title: Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts.
abstract: A stress-induced senescence-like phenotype is induced by exposure of human diploid fibroblasts to subcytotoxic H2O2 stress. Previous studies showed that TGF-beta1 is responsible for the induction of several biomarkers of replicative senescence within 72 h after stress: senescence-like morphology, senescence-associated beta-galactosidase activity, and an increase in the mRNA steady state level of four senescence-associated genes. Other studies showed that the retinoblastoma protein is responsible for the appearance of these biomarkers in the same conditions. Here we show that sustained p38(MAPK) phosphorylation is responsible for both H2O2-induced overexpression of TGF-beta 1 and subsequent TGF-beta 1-induced appearance of these biomarkers. p38(MAPK) phosphorylation is shown to be necessary for a self-sustained TGF-beta 1 overexpression after H2O2 stress through the activation of ATF-2 transcription factor, thereby creating a regulatory loop between sustained p38(MAPK) activation and sustained TGF-beta 1 overexpression after stress. p38(MAPK) activation is also shown to be responsible in part for the growth arrest observed in stress-induced senescence-like phenotype. At 48 h after stress, ATF-2 starts to interact with hypophosphorylated Rb, which allows the biomarkers of stress-induced senescence-like phenotype to appear. This report gives an overall explanation of how a senescence-like phenotype is established after subcytotoxic H2O2 stress.
authors.affiliation: Research Unit of Cellular Biology, University of Namur, Namur, Belgium
authors.forename: Christophe
authors.initials: C
authors.lastname: Frippiat
authors.forename: Janique
authors.initials: J
authors.lastname: Dewelle
authors.forename: José
authors.initials: J
authors.lastname: Remacle
authors.forename: Olivier
authors.initials: O
authors.lastname: Toussaint
mesh_terms: D051698:Activating Transcription Factor 2; D001205:Ascorbic Acid / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002455:Cell Division; D016922:Cellular Senescence; D051152:Clusterin; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D005609:Free Radicals; D005799:Genes, Dominant; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D001616:beta-Galactosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C495242:CLU protein, human; D018797:Cell Cycle Proteins; D051152:Clusterin; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D005609:Free Radicals; D006023:Glycoproteins; D018832:Molecular Chaperones; D016160:Retinoblastoma Protein; C508960:TGFB1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004247:DNA; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; D001205:Ascorbic Acid; D010100:Oxygen