title: Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells.
abstract: Human endometrium-derived mesenchymal stem cells (hMESCs) enter the premature senescence under sublethal oxidative stress, however underlying mechanism remains unknown. Here, we showed that exogenous H2O2 induces a rapid phosphorylation and co-localization of ATM, H2A.X, 53BP1 leading to DNA damage response (DDR) activation. DDR was accompanied with nuclear translocation of p-p53 followed by up-regulation of p21Waf1 and the permanent hypophosphorylation of pRb. Additionally, the increased p38MAPK/MAPKAPK-2 activation persisted in H2O2-treated cells. We suggest that both p53/p21/pRb and p38MAPK/MAPKAPK-2 pathways are responsible for establishing an irreversible cell cycle arrest that is typical of senescence. The process of further stabilization of senescence required prolonged DDR signaling activation that was provided by the permanent ROS production which in turn was regulated by both p38MAPK and the increased functional mitochondria. To reverse senescence, the pharmacological inhibition of p38MAPK was performed. Cell treatment with SB203580 was sufficient to recover partially senescence phenotype, to block the ROS elevation, to decrease the mitochondrial function, and finally to rescue proliferation. Thus, suppression of the p38MAPK pathway resulted in a partial prevention of H2O2-induced senescence of hMESCs. The current study is the first to reveal the molecular mechanism of the premature senescence of hMESCs in response to oxidative stress.
authors.affiliation: Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Borodkina
authors.forename: Alla
authors.initials: A
authors.lastname: Shatrova
authors.forename: Polina
authors.initials: P
authors.lastname: Abushik
authors.forename: Nikolay
authors.initials: N
authors.lastname: Nikolsky
authors.forename: Elena
authors.initials: E
authors.lastname: Burova
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases