title: Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKα dependent manner.
abstract: Oxidative stress induces not only senescence but also autophagy in a variety of mammalian cells. However, the relationship between these two has not been well established and thus, was investigated in the present study using WI38 human diploid fibroblasts (WI38 cells) as a model system. Our results showed that exposure of WI38 cells to H2O2 induced both senescence and autophagy. Downregulation of autophagy protein 5 (Atg5) with Atg5 siRNA inhibited not only autophagy but also senescence induced by H2O2. Further studies showed that Atg5 regulates H2O2-induced senescence primarily by up-regulating the expression of p21 at the level of post-transcription. In addition, we examined the mechanisms by which H2O2 induces autophagy in WI38 cells. Our results revealed that H2O2 increases autophagy independent of the mammalian target of rapamycin (mTOR) negative feedback pathway. Instead, the induction of autophagy by H2O2 depends on the induction of intracellular production of reactive oxygen species (ROS) and activation of the p38 mitogen-activated protein kinase α (p38 MAPKα) pathway.
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Ping
authors.initials: P
authors.lastname: Zou
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Lingbo
authors.initials: L
authors.lastname: Liu
mesh_terms: D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008869:Microtubule-Associated Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D048308:Mitogen-Activated Protein Kinase 14