EIF2? 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 (?) subunit of eIF2 at serine 51 (S51) (eIF?P). An important role of eIF2?P is the regulation of redox homeostasis and adaptation of cells to oxidative stress. Herein, we demonstrate that eIF2?P guards cells from intracellular reactive oxygen species (ROS) via the inhibition of senescence. Specifically, genetic inactivation of either eIF2?P or eIF2? 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 eIF2?P-deficient primary cells is caused by increased ROS and restored by anti-oxidant treatment. Contrary to primary cells, impaired eIF2?P in immortalized mouse fibroblasts or human tumor cells provides tolerance to elevated intracellular ROS levels. However, eIF2?P-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 eIF2?P determines cell destiny through its capacity to control senescence in response to oxidative stress. Also, inhibition of eIF2?P may be a suitable means to increase the anti-tumor effects of pro-oxidant drugs through the induction of senescence.

SUBMITTER: Rajesh K 

PROVIDER: S-EPMC3883705 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature