor Proteins
chemical_list: D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D011506:Proteins; D011509:Proteoglycans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C508304:SDC4 protein, human; D053671:Syndecan-4; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D020169:Caspases; D003849:Deoxyguanosine