title: eIF2α phosphorylation bypasses premature senescence caused by oxidative stress and pro-oxidant antitumor therapies.
abstract: Eukaryotic cells respond to various forms of stress by blocking mRNA translation initiation via the phosphorylation of the alpha (α) subunit of eIF2 at serine 51 (S51) (eIFαP). An important role of eIF2αP is the regulation of redox homeostasis and adaptation of cells to oxidative stress. Herein, we demonstrate that eIF2αP guards cells from intracellular reactive oxygen species (ROS) via the inhibition of senescence. Specifically, genetic inactivation of either eIF2αP or eIF2α kinase PERK in primary mouse or human fibroblasts leads to proliferative defects associated with increased DNA damage, G2/M accumulation and induction of premature senescence. Impaired proliferation of either PERK or eIF2αP-deficient primary cells is caused by increased ROS and restored by anti-oxidant treatment. Contrary to primary cells, impaired eIF2αP in immortalized mouse fibroblasts or human tumor cells provides tolerance to elevated intracellular ROS levels. However, eIF2αP-deficient human tumor cells are highly susceptible to extrinsic ROS generated by the pro-oxidant drug doxorubicin by undergoing premature senescence. Our work demonstrates that eIF2αP determines cell destiny through its capacity to control senescence in response to oxidative stress. Also, inhibition of eIF2αP may be a suitable means to increase the anti-tumor effects of pro-oxidant drugs through the induction of senescence.
authors: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
authors: Kamindla
authors: K
authors: Rajesh
authors: Andreas I
authors: AI
authors: Papadakis
authors: Urszula
authors: U
authors: Kazimierczak
authors: Philippos
authors: P
authors: Peidis
authors: Shuo
authors: S
authors: Wang
authors: Gerardo
authors: G
authors: Ferbeyre
authors: Randal J
authors: RJ
authors: Kaufman
authors: Antonis E
authors: AE
authors: Koromilas
mesh_terms: D019588:Aging, Premature / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress; D010766:Phosphorylation / Q000502:physiology; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D015852:Eukaryotic Initiation Factor-2; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; C460640:EIF2AK3 protein, human